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La hipertensión arterial (HTA) se caracteriza básicamente por la existencia de una disfunción endotelial (DE), con ruptura del equilibrio entre los factores relajantes del vaso sanguíneo (óxido nítrico –NO-, factor hiperpolarizante del endotelio -EDHF) y los factores vasoconstrictores (principalmente endotelinas). Es conocida la disminución a nivel del endotelio de la prostaciclina-PGI2 vasodepresora y el aumento relativo del tromboxano-TXA2 intracelular vasoconstrictor

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En la fisiopatología las características hemodinámicas del Sistema Nervioso Central y los cambios provocados por la HTA alteran la organización funcional de la corteza cerebral, especialmente en las regiones frontal y medial, irrigadas por la arteria cerebral anterior.

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Abstract

Objective: To detect the presence of changes in brain electrical activity that might be used as early markers in patients with risk factors for developing vascular encephalopathy.

Patients and methods: There were studied 84 uncomplicated hypertensive patients, with a normal neurological physical examination and mean age of 49 years compared to 35 functionally healthy subjects. The patients were divided into three groups: slight high blood pressure (SLHBP, n = 24) with diastolic blood pressure (DBP) between 90 and 100 mmHg, moderate high blood pressure (MHBP, n = 40) with DBP between 101 and 114 mmHg, and severe high blood pressure (SHBP, n = 20) with TAD of 115 mmHg or higher. All subjects underwent digital electroencephalogram (dEEG) with quantitative analysis (QEEG).

Results: The patients showed focal, especially frontal paroxysms, and diffuse polymorphic theta activity in these areas, mainly those with SLHBP. Posterior alpha rhythm disorganization, inter-hemispheric asymmetries and frontal monomorphic activity were more often found in SHBP patients. In QEEG was observed an increase in absolute and relative power of slow activities, and a decrease in power of alpha and beta activities. All these findings were more frequent in the left hemisphere.

Conclusion: The hemodynamic characteristics of the Central Nervous System and the changes caused by HBP alter the functional organization of the brain cortex, especially in frontal and midline regions, irrigated by the anterior cerebral artery.

Similar articles

Clinical correlates of quantitative EEG alterations in alcoholic patients.

Coutin-Churchman P, Moreno R, Añez Y, Vergara F. Coutin-Churchman P, et al. Clin Neurophysiol. 2006 Apr;117(4):740-51. doi: 10.1016/j.clinph.2005.12.021. Epub 2006 Feb 21. Clin Neurophysiol. 2006. PMID: 16495144

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national center for biotechnology information

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[Early functional disorders of the brain in uncomplicated hypertensive patients] - PubMed

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Objective: To detect the presence of changes in brain electrical activity that might be used as early markers in patients with risk factors for developing vascular encephalopathy. Patients and methods: There were studied 84 uncomplicated hypertensive patients, with a normal neurological physical examination and mean age of 49 years compared to 35 functionally healthy subjects.

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Mecanismos fisiológicos implicados en el desarrollo de hipertensión esencial
Gasto cardíaco ,Resistencia periférica ,Sistema renina-angiotensina-aldosterona ,Sistema nervioso autónomo

Otros factores: Bradicinina Endotelina EDRF (factor relajante derivado del endotelio) u óxido nítrico ANP (péptido natriurético auricular) Uabaína.
Gasto cardíaco y resistencia periférica: El mantenimiento de una presión arterial normal depende del equilibrio entre el gasto cardíaco y la resistencia vascular periférica. La mayoría de los pacientes con hipertensión esencial tienen un gasto cardíaco normal pero una resistencia periférica elevada.
Sistema renina-angiotensina:La angiotensina II es un potente vasoconstrictor y, por lo tanto, provoca un aumento de la presión arterial. Además, estimula la liberación de aldosterona de la zona glomerulosa de la glándula suprarrenal, lo que provoca un mayor aumento de la presión arterial relacionado con la retención de sodio y agua.

Sistema nervioso autónomo: La estimulación del sistema nervioso simpático puede causar constricción arteriolar y dilatación arteriolar. Así, el sistema nervioso autónomo tiene un papel importante en el mantenimiento de una presión arterial normal.

Disfunción endotélica: Las células endoteliales vasculares desempeñan un papel clave en la regulación cardiovascular al producir varios agentes vasoactivos locales potentes, incluida la molécula vasodilatadora óxido nítrico y el péptido vasoconstrictor endotelina.

Sustancias vasoactivas: Muchos otros sistemas y mecanismos vasoactivos que afectan el transporte de sodio y el tono vascular están involucrados en el mantenimiento de una presión arterial normal.

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ABC of hypertension

There is still much uncertainty about the pathophysiology of hypertension. A small number of patients (between 2% and 5%) have an underlying renal or adrenal disease as the cause for their raised blood pressure. In the remainder, however, no clear single identifiable cause is found and their condition is labelled "essential hypertension". A number of physiological mechanisms are involved in the maintenance of normal blood pressure, and their derangement may play a part in the development of essential hypertension.

This article has been adapted from the newly published 4th edition of ABC of Hypertension. The book is available from the BMJ bookshop and at www.bmjbooks.com

It is probable that a great many interrelated factors contribute to the raised blood pressure in hypertensive patients, and their relative roles may differ between individuals. Among the factors that have been intensively studied are salt intake, obesity and insulin resistance, the renin-angiotensin system, and the sympathetic nervous system. In the past few years, other factors have been evaluated, including genetics, endothelial dysfunction (as manifested by changes in endothelin and nitric oxide), low birth weight and intrauterine nutrition, and neurovascular anomalies.

Physiological mechanisms involved in development of essential hypertension Cardiac outputPeripheral resistanceRenin-angiotensin-aldosterone systemAutonomic nervous systemOther factors:BradykininEndothelinEDRF (endothelial derived relaxing factor) or nitric oxideANP (atrial natriuretic peptide)Ouabain

Cardiac output and peripheral resistance

Maintenance of a normal blood pressure is dependent on the balance between the cardiac output and peripheral vascular resistance. Most patients with essential hypertension have a normal cardiac output but a raised peripheral resistance. Peripheral resistance is determined not by large arteries or the capillaries but by small arterioles, the walls of which contain smooth muscle cells. Contraction of smooth muscle cells is thought to be related to a rise in intracellular calcium concentration, which may explain the vasodilatory effect of drugs that block the calcium channels. Prolonged smooth muscle constriction is thought to induce structural changes with thickening of the arteriolar vessel walls possibly mediated by angiotensin, leading to an irreversible rise in peripheral resistance.

It has been postulated that in very early hypertension the peripheral resistance is not raised and the elevation of the blood pressure is caused by a raised cardiac output, which is related to sympathetic overactivity. The subsequent rise in peripheral arteriolar resistance might therefore develop in a compensatory manner to prevent the raised pressure being transmitted to the capillary bed where it would substantially affect cell homeostasis.

Renin-angiotensin system

The renin-angiotensin system may be the most important of the endocrine systems that affect the control of blood pressure. Renin is secreted from the juxtaglomerular apparatus of the kidney in response to glomerular underperfusion or a reduced salt intake. It is also released in response to stimulation from the sympathetic nervous system.

Renin is responsible for converting renin substrate (angiotensinogen) to angiotensin I, a physiologically inactive substance which is rapidly converted to angiotensin II in the lungs by angiotensin converting enzyme (ACE). Angiotensin II is a potent vasoconstrictor and thus causes a rise in blood pressure. In addition it stimulates the release of aldosterone from the zona glomerulosa of the adrenal gland, which results in a further rise in blood pressure related to sodium and water retention.

The circulating renin-angiotensin system is not thought to be directly responsible for the rise in blood pressure in essential hypertension. In particular, many hypertensive patients have low levels of renin and angiotensin II (especially elderly and black people), and drugs that block the renin-angiotensin system are not particularly effective.

There is, however, increasing evidence that there are important non-circulating "local" renin-angiotensin epicrine or paracrine systems, which also control blood pressure. Local renin systems have been reported in the kidney, the heart, and the arterial tree. They may have important roles in regulating regional blood flow.

Autonomic nervous system

Sympathetic nervous system stimulation can cause both arteriolar constriction and arteriolar dilatation. Thus the autonomic nervous system has an important role in maintaining a normal blood pressure. It is also important in the mediation of short term changes in blood pressure in response to stress and physical exercise.

There is, however, little evidence to suggest that epinephrine (adrenaline) and norepinephrine (noradrenaline) have any clear role in the aetiology of hypertension. Nevertheless, their effects are important, not least because drugs that block the sympathetic nervous system do lower blood pressure and have a well established therapeutic role.

It is probable that hypertension is related to an interaction between the autonomic nervous system and the renin-angiotensin system, together with other factors, including sodium, circulating volume, and some of the more recently described hormones.

*  Cross transplantation experiments with kidneys of hypertensive rats transferred to normotensives, and vice versa, strongly suggest that hypertension has its origins in the kidneys*  Similarly human evidence from renal transplant recipients shows that they are more likely to develop hypertension if the donors' relatives are hypertensive*  This essential hypertension may be due to a genetically inherited abnormality of sodium handling

Endothelial dysfunction

Vascular endothelial cells play a key role in cardiovascular regulation by producing a number of potent local vasoactive agents, including the vasodilator molecule nitric oxide and the vasoconstrictor peptide endothelin. Dysfunction of the endothelium has been implicated in human essential hypertension.

Modulation of endothelial function is an attractive therapeutic option in attempting to minimise some of the important complications of hypertension. Clinically effective antihypertensive therapy appears to restore impaired production of nitric oxide, but does not seem to restore the impaired endothelium dependent vascular relaxation or vascular response to endothelial agonists. This indicates that such endothelial dysfunction is primary and becomes irreversible once the hypertensive process has become established.

Vasoactive substances

Many other vasoactive systems and mechanisms affecting sodium transport and vascular tone are involved in the maintenance of a normal blood pressure. It is not clear, however, what part these play in the development of essential hypertension. Bradykinin is a potent vasodilator that is inactivated by angiotensin converting enzyme. Consequently, the ACE inhibitors may exert some of their effect by blocking bradykinin inactivation.

The thrombotic paradox of hypertension (the Birmingham paradox) Although the blood vessels are exposed to high pressures in hypertension, the main complications of hypertension (stroke and myocardial infarction) paradoxically are thrombotic rather than haemorrhagic.

Endothelin is a recently discovered, powerful, vascular, endothelial vasoconstrictor, which may produce a salt sensitive rise in blood pressure. It also activates local renin-angiotensin systems. Endothelial derived relaxant factor, now known to be nitric oxide, is produced by arterial and venous endothelium and diffuses through the vessel wall into the smooth muscle causing vasodilatation.

Atrial natriuretic peptide is a hormone secreted from the atria of the heart in response to increased blood volume. Its effect is to increase sodium and water excretion from the kidney as a sort of natural diuretic. A defect in this system may cause fluid retention and hypertension.

Sodium transport across vascular smooth muscle cell walls is also thought to influence blood pressure via its interrelation with calcium transport. Ouabain may be a naturally occurring steroid-like substance which is thought to interfere with cell sodium and calcium transport, giving rise to vasoconstriction.

Hypercoagulability

Patients with hypertension demonstrate abnormalities of vessel wall (endothelial dysfunction or damage), the blood constituents (abnormal levels of haemostatic factors, platelet activation, and fibrinolysis), and blood flow (rheology, viscosity, and flow reserve), suggesting that hypertension confers a prothrombotic or hypercoagulable state. These components appear to be related to target organ damage and long term prognosis, and some may be altered by antihypertensive treatment.

Insulin sensitivity

Epidemiologically there is a clustering of several risk factors, including obesity, hypertension, glucose intolerance, diabetes mellitus, and hyperlipidaemia. This has led to the suggestion that these represent a single syndrome (metabolic syndrome X or Reaven's syndrome), with a final common pathway to cause raised blood pressure and vascular damage. Indeed some hypertensive patients who are not obese display resistance to insulin. There are many objections to this hypothesis, but it may explain why the hazards of cardiovascular risk are synergistic or multiplicative rather than just additive.

Genetic factors

Although separate genes and genetic factors have been linked to the development of essential hypertension, multiple genes are most likely contribute to the development of the disorder in a particular individual. It is therefore extremely difficult to determine accurately the relative contributions of each of these genes. Nevertheless, hypertension is about twice as common in subjects who have one or two hypertensive parents, and many epidemiological studies suggest that genetic factors account for approximately 30% of the variation in blood pressure in various populations. This figure can be derived from comparisons of parents with their monozygotic and dizygotic twin children, as well as their other children, and with adopted children. Some familial concordance is, however, due to shared lifestyle (chiefly dietary) factors.

Examples of specific genetic mutations causing hypertension*  Liddle's syndrome, a disorder associated with hypertension, low plasma renin and aldosterone levels, and hypokalaemia, all of which respond to amiloride, an inhibitor of the distal renal epithelial sodium channel*  Glucocorticoid-remediable aldosteronism, a disorder mimicking Conn's syndrome, in which there is a chimeric gene formed from portions of the 11β-hydroxylase gene and the aldosterone synthase gene. This defect results in hyperaldosteronism, which is responsive to dexamethasone and has a high incidence of stroke*  Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency, a disorder that has been associated with 10 different mutations of the CYP11B1 gene*  Syndrome of apparent mineralocorticoid excess, arising from mutations in the gene encoding the kidney enzyme 11α-hydroxysteroid dehydrogenase; the defective enzyme allows normal circulating concentrations of cortisol (which are much higher than those of aldosterone) to activate the mineralocorticoid receptors*  Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency, a disorder with hyporeninaemia hypoaldosteronism, absent secondary sexual characteristics, and hypokalaemia*  Gordon's syndrome (pseudo-hypoaldosteronism): familial hypertension with hyperkalaemia, possibly related to the long arm of chromosome 17*  Sporadic case reports of familial inheritance of phaeochromocytoma (multiple endocrine neoplasia, MEN-II syndrome), Cushing's syndrome, Conn's syndrome, renal artery stenosis due to fibromuscular dysplasia Other associations *  The angiotensinogen gene may be related to hypertension*  The angiotensin converting enzyme gene may be related to left ventricular hypertrophy or hypertensive nephropathy*  α-Adducin gene may be related to salt sensitive hypertension

Some specific genetic mutations can rarely cause hypertension. Experimental models of genetic hypertension have shown that the inherited tendency to hypertension resides primarily in the kidney. For example, animal and human studies show that a transplanted kidney from a hypertensive donor raises the blood pressure and increases the need for antihypertensive drugs in recipients coming from "normotensive" families. Conversely a kidney from a normotensive donor does not raise the blood pressure in the recipient.

Increased plasma levels of angiotensinogen, the protein substrate acted on by renin to generate angiotensin I, have also been reported in hypertensive subjects and in children of hypertensive parents.

Hypertension is rarely found in rural or "tribal" areas of Africa, but it is very common in African cities and in black populations in Britain and the United States. Whereas the rural/urban differences in Africa are clearly due to lifestyle and dietary factors, the finding that hypertension is commoner in black people compared with white people may have some genetic basis. There is some evidence from salt loading studies in medical students that black Americans are more susceptible to a given salt load than white Americans, and may be more sensitive to the beneficial effects of salt restriction.

Intrauterine influences

There is increasing evidence that fetal influences, particularly birth weight, may be a determinant of blood pressure in adult life. For example, babies who are small at birth are more likely to have higher blood pressure during adolescence and to be hypertensive as adults. Babies who are small for their age are also more likely to have metabolic abnormalities that have been associated with the later development of hypertension and cardiovascular disease, such as insulin resistance, diabetes mellitus, hyperlipidaemia, and abdominal obesity (the "Barker hypothesis"). Insulin resistance almost certainly contributes to the increased prevalence of coronary disease seen in adults of low birth weight.

It is possible, however, that genetic factors influence the Barker hypothesis. Mothers with above average blood pressure in pregnancy give birth to smaller babies who subsequently develop above average blood pressure themselves and eventually hypertension. It is entirely likely that the similarity of blood pressures in mother and child are genetic and, in a modern "healthy" society, unrelated to intrauterine undernutrition.

Diastolic dysfunction

In hypertensive left ventricular hypertrophy, the ventricle cannot relax normally in diastole. Thus, to produce the necessary increase in ventricular input, especially during exercise, there is an increase in left atrial pressure rather than the normal reduction in ventricular pressure, which produces a suction effect as described above. This can lead to an increase in pulmonary capillary pressure that is sufficient to induce pulmonary congestion. The rise in atrial pressure can also lead to atrial fibrillation, and in hypertrophied ventricles dependent on atrial systole the loss of atrial transport can result in a significant reduction in stroke volume and pulmonary oedema. Exercise induced subendocardial ischaemia can also produce an "exaggerated" impairment of diastolic relaxation of the hypertrophied myocardium.

Further reading

Barker DJP, Osmond C, Golding J, Kuh D, Wadsworth MEJ. Growth in  utero, blood pressure in childhood and adult life and mortality  from cardiovascular disease. BMJ 1989;298:564-7.

Dzau VJ. Circulating versus local renin-angiotensin system in  cardiovascular homeostasis. Circulation 1988;77(suppl 1):I4-13.

Harrap SB. Hypertension: genes versus environment. Lancet  1994;344:169-71.

Hughes AD, Schachter M. Hypertension and blood vessels. Br Med  Bull 1994;50:356-70.

Kurtz TW. Genetic models of hypertension. Lancet 1994;344:167-8.

Lip GYH, Li-Saw-Hee FL. Does hypertension confer a  hypercoagulable state? J Hypertens 1998;16:913-6.

Mathias CJ. Role of sympathetic efferent nerves in blood pressure  regulation and in hypertension. Hypertension 1991;18:22-30.

Sagnella G, Macgregor GA. Atrial natriuretic peptides. Q J Med  1990;77:1001-7.

Articles from The BMJ are provided here courtesy of BMJ Publishing Group

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ABC of hypertension: The pathophysiology of hypertension

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ABC of hypertension There is still much uncertainty about the pathophysiology of hypertension. A small number of patients (between 2% and 5%) have an underlying renal or adrenal disease as the cause for their raised blood pressure. In the remainder, however, no clear single identifiable cause is found and their condition is labelled "essential hypertension".

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Un mecanismo importante a considerar es el sistema nervioso simpático ya que el incremento de su actividad está asociado a la presión arterial alta. Su estimulación genera una mayor contractibilidad vascular ocasionando mayor resistencia periférica, incremento en el gasto cardiaco y retención de líquidos a nivel renal.

La presencia de hipertensión arterial crea un círculo vicioso de retroalimentación, donde la hipertensión activa este sistema produciendo mayor hipertensión. La presión elevada generará vasoconstricción de la arteria renal aferente, lo que la ser percibido como una caída del volumen, y por lo tanto como una disminución de presión por el riñón que responde secretando renina y convirtiendo el angiotensiógeno en angiotensina I y luego ésta en angiotensina II por la enzima convertidora de angiotensina.

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https://www.ncbi.nlm.nih.gov/books/NBK551627/
La endotelina es un péptido de 21 aminoácidos de longitud que es un
vasoconstrictor producido a partir de células endoteliales, células de músculo liso
vascular (CMLV), macrófagos y médula renal. Se sabe que producen endotelina-
1 (ET-1) que actúa sobre los receptores de ET-1 de tipo A (ETA) y receptor de
ET-1 de tipo B (ETB). Estos receptores son receptores de superficie celular
acoplados a proteína G, y ETA está presente principalmente en las células del
músculo liso. Los receptores ETB aparecen en las células epiteliales endoteliales
y renales. Ambos están presentes en los pulmones. La ET-1 se conoce como un
potente vasoconstrictor con propiedades proliferativas, profibróticas,
prooxidativas, proinflamatorias y que mantiene el tono de las CMLV. Otros ET
descubiertos incluyen ET-2 y ET-3. Las endotelinas están involucradas en el
desacoplamiento neurovascular, afectan las funciones cognitivas y la presión
arterial.
Biosíntesis
La síntesis de ET se regula a nivel de transcripción. La primera proteína transcrita
sería procesada por una proproteína convertasa de tipo furina. Este proceso
produce una molécula llamada 'gran ET-1', un intermedio inactivo. La enzima
convertidora de endotelina (ECE) actúa sobre la ET-1 grande, convirtiéndola en
ET-1. La conversión ECE consta de dos pasos: Big ET-1 a ET-1 (1-31) por
quimasa y luego a ET-1 por neprilisina.
Señalización celular
La vasoconstricción arterial es principalmente por ETA, mientras que la
vasoconstricción venosa es por ETB. De lo contrario, la vasodilatación está
mediada por la activación del receptor ETB. El mismo vaso sufre una constricción
cuando la ET-1 penetra más profundamente en la capa de músculo liso y activa
los receptores ETA.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156553/#!po=78.2051
La presión arterial elevada debe deberse a una elevada salida cardíaca, a una
elevada resistencia vascular periférica o a una combinación de ambos. Cada uno
de estos mecanismos está regulado, a su vez, por procesos hemodinámicos,
neuronales, humorales y renales, todos los cuales varían en su contribución de
un individuo a otro (Figura 1). A medida que las personas envejecen, la causa
predominante de la hipertensión tiende a ser una resistencia vascular periférica
elevada, a menudo en combinación con una mayor rigidez de los vasos, lo que
se manifiesta clínicamente como hipertensión sistólica aislada. Agrupación
familiar implica una predisposición genética cuya interacción con factores
ambientales, como la ingesta de sal y calorías y el grado de ejercicio físico,
determina en última instancia cuán grave será el aumento de la presión arterial.

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Intervienen múltiples factores que tienen, en su mayoría, una base genética. Sin embargo, entre todos estos factores ha podido mostrarse que es el sistema renina-angiotensina-aldosterona (SRAA)
AII produce, pues, vasoconstricción arteriolar con aumento de la presión arterial sistémica al incrementar la resistencia periférica. Además de su acción vasoconstrictora directa sobre el músculo liso, AII facilita la liberación y aumenta la sensibilidad a la noradrenalina. El efecto neto es que AII desempeña un importante papel en el mantenimiento de la presión arterial en todas las circunstancias en que hay un aumento de la secreción de renina.

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Fisiopatología de la hipertensión arterial: nuevos conceptos

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SIMPOSIO redefinición de la hipertensión arterial

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https://www.aebm.org/formacion%20distancia/distancia%202010-2011/Actualizaciones%202010-2011/monografias%202010/7.-%20Hipertension.pdf

Existen mecanismos fisiológicos involucrados en el desarrollo de la hipertensión arterial (HTA) como son:
-Gasto cardiaco
- Resistencia vascular periférica
- Sistema Renina-angiotensina-aldosterona
-Sistema nervioso autónomo
- Otros factores:
Bradicinina
Endotelina
EDRF (endothelial derived relaxing factor) u óxido nítrico
ANP (peptido natriurético atrial)
Ouabaina

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El sistema renina-angiotensina ha sido uno de los mecanismos más estudiados en relación con la fisiopatología de la hipertensión arterial primaria, debido a que este sistema tiene diversos efectos sobre múltiples órganos blanco en el organismo, que ocasionan el incremento de la presión arterial, ya sea por aumento de la resistencia vascular o por incremento en el volumen de líquido extracelular. Todos los efectos de la angiotensina II sobre el riñón ocasionan la disminución de la excreción de Na+ por este órgano, el incremento en el volumen del líquido extracelular, del volumen sanguíneo y la presión arterial.

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Citado por SciELO

Similares en SciELO

Facultad de Ciencias Médicas "Enrique Cabrera"
Instituto de Ciencias Básicas y Preclínicas "Victoria de Girón"

El sistema renina-angiotensina y el riñón en la fisiopatología de la hipertensión arterial esencial
Dra. María O. Barber Fox y Dr. Ernesto Barber Gutiérrez
Se presentó una actualización de los principales efectos de este sistema sobre la función renal y su posible relación con el desarrollo de la enfermedad hipertensiva primaria. El sistema renina-angiotensina ha sido uno de los mecanismos más estudiados en relación con la fisiopatología de la hipertensión arterial primaria. Este sistema tiene diversos efectos sobre múltiples órganos blanco en el organismo, que ocasionan el incremento de la presión arterial, ya sea por aumento de la resistencia vascular o por incremento en el volumen de líquido extracelular. Sin duda alguna, cobra gran importancia dentro de los mecanismos del sistema renina-angiotensina, aquellos que tienen lugar en el riñón, como órgano predominante en el control a largo plazo de la presión arterial. En conclusión, todos los efectos de la angiotensina II sobre el riñón ocasionan la disminución de la excreción de Na+ por este órgano, el incremento en el volumen del líquido extracelular, del volumen sanguíneo y la presión arterial.

DeCS: HIPERTENSION/ fisiopatología; SISTEMA RENINA-ANGIOTENSINA; RIÑON.

La relación del sistema renal con la hipertensión arterial ha sido objeto de investigación y estudio, a través del tiempo, por múltiples científicos.1,2 Esto se debe al papel clave que tiene el riñón, según han arrojado en sus resultados, muchos de los estudios realizados al respecto,3-6 en el desarrollo de la enfermedad hipertensiva, así como por tratarse del mecanismo renal, el predominante en la regulación a largo plazo de la presión arterial.

Por otro lado dentro del estudio de la participación del riñón en los procesos fisiopatológicos de la enfermedad hipertensiva primaria, han cobrado y cobran gran importancia aquellos en los que está implicado el sistema renina-angiotensina (SRA);7-10 de ahí que el objetivo de esta revisión se haya centrado en realizar un estudio actualizado de este sistema y su participación a través del riñón, en los mecanismos que ocasionan la hipertensión arterial primaria.

El SRA, engloba un conjunto de reacciones químicas, en forma de cascada enzimática, que es desencadenada por la liberación de una proteasa, producida en el complejo yuxtaglomerular del riñón: la renina.11

La liberación de la renina allí formada, está regulada por la acción integrada de diferentes factores,12 que actúan sobre las células yuxtaglomerulares (CYG), como son: la estimulación simpática a los vasos renales, la disminución de la presión de perfusión al riñón, el mecanismo barorreceptor de las CYG, el mecanismo de la mácula densa; los factores humorales como: la angiotensina II (AII), la endotelina 1, la vasopresina, el péptido atrial natriurético (PAN),el óxido nítrico (ON), la prostaglandina E2 (PGE2), la prostaciclina, la dopamina, la histamina y otros.

De manera general aquellos factores que estimulan la liberación de renina por las CYG, lo hacen a través de incrementar la formación de AMPc en estas, lo cual se muestra en la figura 1. Este es el caso de la estimulación simpática, la disminución de la distensión de los barorreceptores yuxtaglomerulares, la acción de mediadores locales, como son la PGE2 y la prostaciclina, histamina, dopamina, etc.

Fig. 1. Mecanismos intracelulares a través de los cuales diferentes factores mecánicos, humorales y nerviosos, regulan la liberación de renina. Vía AMPc estimula la liberación de renina, vías IP3 y formación de GMPc, inhiben la liberación de esta proteasa.

De forma diferente aquellos factores de los ya mencionados que determinan inhibición de la liberación de renina, estimulan alguno de los 2 mecanismos intracelulares siguientes: la activación de la fosfolipasa C (PLC) con aumento del Ca2+ intracelular (AII, vasopresina y endotelina 1), o el incremento de GMPc, como es el caso del ON y el PAN (fig.1).13

Una vez liberada la renina, esta actúa sobre su sustrato, una proteína plasmática de origen hepático, cuya reacción tiene como producto la angiotensina I, sobre la cual actúa otra proteasa, la enzima convertidora, que finalmente da lugar a la formación del potente péptido vasoactivo II (fig. 2).

Fig. 2. Cascada enzimática que comprende el sistema renina-angiotensina, hasta la formación de angiotensina II, la cual interactúa con los receptores AT1 y AT2 .

La AII interactúa con receptores de membranas del tipo AT1 y AT2 (los primeros más abundantes, sobre los que ejerce sus efectos agonistas), ubicados en múltiples tejidos del organismo: el cardiovascular, el sistema nervioso central y periférico, glándulas suprarrenales y con una abundante población en el sistema renal.14-16

Luego, la AII es convertida en angiotensina III y otros pequeños fragmentos peptídicos, los cuales poseen muy escasa acción vasoconstrictora, por proteasas, llamadas angiotensinasas, de las cuales la aminopeptidasa A es la más abundante en el organismo.17,18

La angiotensina II es más conocida por su potente poder vasoactivo, sin embargo, esta posee diversas funciones en el organismo que contribuyen a la regulación de la presión arterial media. La diversidad de sus acciones relacionadas con el control de esa variable, se pueden observar en la figura 3,19 donde la AII tiene un amplio campo de acción en el organismo, cuya resultante es el aumento de la presión en el circuito arterial.

Fig. 3. Esquema general de la diversidad de acciones que posee la angiotensina II en el organismo, que ocasionan al aumento de la presión arterial.

Acciones de la angiotensina II sobre el riñón

En la figura 4 se se pueden ver aquellas acciones de la angiotensina II, que afectan directamente la función renal, para simplificar y facilitar un mejor ajuste al tema que se trata. Todos estos mecanismos han sido estudiados como posibles a participar en la patogénesis de la enfermedad hipertensiva.20

Fig. 4. Acciones de la angiotensina II sobre la presión arterial, que actúa específicamente a través del sistema renal.

Como puede observarse en la figura, la angiotensina II afecta la función renal actuando sobre el flujo sanguíneo (FSR), la filtración glomerular (IFG), efectos que desempeñan un papel importante en la autorregulación de estos, y sobre el transporte tubular.

La AII provoca cambios hemodinámicos en el riñón, consecuencia de la vasoconstricción que afecta fundamentalmente a la arteriola eferente, razón por la cual disminuye el flujo plasmático renal y mantiene la filtración glomerular ante la caída del primero; fenómeno que ocasiona una elevación de la fracción de filtración y consecuentes alteraciones del equilibrio de Starling en los capilares peritubulares: aumento de la presión coloidosmótica del plasma (pp) y disminución de la presión hidrostática (Pcap); estos hechos favorecen la reabsorción de líquido tubular.

Con el paso del tiempo la caída de la filtración sobreviene como consecuencia de la disminución del flujo sanguíneo al riñón provocada por la angiotensina II. A lo anterior se adiciona la contracción del mesangio glomerular y el depósito de fibronectina, laminina y colágeno en la barrera de filtración, que también estimula este péptido; lo que contribuye aún más, en diferentes plazos de tiempo, a la reducción de la filtración, por disminución del área de superficie de difusión de las sustancias y por aumento del grosor de la barrera filtrante, respectivamente.21

En relación con la función tubular, la AII, por un lado, estimula directamente la reabsorción de sodio y agua en los túbulos renales (túbulo proximal y en el segmento grueso de la rama ascendente del asa de Henle), y por otro lado, desarrolla indirectamente esta función, por la estimulación de la liberación de aldosterona, la cual determina incremento en la reabsorción de sodio en el túbulo distal y colector.22

Además, ha sido comprobado que la AII estimula el crecimiento de la pared de los vasos en el organismo y en especial en el riñón.23 Esto provoca una disminución de la luz de la vasculatura renal que, contribuye también, a los cambios hemodinámicos señalados.

El mecanismo por el cual la AII provoca vasoconstricción y estimula el crecimiento de la pared de los vasos se muestra en la figura 5.

Fig. 5. Mecanismo de acción de la angiotensina II, actuando sobre receptores de membrana específicos AT1 para esta. La interacción de este péptido vasoactivo sobre estos receptores, desencadena la activación de la vía del fosfatidilinositol, la cual se bifurca después de la hidrólisis del fosfatidilinositol 4, 5 difosfato (PIP2), un lípido existente en la membrana, en la formación a partir de este, de 2 segundos mensajeros, el diacilglicerol (DAG) y el fosfoinositol trifosfato (IP3), cada uno de los cuales tiene mecanismos de acción diferentes en la célula, que ocasiona los incrementos del pH y de Ca++ intracelulares, respectivamente.

La AII interactúa con receptores específicos de la membrana citoplasmática denominados receptores AT1, cuya interacción conduce, en la membrana de las células musculares vasculares, al desencadenamiento de la vía del fosfatidilinositol, provocando el aumento de los niveles citoplasmáticos de Ca2+, por vía del inositolfosfato (IP3), y la intensificación de la actividad del intercambiador Na+ -H+ por vía del diacilglicerol (DAG). Mecanismos estos, causantes de la mayor contractilidad del músculo vascular y de la estimulación de la síntesis de proteína, respectivamente. La mayor contractilidad del músculo liso vascular conduce a una vasoconstricción potente y la mayor síntesis de proteína en la célula muscular vascular, a una hipertrofia de la pared del vaso, con el consiguiente aumento, por ambas causas, de la resistencia vascular renal en este caso.24

En conclusión, la vasoconstricción e hipertrofia vascular, con aumento consecuente de la resistencia vascular renal, determinan las disminuciones de flujo sanguíneo y filtración glomerular; a lo cual se adiciona la disminución del área y el aumento del grosor de la barrera de filtración, que dificulta aún más esa función. El aumento de reabsorción de sodio y agua por efectos sobre los túbulos renales y el desequilibrio provocado en las fuerzas de Starling en el capilar tubular, son todos efectos de la AII sobre el riñón, que ocasionan la disminución de la excreción de Na+ por este órgano, al incremento en el volumen del líquido extracelular (LEC), el volumen sanguíneo (VS) y la presión arterial.

Algunas evidencias encontradas en modelos animales de hipertensión experimental, reconocidos por su semejanza con la hipertensión esencial en humanos y algunos estudios realizados en el hombre, señalan la existencia de disregulaciones de los receptores de membrana para la angiotensina II, en el riñón,25,26 más que su incremento en este cuadro.

Resulta un dato de gran importancia, con respecto al tema analizado en este capítulo, que los niveles plasmáticos de angiotensina II, se han encontrado normales o bajos en 90 % de los pacientes hipertensos esenciales.27 Las disregulaciones de los receptores de membrana para esta hormona, son el aspecto analizado en algunos trabajos de investigación realizados más recientemente, en relación con el desarrollo incrementado de las acciones de la AII sobre el riñón en animales hipertensos experimentales estudiados, lo que pudiera constituir un factor más a tener en cuenta en la multiplicidad de mecanismos que se han invocado hasta el momento para el análisis de la fisiopatología de la hipertensión arterial primaria.

Summary

An updating of the main effects of this system on the renal function and its possible relationship with the development of primary hypertensive disease is presented. The renin-angiotensin system has been one of the most studied mechanisms in connection with the physiopathology of primary arterial hypertension. This system has diverse effects on the multiple target organ in the organism that cause the increase of arterial pressure due to the rise of vascular resistance or to the augmentation of the volume of extracellular fluid. Among the mechanisms of the renin-angiotensin system, those taking place in the kidney, as a predominant organ in the long term control of arterial hypertension, are undoubtedly very important. It was concluded that all the effects of angiotensin II on the kidney produce the reduction of the excretion of Na+ by this organ, an increase of the volume of extracellular fluid, of blood volume and of arterial pressure.

Subject headings: HYPERTENSION / physiopathology; RENIN-ANGIOTENSIN SYSTEM; KIDNEY.

Referencias bibliográficas

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2. Guyton AC, Coleman TG. Quantitative analysis of the pathophysiology of hypertension. J Am Soc Nephrol 1999;10(10):2248-58.

3. Wright J, Kalra P. The kidney in hypertension. Practitioner 2001;245:41-6.

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5. Río S del, Barber MO, Barber E. Volemia y excreción urinaria en ratas hipertensas tratadas con nifedipina o diuréticos. Rev Cubana Invest Biomed 2001;20(2):99-103.

6. Herrera VL, López LV, Ruiz-Opazo N. Alpha1 Na,K-ATPase and Na,K,2Cl-cotransporte/D3mit3 loci interact to increase susceptibility to salt-sensitive hypertension in Dahl S(HSD) rats. Mol Med 2001;7(2):125-34.

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8. Saito S, Hirata Y, Emori T, Imai T, Marumo F. Angiotensin II activates endothelial constitutive nitric oxide synthase via AT1 receptors. Hypertens Res 1996;19(3):201-6.

9. Lumbers ER. Angiotensin and aldosterone. Regulatory Peptides 1999; 80: 391-100.

10. Cervenka L, Wang CT, Mitchell KD, Navar LG. Proximal tubular angiotensin II levels and renal functional responses to AT1 receptor blockade in nonclipped kidneys of Goldblatt hypertensive rats. Hypertension 1999;33(1):102-7.

11. Ondetti MA, Cushman DW. Enzymes of the renin-angiotensin system and their inhibitors. Am Rev Biochem 1982;51:283.

12. C Wagner, A Kurtz. Regulation of renal renin release. Curr Opin Nephrol Hypertens 1998;7( 4):437-441.

13. Pedraza Chaverri J, Ibarra Rubio ME, Cruz C, Tapia E. Intracellular messengers in the regulation of renin secretion. Rev Invest Clin 1989;41(2):165-75.

14. Zhuo J, Ohishi M, Mendelsohn FA. Roles of AT1 and AT2 receptors in the hypertensive Ren-2 gene transgenic rat kidney. Hypertension 1999;33(1 pt 2):347-53.

15. Licea H, Walters MR, Navar LG. Renal nuclear Angiotensin II receptors in normal and hypertensive rats. Acta Physiol Hung 2002; 89(4):427-38.

16. van Rodijnen WF, van Lambalgen TA, van Wijhe MH, Tangelder GJ, Ter Wee PM. Renal microvascular actions of angiotensin II fragments. Am J Physiol Renal Physiol 2002;283(1):F86-92.

17. Healy DP, Song L. Kidney aminopeptidase A and hypertension, part I: spontaneously hypertensive rats. Hypertension 1999;33(2):740-5.

18. Song L, Healy DP. Kidney aminopeptidase A and hypertension, part II: effects of angiotensin II. Hypertension 1999;33(2):746-52.

19. Vaz-da-Silva M. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor antagonists. Pharmacologic features. Rev Port Cardiol 2000;19(Suppl 2):II19-32.

20. Hall JE, Brands MW, Henegar JR. Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney J Am Soc Nephrol 1999;10(Suppl 12):S258-65. .

21. Fawcett DW. Tratado de Histología. 12.ed. Madrid: McGrow-Hill Interamericana; 1997. p.794-800.

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25. Endo Y, Arima S, Yaoita H, Tsunoda K, Omata K, Ito S. Vasodilation mediated by angiotensin II type 2 receptor is impaired in afferent arterioles of young spontaneously hypertensive rats. J Vasc Res 1998;35(6):421-7.

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27. Rosivall L. Renovascular effects of angiotensin II. Kidney 1990;(38):18-21.

Recibido: 20 de marzo de 2003. Aprobado: 10 de junio de 2003.
Dra. María O. Barber Fox. Avenida Vento No. 9504, entre 6 y 10, Altahabana, municipio Boyeros, Ciudad de La Habana, Cuba. Teléfono: 44-1210. Correo electrónico: mobf@infomed.sld.cu

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El sistema renina-angiotensina y el riñón en la fisiopatología de la hipertensión arterial esencial

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Citado por SciELO Similares en SciELO Facultad de Ciencias Médicas "Enrique Cabrera" Instituto de Ciencias Básicas y Preclínicas "Victoria de Girón" Dra. María O. Barber Fox y Dr. Ernesto Barber Gutiérrez Se presentó una actualización de los principales efectos de este sistema sobre la función renal y su posible relación con el desarrollo de la enfermedad hipertensiva primaria.

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https://scc.org.co/wp-content/uploads/2012/08/capitulo4.pdf
Los hipertensos son una mezcla de diversos estados fisiopatológicos y no una condición homogénea, por eso existen hipertensos con gasto cardíaco elevado y resistencia periférica total normal, hipertensos con resistencia periférica elevada y gasto cardíaco normal o bajo y también otros que presentan ambos factores (resistencia periférica y gasto cardíaco) elevados. Algunos hipertensos cursan con estados hiperadrenérgicos, otros presentan un componente metabólico notable, etc.

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Los principales mecanismos fisiopatológicos para la aparición de hipertensión arterial sistémica son:
a) la disminución en excreción renal de sodio, que aumenta el volumen y precarga
b) la activación de endotelina 1, que ocasiona vasoconstricción sistémica
c) a nivel vascular la disfunción endotelial por especies reactivas de oxígeno evita la liberación de óxido nitroso, un potente vasodilatador
d) la hiperactividad simpática, tanto central y periférica, que aumenta las resistencias periféricas.

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El fenómeno iniciador de la hipertensión parece ser la existencia de factores genéticos que reducen la excreción renal de Na con presión arterial normal.
Se sostiene que la causa primaria es el aumento de la resistencia periférica, ya por factores que inducen vasoconstricción funcional, ya por factores que provocan alteraciones estructurales en la pared vascular (hipertrofia, remodelación, hiperplasia de células musculares lisas) que terminan en el aumento de grosor de la pared arterial y/o estrechamiento luminal.

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Distintos factores fisiopatológicos pueden ser los desencadenantes de la hipertensión, como el estrés, estilo de vida, etc. Cambios estructurales y/o funcionales como la disfunción endotelial y remodelación vascular. Un mecanismo importante es el del sistema nervioso simpático, ya que el incremento de una actividad en el mismo se asocia a una presión alta, debido a que su estimulación genera una mayor contractibilidad vascular ocasionando una mayor resistencia periférica, un incremento en el gasto cardíaco y retención de líquidos a nivel renal. También el desbalance autonómico, como el aumento en el tono simpático y reducción del parasimpático contribuye a la patogénesis de la hipertensión arterial, pues al disminuir el efeco parasimpáttico la frecuencia cardiaca aumenta. El sistema renina - angiotensina, es considerado un círculo de retroalimentación; la presión elevada generará vasoconstricción de la arteria renal aferente, loq ue se percibe como una caída del volumen y por esto una disminución de la presión del riñón que responde secretando renina y convirtiendo en angiotensiógeno en angioensina I y esta a angiotensina II por la enzima convertidora de angiotensina, esto produciendo una mayor vasoconstricción estimulando a la endotelina y por lo tanto eleva la presión arterial.

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Se han descritos otros múltiples mecanismos, que pueden intervenir en la patogenia de la hipertensión esencial, siendo su evidencia menos contundente.
1.  Leptina
2.  Péptidos vasoactivos
- Péptidos natriuréticos:  Péptido auricular natriurético (PAN),  Péptido natriurético cerebral (BNP) y  Péptido natriurético tipo C (CNP).
-  Bradicininas
-  Otros péptidos vasoactivos: Adenosina, serotonina, vasopresina.
- Prostaglandinas.

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http://www.scielo.org.pe/scielo.php?script=sci_arttext&pid=S2304-51322018000200004
Se ha podido mostrar que es el sistema renina-angiotensina-aldosterona (SRAA) el que tiene mayor importancia, puesto que condiciona la acción de otros factores humorales y/o neurales, tales como producción de endotelina, la inhibición del óxido nítrico o de la prostaciclina, la acción de catecolaminas o de vasopresina, del factor ouabaína-sensible o FDE, del tromboxano A2 (TxA2) y de diversas sustancias vasopresoras endógenas.

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Fisiopatología de la hipertensión arterial: nuevos conceptos

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SIMPOSIO redefinición de la hipertensión arterial

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La presión arterial tiene diversos mecanismos que actúan en su control.
Los mecanismos por los cuales pueden estar afectados son:
- Sistema renina-angiotensina-aldosterona
- Papel de los péptidos natriuréticos
- El endotelio
- Sistema nervioso simpático.
- Sistema inmunitario.

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Las acciones de la angiotensina II incluyen: contracción del músculo liso vascular arterial y venoso, estimulación de la síntesis y secreción de aldosterona, liberación de noradrenalina en las terminaciones simpáticas, modulación del transporte del sodio (Na) por las células tubulares renales, aumento del estrés oxidativo por activación de oxidasas NADH y NADPH dependientes, estimulación de la vasopresina/ ADH, estimulación del centro dipsógeno en el sistema nervioso central, antagonismo del sistema del péptido atrial natriurético-natural (BNP) y tipo C (CNP)-(12), incremento de la producción de endotelina (ET1) y de prostaglandinas vasoconstrictoras (TXA2, PgF2α).

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Citado por SciELO

Similares en SciELO
Fisiopatología de la hipertensión arterial Pathophysiology of arterial hypertension Patrick Wagner-Grau¹
1 Presidente, Sociedad Peruana de Hipertensión Arterial.
Resumen
Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores y los vasodilatadores. Contribuyen a lo anterior, de modo importante, diversos factores hormonales, como el sistema captación y descarboxilación de los precursores de grupos amino (APUD) digestivo y el síndrome anémico.

Palabras clave: Hipertensión, fisiopatología; sistema renina angiotensina; hidrolasas diester fosforicas; anemia.
Abstract
Several factors are implicated in the pathophysiology of essential hypertension. The basic element is endothelial dysfunction and imbalance between vasoconstrictor and vasodilator factors. Various hormonal factors contribute importantly to this, such as the digestive amine precursor uptake decarboxylase (APUD) system and certain enzymes contributing to the anemic syndrome.

Keywords: Hypertension, pathophysiology; renin angiotensin system; phosphoric diester hydrolases; anemia.

La hipertensión arterial (HTA) se caracteriza básicamente por la existencia de una disfunción endotelial (DE), con ruptura del equilibrio entre los factores relajantes del vaso sanguíneo (óxido nítrico –NO-, factor hiperpolarizante del endotelio -EDHF) y los factores vasoconstrictores (principalmente endotelinas). Es conocida la disminución a nivel del endotelio de la prostaciclina-PGI2 vasodepresora y el aumento relativo del tromboxano-TXA2 intracelular vasoconstrictor (1).

Revisaremos algunos de los principales factores.

Las endotelinas (ETs) son factores vasoconstrictores locales muy potentes, cerca de 10 a 100 veces más poderosos que la angiotensina II (2). Se sabe actualmente que se trata de un sistema complejo: pre–proendotelina ð proendotelina ð ET1. A nivel de la proendotelina actúa una enzima convertidora de la endotelina (ECE), formándose principalmente ET1, pero también en menor proporción, ET2 y ET3 (3). Solo la ET1 parece poseer acción vasoconstrictora sistémica.

La ET1 ejerce diversas acciones: sobre el tono vascular (4), la excreción renal de sodio y agua (5) y la producción de la matriz extracelular (6). Se ha descrito disfunción del sistema ET1 en estados de proteinuria crónica, en la acumulación de matriz extracelular glomerular e intersticial, así como en la nefropatía diabética, en la glomerulopatía hipertensiva y en otros tipos de glomerulonefritis (7,8).

El endotelio es la principal fuente de ET1, pero no es la única. ET1 es sinterizada por las células epiteliales, las células musculares lisas vasculares, los macrófagos y en el seno de numerosos tejidos en los que se liga a sus receptores para ejercer su efecto. Sus dos receptores específicos, ETA y ETB, son capaces de iniciar efectos biológicos sinérgicos o diferentes, en el seno de una misma célula o entre tipos celulares distintos.

La concentración extracelular local de ET1 es regulada en su mayor parte por su internalización, y su aclaramiento por el receptor ETB endotelial (8-11), así como por su secreción mayormente abluminal, hacen que ella (la ET1) actúe principalmente de manera autocrina o paracrina, permitiendo efectos confinados al microambiente local. Una gran variedad de factores modula su expresión, incluyendo la localización de las enzimas de su vía de biosíntesis, diversos agentes vasoactivos, citoquinas, factores de crecimiento o varias sustancias inflamatorias ( figura 1).

Sus efectos biológicos difieren de acuerdo a su concentración en el seno de cada tejido.

La ET1 es de vida media muy breve, a causa de la captura por su receptor, no por su degradación. Su concentración plasmática varía de 0,5 a 2,0 pg/mL, la que no revela verdaderamente su actividad.

La ET1 está implicada, de modo importante, en el proceso de remodelamiento vascular y de regulación de la proliferación celular. Se trata, en efecto, de una sustancia mitogénica extraordinariamente potente, que produce hiperplasia e hipertrofia del músculo liso vascular (10,11).
EL SISTEMA RENINA - ANGIOTENSINA - ALDOSTERONA (SRAA)
Se trata de un sistema sumamente complejo, que comprende una serie de proteínas y 4 angiotensinas (I, II, III y IV) con actividades propias y específicas ( figura 2).

El SRAA, además de sus acciones propiamente vasculares, induce estrés oxidativo a nivel tisular, el que produce tanto cambios estructurales como funcionales, especialmente disfunción endotelial, que configuran la patología hipertensiva ( figura 3).

Las acciones de la angiotensina II incluyen: contracción del músculo liso vascular arterial y venoso, estimulación de la síntesis y secreción de aldosterona (¿por acción de la AIII?), liberación de noradrenalina en las terminaciones simpáticas, modulación del transporte del sodio (Na) por las células tubulares renales, aumento del estrés oxidativo por activación de oxidasas NADH y NADPH dependientes, estimulación de la vasopresina/ ADH, estimulación del centro dipsógeno en el sistema nervioso central, antagonismo del sistema del péptido atrial natriurético-natural (BNP) y tipo C (CNP)-(12), incremento de la producción de endotelina (ET1) y de prostaglandinas vasoconstrictoras (TXA2, PgF2α).

La AII y la aldosterona poseen, asimismo, acciones no hemodinámicas: aumento del VEGF con actividad proinflamatoria, estimulación de la producción de especies reactivas de oxígeno (ROS) nefrotóxicas, incremento de la proliferación celular y de la remodelación tisular, con aumento de la síntesis de citoquinas profibróticas y factores de crecimiento y reducción de la síntesis del NO y del BNP (12).

Además, ambas (AII y aldosterona) incrementan el tejido colágeno a nivel cardiaco y vascular, por inhibición de la actividad de la metaloproteinasa (MMP1) que destruye el colágeno e incremento de los inhibidores tisulares específicos de la MMP1 (TIMPs). El resultado es el incremento del colágeno 3 en el corazón y vasos sanguíneos de los pacientes hipertensos. Estos efectos son mediados por el aumento de la expresión del factor de crecimiento de tumor TGFβ1 (13). Finalmente, ambas sustancias poseen acción estimulante sobre el factor de crecimiento del tejido conectivo (CTGF) (13).

Existen por lo menos 4 receptores de la AII, cada uno de ellos con características propias: AT1, AT2, AT3 y AT4 ( figura 4).

En las tablas 1 y 2 se detalla los diversos efectos de la AII mediados por los receptores AT1 y AT2.

Se describe actualmente nuevas angiotensinas de acción vasodepresora, que provienen de la A1-7, que es una proteína esencialmente vasodilatadora y antiproliferativa. La A1–9 es de actividad intermedia entre la A1 y la A1-7. La A1–9 se convierte en A1-7 y nunca en A II (14). La A1–9 se convierte en A1-7 por acción de una endopeptidasa tisular, la neprilisina, de alta concentración en el endotelio vascular. Una nueva angiotensina, la A1–12, posee también acción vasodepresora (15).

Se ha descrito dos enzimas convertidoras de angiotensina (ECAs): la ECA1, que es la enzima fisiológica clásica, y la ECA2, que es la enzima que lleva a la formación de la A1–7, deprimida en algunos pacientes con HTA (14).

El remodelamiento vascular, estimulado por el SRAA, es diferente en las arterias grandes y en las pequeñas. En el primer caso, se trata de una remodelación hipertrófica; en el segundo, de una remodelación eutrófica ( figura 5).

EL FACTOR DIGITÁLICO ENDÓGENO (FDE)
Factor ouabaíno–sensible. Se trata de un factor hormonal, descrito hace varios años, que inhibe a la bomba Na – K – Mg – ATPasa (16), con intensa actividad vasoconstrictora, de acción natriurética. Tiene un PM de 500–1000 D y es de probable origen hipotalámico. Su concentración se halla elevada en cerca de 50% de pacientes hipertensos esenciales (16).

Su efecto natriurético se expresa de modo evidente e importante después de un aporte de sodio por vía oral ( figura 6).

Resulta posible establecer un rol fisiopatológico en la HTA por incremento de la actividad plasmática del FDE, tal como se expresa en la figura 7.

HORMONAS GASTROINTESTINALES DEL SISTEMA – Captación y descarboxilación de los precursores de grupos amino ( Amine precursor uptake descarboxilase - APUD)

Muchas de estas hormonas, secretadas por diversas células especializadas del aparato digestivo, poseen una intensa acción vascular. Así, p ej., el péptido intestinal vasoactivo (VIP) es intensamente vasodilatador, la coherina es vasoconstrictora, la colecistokinina (CCK) es vasodilatadora, la sustancia P también es vasodilatadora. Lo mismo, la bombesina, las endorfinas y los eicosanoides (17).

Existe la posibilidad de que estas hormonas contribuyan a la regulación de la presión arterial, regulación que se perdería en la HTA esencial.

Podría, entonces, existir una cierta asociación entre las patologías funcionales digestivas con la HTA.

Se especula acerca de la existencia de un eje hipotálamo–hipófiso–reno– suprarrenal–intestinal de regulación de la presión arterial, que pudiera alterarse en algunos casos de HTA esencial (17). Rol de la anemia en la HTA

La hemoglobina es renoprotectora. La disminución de la hemoglobina promueve fibrosis intersticial renal, que puede llevar a una enfermedad renal crónica (ERC) hipertensiva.

Existe una probable estimulación del SRAA a la vía de las caspasas, que son enzimas proapoptóticas sobre las células eritropoyéticas y vasoconstrictoras, por un bloqueo de la PGI2 y el NO (18).
REFERENCIAS BIBLIOGRÁFICAS
1. Hickey KA, Rubanyi G, Paul 1. RJ, Highsmith RF. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol. 1985;248(5 Pt 1):C550-6.

2. Yanagisawa M. Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5.

3. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA. 1989;86(8):2863-7.

4. Ar ai H, Hori S, Ar amori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990:348(6303):730–2.

5. Sakamoto A, Yanagisawa M, Sakurai T, Takuwa Y, Yanagisawa H, Masaki T. Cloning and functional expression of human cDNA for the ETB endothelin receptor. Biochem Biophys Res Commun. 1991;178:656–63.

6. Schiffrin EL. Vascular endothelin in hypertension. Vascul Pharmacol. 2005;43:19–29.

7. Kotelevtsev Y, Webb DJ. Endothelin as a natriuretic hormone: the case for a paracrine action mediated by nitric oxide. Cardiovasc Res. 2001;51(3):481–8.

8. Dussaule JC, Boffa JJ, Tharaux PL, Fakhouri F, Ardaillou R, Chatziantoniou C. Endothelin, renal diseases and hypertension. Adv Nephrol Necker Hosp. 2000;30:281–303.

9. Fukuroda T, Fujikawat, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun. 1994;199(3):1461-5.

10. Ozaki S, Ohwaki K, Ihara M, Fukuroda T, Ishikawa K, Yano M. ETB-mediated regulation of extracellular levels of endothelin-1 in cultured human endothelial cells. Biochem Biophys Res Commun. 1995;209(2):483–9.

11. Dupuis J, Stewart DJ, Cernacek P, Gosselin G. Human pulmonary circulation is an important site for both clearance and production of endothelin in the anesthetized dog. Circulation. 1996;94(7):1578–84.

12. Pagliaro P, Penna C. Rethinking the 12. renin-angiotensin system and its role in cardiovascular regulation. Cardiovasc Drugs Ther. 2005;19(1):77–87.

13. Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA. 1996;275(19):1507–13.

14. Dzau VJ, Re T. Tissue angiotensin system in cardiovascular system. Basic Res Cardiol. 2008;93(suppl 2):7–14.

15. Jessup JA, Trask AJ, Chappell MC, Nagata S, Kato J, Kitamura K, Ferrario CM. Localization of the novel angiotensin peptide, angiotensin-(1- 12), in heart and kidney of hypertensive and normotensive rats. Am J Physiol Heart Circ Physiol. 2008;294(6):H2614-H2618,

16. Wagner P. El factor digitálico endógeno. Hipertensión. 1996;2(3):111.

17. Wagner P. La anemia, consider aciones fisiopatológicas, clínicas y terapéuticas. Capítulo 7. 4ª edición. 2008:160.

18. Kurella Tamura M, Xie D, Yaffe K, Cohen DL, Teal V, Kasner SE, Messé SR, Sehgal AR, Kusek J, Desalvo KB, Cornish-Zirker D, Cohan J, Seliger SL, Chertow GM, Go AS. Vascular Risk Factors and Cognitive Impairment in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study. Clin J Am Soc Nephrol. 2010 Oct 28. [Publicación electrónica antes de la impresión].
Correspondencia:
Patrick Wagner-Grau
pwagner2310@yahoo.es

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Fisiopatología de la hipertensión arterial

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Citado por SciELO Similares en SciELO Fisiopatología de la hipertensión arterial Pathophysiology of arterial hypertension Patrick Wagner-Grau1 1 Presidente, Sociedad Peruana de Hipertensión Arterial. Resumen Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores y los vasodilatadores.

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La regulación de la PA en pacientes hipertensos difiere de la de pacientes sanos en que los barorreceptores y sistemas de control de volumen presión sanguíneo renal parecen estar configurados a un nivel más alto de presión arterial. Katzung 14 ed.

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En la HTA existe disfunción endotelial con desequilibrio en los factores relajantes del vaso sanguíneo y los factores vasoconstrictores.
Principales factores:
endotelinas: ejercen acción en tono vascular, excreción de sodio.
el sistema renina-angiotensina-aldosterona: acciones vasculares, AII contracción del musculo liso vascular, estimulación de síntesis y secreción de aldosterona.
factor digitálico endógeno: actividad vasoconstrictora, acción natriurética.

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Citado por SciELO

Similares en SciELO
Fisiopatología de la hipertensión arterial Pathophysiology of arterial hypertension Patrick Wagner-Grau¹
1 Presidente, Sociedad Peruana de Hipertensión Arterial.
Resumen
Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores y los vasodilatadores. Contribuyen a lo anterior, de modo importante, diversos factores hormonales, como el sistema captación y descarboxilación de los precursores de grupos amino (APUD) digestivo y el síndrome anémico.

Palabras clave: Hipertensión, fisiopatología; sistema renina angiotensina; hidrolasas diester fosforicas; anemia.
Abstract
Several factors are implicated in the pathophysiology of essential hypertension. The basic element is endothelial dysfunction and imbalance between vasoconstrictor and vasodilator factors. Various hormonal factors contribute importantly to this, such as the digestive amine precursor uptake decarboxylase (APUD) system and certain enzymes contributing to the anemic syndrome.

Keywords: Hypertension, pathophysiology; renin angiotensin system; phosphoric diester hydrolases; anemia.

La hipertensión arterial (HTA) se caracteriza básicamente por la existencia de una disfunción endotelial (DE), con ruptura del equilibrio entre los factores relajantes del vaso sanguíneo (óxido nítrico –NO-, factor hiperpolarizante del endotelio -EDHF) y los factores vasoconstrictores (principalmente endotelinas). Es conocida la disminución a nivel del endotelio de la prostaciclina-PGI2 vasodepresora y el aumento relativo del tromboxano-TXA2 intracelular vasoconstrictor (1).

Revisaremos algunos de los principales factores.

Las endotelinas (ETs) son factores vasoconstrictores locales muy potentes, cerca de 10 a 100 veces más poderosos que la angiotensina II (2). Se sabe actualmente que se trata de un sistema complejo: pre–proendotelina ð proendotelina ð ET1. A nivel de la proendotelina actúa una enzima convertidora de la endotelina (ECE), formándose principalmente ET1, pero también en menor proporción, ET2 y ET3 (3). Solo la ET1 parece poseer acción vasoconstrictora sistémica.

La ET1 ejerce diversas acciones: sobre el tono vascular (4), la excreción renal de sodio y agua (5) y la producción de la matriz extracelular (6). Se ha descrito disfunción del sistema ET1 en estados de proteinuria crónica, en la acumulación de matriz extracelular glomerular e intersticial, así como en la nefropatía diabética, en la glomerulopatía hipertensiva y en otros tipos de glomerulonefritis (7,8).

El endotelio es la principal fuente de ET1, pero no es la única. ET1 es sinterizada por las células epiteliales, las células musculares lisas vasculares, los macrófagos y en el seno de numerosos tejidos en los que se liga a sus receptores para ejercer su efecto. Sus dos receptores específicos, ETA y ETB, son capaces de iniciar efectos biológicos sinérgicos o diferentes, en el seno de una misma célula o entre tipos celulares distintos.

La concentración extracelular local de ET1 es regulada en su mayor parte por su internalización, y su aclaramiento por el receptor ETB endotelial (8-11), así como por su secreción mayormente abluminal, hacen que ella (la ET1) actúe principalmente de manera autocrina o paracrina, permitiendo efectos confinados al microambiente local. Una gran variedad de factores modula su expresión, incluyendo la localización de las enzimas de su vía de biosíntesis, diversos agentes vasoactivos, citoquinas, factores de crecimiento o varias sustancias inflamatorias ( figura 1).

Sus efectos biológicos difieren de acuerdo a su concentración en el seno de cada tejido.

La ET1 es de vida media muy breve, a causa de la captura por su receptor, no por su degradación. Su concentración plasmática varía de 0,5 a 2,0 pg/mL, la que no revela verdaderamente su actividad.

La ET1 está implicada, de modo importante, en el proceso de remodelamiento vascular y de regulación de la proliferación celular. Se trata, en efecto, de una sustancia mitogénica extraordinariamente potente, que produce hiperplasia e hipertrofia del músculo liso vascular (10,11).
EL SISTEMA RENINA - ANGIOTENSINA - ALDOSTERONA (SRAA)
Se trata de un sistema sumamente complejo, que comprende una serie de proteínas y 4 angiotensinas (I, II, III y IV) con actividades propias y específicas ( figura 2).

El SRAA, además de sus acciones propiamente vasculares, induce estrés oxidativo a nivel tisular, el que produce tanto cambios estructurales como funcionales, especialmente disfunción endotelial, que configuran la patología hipertensiva ( figura 3).

Las acciones de la angiotensina II incluyen: contracción del músculo liso vascular arterial y venoso, estimulación de la síntesis y secreción de aldosterona (¿por acción de la AIII?), liberación de noradrenalina en las terminaciones simpáticas, modulación del transporte del sodio (Na) por las células tubulares renales, aumento del estrés oxidativo por activación de oxidasas NADH y NADPH dependientes, estimulación de la vasopresina/ ADH, estimulación del centro dipsógeno en el sistema nervioso central, antagonismo del sistema del péptido atrial natriurético-natural (BNP) y tipo C (CNP)-(12), incremento de la producción de endotelina (ET1) y de prostaglandinas vasoconstrictoras (TXA2, PgF2α).

La AII y la aldosterona poseen, asimismo, acciones no hemodinámicas: aumento del VEGF con actividad proinflamatoria, estimulación de la producción de especies reactivas de oxígeno (ROS) nefrotóxicas, incremento de la proliferación celular y de la remodelación tisular, con aumento de la síntesis de citoquinas profibróticas y factores de crecimiento y reducción de la síntesis del NO y del BNP (12).

Además, ambas (AII y aldosterona) incrementan el tejido colágeno a nivel cardiaco y vascular, por inhibición de la actividad de la metaloproteinasa (MMP1) que destruye el colágeno e incremento de los inhibidores tisulares específicos de la MMP1 (TIMPs). El resultado es el incremento del colágeno 3 en el corazón y vasos sanguíneos de los pacientes hipertensos. Estos efectos son mediados por el aumento de la expresión del factor de crecimiento de tumor TGFβ1 (13). Finalmente, ambas sustancias poseen acción estimulante sobre el factor de crecimiento del tejido conectivo (CTGF) (13).

Existen por lo menos 4 receptores de la AII, cada uno de ellos con características propias: AT1, AT2, AT3 y AT4 ( figura 4).

En las tablas 1 y 2 se detalla los diversos efectos de la AII mediados por los receptores AT1 y AT2.

Se describe actualmente nuevas angiotensinas de acción vasodepresora, que provienen de la A1-7, que es una proteína esencialmente vasodilatadora y antiproliferativa. La A1–9 es de actividad intermedia entre la A1 y la A1-7. La A1–9 se convierte en A1-7 y nunca en A II (14). La A1–9 se convierte en A1-7 por acción de una endopeptidasa tisular, la neprilisina, de alta concentración en el endotelio vascular. Una nueva angiotensina, la A1–12, posee también acción vasodepresora (15).

Se ha descrito dos enzimas convertidoras de angiotensina (ECAs): la ECA1, que es la enzima fisiológica clásica, y la ECA2, que es la enzima que lleva a la formación de la A1–7, deprimida en algunos pacientes con HTA (14).

El remodelamiento vascular, estimulado por el SRAA, es diferente en las arterias grandes y en las pequeñas. En el primer caso, se trata de una remodelación hipertrófica; en el segundo, de una remodelación eutrófica ( figura 5).

EL FACTOR DIGITÁLICO ENDÓGENO (FDE)
Factor ouabaíno–sensible. Se trata de un factor hormonal, descrito hace varios años, que inhibe a la bomba Na – K – Mg – ATPasa (16), con intensa actividad vasoconstrictora, de acción natriurética. Tiene un PM de 500–1000 D y es de probable origen hipotalámico. Su concentración se halla elevada en cerca de 50% de pacientes hipertensos esenciales (16).

Su efecto natriurético se expresa de modo evidente e importante después de un aporte de sodio por vía oral ( figura 6).

Resulta posible establecer un rol fisiopatológico en la HTA por incremento de la actividad plasmática del FDE, tal como se expresa en la figura 7.

HORMONAS GASTROINTESTINALES DEL SISTEMA – Captación y descarboxilación de los precursores de grupos amino ( Amine precursor uptake descarboxilase - APUD)

Muchas de estas hormonas, secretadas por diversas células especializadas del aparato digestivo, poseen una intensa acción vascular. Así, p ej., el péptido intestinal vasoactivo (VIP) es intensamente vasodilatador, la coherina es vasoconstrictora, la colecistokinina (CCK) es vasodilatadora, la sustancia P también es vasodilatadora. Lo mismo, la bombesina, las endorfinas y los eicosanoides (17).

Existe la posibilidad de que estas hormonas contribuyan a la regulación de la presión arterial, regulación que se perdería en la HTA esencial.

Podría, entonces, existir una cierta asociación entre las patologías funcionales digestivas con la HTA.

Se especula acerca de la existencia de un eje hipotálamo–hipófiso–reno– suprarrenal–intestinal de regulación de la presión arterial, que pudiera alterarse en algunos casos de HTA esencial (17). Rol de la anemia en la HTA

La hemoglobina es renoprotectora. La disminución de la hemoglobina promueve fibrosis intersticial renal, que puede llevar a una enfermedad renal crónica (ERC) hipertensiva.

Existe una probable estimulación del SRAA a la vía de las caspasas, que son enzimas proapoptóticas sobre las células eritropoyéticas y vasoconstrictoras, por un bloqueo de la PGI2 y el NO (18).
REFERENCIAS BIBLIOGRÁFICAS
1. Hickey KA, Rubanyi G, Paul 1. RJ, Highsmith RF. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol. 1985;248(5 Pt 1):C550-6.

2. Yanagisawa M. Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5.

3. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA. 1989;86(8):2863-7.

4. Ar ai H, Hori S, Ar amori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990:348(6303):730–2.

5. Sakamoto A, Yanagisawa M, Sakurai T, Takuwa Y, Yanagisawa H, Masaki T. Cloning and functional expression of human cDNA for the ETB endothelin receptor. Biochem Biophys Res Commun. 1991;178:656–63.

6. Schiffrin EL. Vascular endothelin in hypertension. Vascul Pharmacol. 2005;43:19–29.

7. Kotelevtsev Y, Webb DJ. Endothelin as a natriuretic hormone: the case for a paracrine action mediated by nitric oxide. Cardiovasc Res. 2001;51(3):481–8.

8. Dussaule JC, Boffa JJ, Tharaux PL, Fakhouri F, Ardaillou R, Chatziantoniou C. Endothelin, renal diseases and hypertension. Adv Nephrol Necker Hosp. 2000;30:281–303.

9. Fukuroda T, Fujikawat, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun. 1994;199(3):1461-5.

10. Ozaki S, Ohwaki K, Ihara M, Fukuroda T, Ishikawa K, Yano M. ETB-mediated regulation of extracellular levels of endothelin-1 in cultured human endothelial cells. Biochem Biophys Res Commun. 1995;209(2):483–9.

11. Dupuis J, Stewart DJ, Cernacek P, Gosselin G. Human pulmonary circulation is an important site for both clearance and production of endothelin in the anesthetized dog. Circulation. 1996;94(7):1578–84.

12. Pagliaro P, Penna C. Rethinking the 12. renin-angiotensin system and its role in cardiovascular regulation. Cardiovasc Drugs Ther. 2005;19(1):77–87.

13. Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA. 1996;275(19):1507–13.

14. Dzau VJ, Re T. Tissue angiotensin system in cardiovascular system. Basic Res Cardiol. 2008;93(suppl 2):7–14.

15. Jessup JA, Trask AJ, Chappell MC, Nagata S, Kato J, Kitamura K, Ferrario CM. Localization of the novel angiotensin peptide, angiotensin-(1- 12), in heart and kidney of hypertensive and normotensive rats. Am J Physiol Heart Circ Physiol. 2008;294(6):H2614-H2618,

16. Wagner P. El factor digitálico endógeno. Hipertensión. 1996;2(3):111.

17. Wagner P. La anemia, consider aciones fisiopatológicas, clínicas y terapéuticas. Capítulo 7. 4ª edición. 2008:160.

18. Kurella Tamura M, Xie D, Yaffe K, Cohen DL, Teal V, Kasner SE, Messé SR, Sehgal AR, Kusek J, Desalvo KB, Cornish-Zirker D, Cohan J, Seliger SL, Chertow GM, Go AS. Vascular Risk Factors and Cognitive Impairment in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study. Clin J Am Soc Nephrol. 2010 Oct 28. [Publicación electrónica antes de la impresión].
Correspondencia:
Patrick Wagner-Grau
pwagner2310@yahoo.es

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Fisiopatología de la hipertensión arterial

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Citado por SciELO Similares en SciELO Fisiopatología de la hipertensión arterial Pathophysiology of arterial hypertension Patrick Wagner-Grau1 1 Presidente, Sociedad Peruana de Hipertensión Arterial. Resumen Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores y los vasodilatadores.

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En la exposición, se mencionó que parte de la fisiopatología de la HTA, se da una hiperactividad del SNS lo que produce un aumento de catecolaminas como Epinefrina /Norepinefrina, conllevando esto en a un aumento también de la frecuencia cardiaca y resistencia vascular, aumento de renina, aumento de la Angiotensina II, en consecuencia aumento de la presión arterial.

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http://www.scielo.org.pe/pdf/afm/v71n4/a03v71n4.pdf
Según la exposición la hipertensión arterial se caracteriza por la existencia de una disfunción endotelial con ruptura del equilibrio entre los factores relajantes del vaso sanguíneo como son el óxido nítrico y el factor hiperpolarizante del endotelio con los factores vasoconstrictores que son principalmente endotelinas.

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El sistema renina – angiotensina – aldosterona (SRAA) Se  trata  de  un  sistema  sumamente complejo,  que  comprende  una  serie  de proteínas  y  4  angiotensinas  (I,  II,  III  y IV) con actividades propias y específicas. El  SRAA,  además  de  sus  acciones propiamente  vasculares,  induce  estrés oxidativo  a  nivel  tisular,  el  que  produce  tanto  cambios  estructurales  como funcionales,  especialmente  disfunción endotelial, que configuran la patología hipertensiva.

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Vista de Fisiopatología de la hipertensión arterial

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Volver a los detalles del artículo Fisiopatología de la hipertensión arterial Descargar Descargar PDF

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En el caso del sistema renina-angiotensina-aldosterona (RAAS), se puede decir que es un sistema hormonal el cual se encarga de regular la presión sanguínea y el balance de sodio y potasio. El riñón a través del aparato yuxtaglomerular secretar la renina, la cual cataliza la conversión del angiotensinógeno, una glicoproteína secretada en el hígado, en angiotensina I que, a su vez, por acción de la enzima convertidora de angiotensina (ECA), se convierte en angiotensina II (A-II).

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Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. son:
-ENDOTELINAS
-EL SISTEMA RENINA - ANGIOTENSINA - ALDOSTERONA (SRAA)
-EL FACTOR DIGITÁLICO ENDÓGENO (FDE)
-HORMONAS GASTROINTESTINALES DEL SISTEMA.

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Citado por SciELO

Similares en SciELO
Fisiopatología de la hipertensión arterial Pathophysiology of arterial hypertension Patrick Wagner-Grau¹
1 Presidente, Sociedad Peruana de Hipertensión Arterial.
Resumen
Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores y los vasodilatadores. Contribuyen a lo anterior, de modo importante, diversos factores hormonales, como el sistema captación y descarboxilación de los precursores de grupos amino (APUD) digestivo y el síndrome anémico.

Palabras clave: Hipertensión, fisiopatología; sistema renina angiotensina; hidrolasas diester fosforicas; anemia.
Abstract
Several factors are implicated in the pathophysiology of essential hypertension. The basic element is endothelial dysfunction and imbalance between vasoconstrictor and vasodilator factors. Various hormonal factors contribute importantly to this, such as the digestive amine precursor uptake decarboxylase (APUD) system and certain enzymes contributing to the anemic syndrome.

Keywords: Hypertension, pathophysiology; renin angiotensin system; phosphoric diester hydrolases; anemia.

La hipertensión arterial (HTA) se caracteriza básicamente por la existencia de una disfunción endotelial (DE), con ruptura del equilibrio entre los factores relajantes del vaso sanguíneo (óxido nítrico –NO-, factor hiperpolarizante del endotelio -EDHF) y los factores vasoconstrictores (principalmente endotelinas). Es conocida la disminución a nivel del endotelio de la prostaciclina-PGI2 vasodepresora y el aumento relativo del tromboxano-TXA2 intracelular vasoconstrictor (1).

Revisaremos algunos de los principales factores.

Las endotelinas (ETs) son factores vasoconstrictores locales muy potentes, cerca de 10 a 100 veces más poderosos que la angiotensina II (2). Se sabe actualmente que se trata de un sistema complejo: pre–proendotelina ð proendotelina ð ET1. A nivel de la proendotelina actúa una enzima convertidora de la endotelina (ECE), formándose principalmente ET1, pero también en menor proporción, ET2 y ET3 (3). Solo la ET1 parece poseer acción vasoconstrictora sistémica.

La ET1 ejerce diversas acciones: sobre el tono vascular (4), la excreción renal de sodio y agua (5) y la producción de la matriz extracelular (6). Se ha descrito disfunción del sistema ET1 en estados de proteinuria crónica, en la acumulación de matriz extracelular glomerular e intersticial, así como en la nefropatía diabética, en la glomerulopatía hipertensiva y en otros tipos de glomerulonefritis (7,8).

El endotelio es la principal fuente de ET1, pero no es la única. ET1 es sinterizada por las células epiteliales, las células musculares lisas vasculares, los macrófagos y en el seno de numerosos tejidos en los que se liga a sus receptores para ejercer su efecto. Sus dos receptores específicos, ETA y ETB, son capaces de iniciar efectos biológicos sinérgicos o diferentes, en el seno de una misma célula o entre tipos celulares distintos.

La concentración extracelular local de ET1 es regulada en su mayor parte por su internalización, y su aclaramiento por el receptor ETB endotelial (8-11), así como por su secreción mayormente abluminal, hacen que ella (la ET1) actúe principalmente de manera autocrina o paracrina, permitiendo efectos confinados al microambiente local. Una gran variedad de factores modula su expresión, incluyendo la localización de las enzimas de su vía de biosíntesis, diversos agentes vasoactivos, citoquinas, factores de crecimiento o varias sustancias inflamatorias ( figura 1).

Sus efectos biológicos difieren de acuerdo a su concentración en el seno de cada tejido.

La ET1 es de vida media muy breve, a causa de la captura por su receptor, no por su degradación. Su concentración plasmática varía de 0,5 a 2,0 pg/mL, la que no revela verdaderamente su actividad.

La ET1 está implicada, de modo importante, en el proceso de remodelamiento vascular y de regulación de la proliferación celular. Se trata, en efecto, de una sustancia mitogénica extraordinariamente potente, que produce hiperplasia e hipertrofia del músculo liso vascular (10,11).
EL SISTEMA RENINA - ANGIOTENSINA - ALDOSTERONA (SRAA)
Se trata de un sistema sumamente complejo, que comprende una serie de proteínas y 4 angiotensinas (I, II, III y IV) con actividades propias y específicas ( figura 2).

El SRAA, además de sus acciones propiamente vasculares, induce estrés oxidativo a nivel tisular, el que produce tanto cambios estructurales como funcionales, especialmente disfunción endotelial, que configuran la patología hipertensiva ( figura 3).

Las acciones de la angiotensina II incluyen: contracción del músculo liso vascular arterial y venoso, estimulación de la síntesis y secreción de aldosterona (¿por acción de la AIII?), liberación de noradrenalina en las terminaciones simpáticas, modulación del transporte del sodio (Na) por las células tubulares renales, aumento del estrés oxidativo por activación de oxidasas NADH y NADPH dependientes, estimulación de la vasopresina/ ADH, estimulación del centro dipsógeno en el sistema nervioso central, antagonismo del sistema del péptido atrial natriurético-natural (BNP) y tipo C (CNP)-(12), incremento de la producción de endotelina (ET1) y de prostaglandinas vasoconstrictoras (TXA2, PgF2α).

La AII y la aldosterona poseen, asimismo, acciones no hemodinámicas: aumento del VEGF con actividad proinflamatoria, estimulación de la producción de especies reactivas de oxígeno (ROS) nefrotóxicas, incremento de la proliferación celular y de la remodelación tisular, con aumento de la síntesis de citoquinas profibróticas y factores de crecimiento y reducción de la síntesis del NO y del BNP (12).

Además, ambas (AII y aldosterona) incrementan el tejido colágeno a nivel cardiaco y vascular, por inhibición de la actividad de la metaloproteinasa (MMP1) que destruye el colágeno e incremento de los inhibidores tisulares específicos de la MMP1 (TIMPs). El resultado es el incremento del colágeno 3 en el corazón y vasos sanguíneos de los pacientes hipertensos. Estos efectos son mediados por el aumento de la expresión del factor de crecimiento de tumor TGFβ1 (13). Finalmente, ambas sustancias poseen acción estimulante sobre el factor de crecimiento del tejido conectivo (CTGF) (13).

Existen por lo menos 4 receptores de la AII, cada uno de ellos con características propias: AT1, AT2, AT3 y AT4 ( figura 4).

En las tablas 1 y 2 se detalla los diversos efectos de la AII mediados por los receptores AT1 y AT2.

Se describe actualmente nuevas angiotensinas de acción vasodepresora, que provienen de la A1-7, que es una proteína esencialmente vasodilatadora y antiproliferativa. La A1–9 es de actividad intermedia entre la A1 y la A1-7. La A1–9 se convierte en A1-7 y nunca en A II (14). La A1–9 se convierte en A1-7 por acción de una endopeptidasa tisular, la neprilisina, de alta concentración en el endotelio vascular. Una nueva angiotensina, la A1–12, posee también acción vasodepresora (15).

Se ha descrito dos enzimas convertidoras de angiotensina (ECAs): la ECA1, que es la enzima fisiológica clásica, y la ECA2, que es la enzima que lleva a la formación de la A1–7, deprimida en algunos pacientes con HTA (14).

El remodelamiento vascular, estimulado por el SRAA, es diferente en las arterias grandes y en las pequeñas. En el primer caso, se trata de una remodelación hipertrófica; en el segundo, de una remodelación eutrófica ( figura 5).

EL FACTOR DIGITÁLICO ENDÓGENO (FDE)
Factor ouabaíno–sensible. Se trata de un factor hormonal, descrito hace varios años, que inhibe a la bomba Na – K – Mg – ATPasa (16), con intensa actividad vasoconstrictora, de acción natriurética. Tiene un PM de 500–1000 D y es de probable origen hipotalámico. Su concentración se halla elevada en cerca de 50% de pacientes hipertensos esenciales (16).

Su efecto natriurético se expresa de modo evidente e importante después de un aporte de sodio por vía oral ( figura 6).

Resulta posible establecer un rol fisiopatológico en la HTA por incremento de la actividad plasmática del FDE, tal como se expresa en la figura 7.

HORMONAS GASTROINTESTINALES DEL SISTEMA – Captación y descarboxilación de los precursores de grupos amino ( Amine precursor uptake descarboxilase - APUD)

Muchas de estas hormonas, secretadas por diversas células especializadas del aparato digestivo, poseen una intensa acción vascular. Así, p ej., el péptido intestinal vasoactivo (VIP) es intensamente vasodilatador, la coherina es vasoconstrictora, la colecistokinina (CCK) es vasodilatadora, la sustancia P también es vasodilatadora. Lo mismo, la bombesina, las endorfinas y los eicosanoides (17).

Existe la posibilidad de que estas hormonas contribuyan a la regulación de la presión arterial, regulación que se perdería en la HTA esencial.

Podría, entonces, existir una cierta asociación entre las patologías funcionales digestivas con la HTA.

Se especula acerca de la existencia de un eje hipotálamo–hipófiso–reno– suprarrenal–intestinal de regulación de la presión arterial, que pudiera alterarse en algunos casos de HTA esencial (17). Rol de la anemia en la HTA

La hemoglobina es renoprotectora. La disminución de la hemoglobina promueve fibrosis intersticial renal, que puede llevar a una enfermedad renal crónica (ERC) hipertensiva.

Existe una probable estimulación del SRAA a la vía de las caspasas, que son enzimas proapoptóticas sobre las células eritropoyéticas y vasoconstrictoras, por un bloqueo de la PGI2 y el NO (18).
REFERENCIAS BIBLIOGRÁFICAS
1. Hickey KA, Rubanyi G, Paul 1. RJ, Highsmith RF. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol. 1985;248(5 Pt 1):C550-6.

2. Yanagisawa M. Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5.

3. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA. 1989;86(8):2863-7.

4. Ar ai H, Hori S, Ar amori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990:348(6303):730–2.

5. Sakamoto A, Yanagisawa M, Sakurai T, Takuwa Y, Yanagisawa H, Masaki T. Cloning and functional expression of human cDNA for the ETB endothelin receptor. Biochem Biophys Res Commun. 1991;178:656–63.

6. Schiffrin EL. Vascular endothelin in hypertension. Vascul Pharmacol. 2005;43:19–29.

7. Kotelevtsev Y, Webb DJ. Endothelin as a natriuretic hormone: the case for a paracrine action mediated by nitric oxide. Cardiovasc Res. 2001;51(3):481–8.

8. Dussaule JC, Boffa JJ, Tharaux PL, Fakhouri F, Ardaillou R, Chatziantoniou C. Endothelin, renal diseases and hypertension. Adv Nephrol Necker Hosp. 2000;30:281–303.

9. Fukuroda T, Fujikawat, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun. 1994;199(3):1461-5.

10. Ozaki S, Ohwaki K, Ihara M, Fukuroda T, Ishikawa K, Yano M. ETB-mediated regulation of extracellular levels of endothelin-1 in cultured human endothelial cells. Biochem Biophys Res Commun. 1995;209(2):483–9.

11. Dupuis J, Stewart DJ, Cernacek P, Gosselin G. Human pulmonary circulation is an important site for both clearance and production of endothelin in the anesthetized dog. Circulation. 1996;94(7):1578–84.

12. Pagliaro P, Penna C. Rethinking the 12. renin-angiotensin system and its role in cardiovascular regulation. Cardiovasc Drugs Ther. 2005;19(1):77–87.

13. Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA. 1996;275(19):1507–13.

14. Dzau VJ, Re T. Tissue angiotensin system in cardiovascular system. Basic Res Cardiol. 2008;93(suppl 2):7–14.

15. Jessup JA, Trask AJ, Chappell MC, Nagata S, Kato J, Kitamura K, Ferrario CM. Localization of the novel angiotensin peptide, angiotensin-(1- 12), in heart and kidney of hypertensive and normotensive rats. Am J Physiol Heart Circ Physiol. 2008;294(6):H2614-H2618,

16. Wagner P. El factor digitálico endógeno. Hipertensión. 1996;2(3):111.

17. Wagner P. La anemia, consider aciones fisiopatológicas, clínicas y terapéuticas. Capítulo 7. 4ª edición. 2008:160.

18. Kurella Tamura M, Xie D, Yaffe K, Cohen DL, Teal V, Kasner SE, Messé SR, Sehgal AR, Kusek J, Desalvo KB, Cornish-Zirker D, Cohan J, Seliger SL, Chertow GM, Go AS. Vascular Risk Factors and Cognitive Impairment in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study. Clin J Am Soc Nephrol. 2010 Oct 28. [Publicación electrónica antes de la impresión].
Correspondencia:
Patrick Wagner-Grau
pwagner2310@yahoo.es

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Fisiopatología de la hipertensión arterial

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Citado por SciELO Similares en SciELO Fisiopatología de la hipertensión arterial Pathophysiology of arterial hypertension Patrick Wagner-Grau1 1 Presidente, Sociedad Peruana de Hipertensión Arterial. Resumen Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores y los vasodilatadores.

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https://academic.oup.com/bjaed/article/4/3/71/292146
Hipertensión: fisiopatología y tratamient
Se habla de que los pacientes con hipertensión arterial pueden tener un aumento del gasto cardíaco, un aumento de la resistencia vascular sistémica, o ambos. En el grupo de edad más joven, el gasto cardíaco suele estar elevado, mientras que en los pacientes de mayor edad el aumento de la resistencia vascular sistémica y el aumento de la rigidez de la vasculatura desempeñan un papel dominante.
El tono vascular puede estar elevado debido al aumento de la estimulación de los receptores adrenérgicos α o al aumento de la liberación de péptidos como la angiotensina o las endotelinas. La vía final es un aumento del calcio citosólico en el músculo liso vascular que causa vasoconstricción. Varios factores de crecimiento, incluidas la angiotensina y las endotelinas, provocan un aumento de la masa del músculo liso vascular denominado remodelación vascular. Tanto un aumento de la resistencia vascular sistémica como un aumento de la rigidez vascular aumentan la carga impuesta al ventrículo izquierdo; esto induce hipertrofia ventricular izquierda y disfunción diastólica ventricular izquierda.

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Abstract. Arterial hypertension is a major cause of morbidity and mortality because of its association with coronary heart disease, cerebrovascular disease and

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Desde el siglo pasado se propusieron mecanismos para la producción de la HTA, mostrando al riñón como causante, debido a un defecto en la excreción renal de sodio. Posteriormente, se descubrió la importancia del sistema renina-angiotensina-aldosterona (SRAA) en la regulación de la presión arterial (PA) y del equilibrio hidroelectrolítico. Últimamente junto al estrés oxidativo, aparecen nuevos mecanismos que implican células inmunológicas y sus mediadores en el desarrollo de HTA.
Los linfocitos T (TL) y las células presentadoras de antígenos (APC) son componentes del sistema inmunitario capaces de generar citocinas proinflamatorias. Causan daño endotelial, vasoconstricción y disminución de la excreción urinaria de sodio. Los TL CD4+ y CD8+ son células efectoras, causalmente implicadas en el desarrollo de la HTA, mientras que las tipo γδLos TL desempeñan su papel patogénico en la HT potenciando la disfunción endotelial.

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- La presión arterial es el producto del gasto cardíaco y la resistencia vascular sistémica. De ello se deduce que los pacientes con hipertensión arterial pueden tener un aumento del gasto cardíaco, un aumento de la resistencia vascular sistémica, o ambos.
- El tono vascular puede estar elevado debido al aumento de la estimulación de los receptores adrenérgicos α o al aumento de la liberación de péptidos como la angiotensina o las endotelinas.
- La vía final es un aumento del calcio citosólico en el músculo liso vascular que causa vasoconstricción.
- Varios factores de crecimiento, incluidas la angiotensina y las endotelinas, provocan un aumento de la masa del músculo liso vascular denominado remodelación vascular.
- Tanto un aumento de la resistencia vascular sistémica como un aumento de la rigidez vascular aumentan la carga impuesta al ventrículo izquierdo; esto induce hipertrofia ventricular izquierda y disfunción diastólica ventricular izquierda.

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Abstract. Arterial hypertension is a major cause of morbidity and mortality because of its association with coronary heart disease, cerebrovascular disease and

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http://www.scielo.org.pe/pdf/afm/v71n4/a03v71n4.pdf
El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores y los vasodilatadores.
Factores:
-Endotelinas
- El sistema renina – angiotensina - aldosterona (SRAA)
- El factor digitálico endógeno (FDE)
-  Hormonas gastrointestinales del sistema

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TÍTULO: Fisiopatología de la hipertensión arterial

AÑO: 2010

La fisiopatología de la hipertensión arterial es compleja, pues intervienen múltiples factores que, en su mayoría, tienen una base genética. Se ha podido mostrar que es el sistema renina-angiotensina-aldosterona (SRAA) el que tiene mayor importancia, puesto que condiciona la acción de otros factores humorales y/o neurales, tales como producción de endotelina, la inhibición del óxido nítrico o de la prostaciclina, la acción de catecolaminas o de vasopresina, del factor ouabaína-sensible o FDE, del tromboxano A2 (TxA2) y de diversas sustancias vasopresoras endógenas.

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Citado por SciELO

Similares en SciELO
Fisiopatología de la hipertensión arterial Pathophysiology of arterial hypertension Patrick Wagner-Grau¹
1 Presidente, Sociedad Peruana de Hipertensión Arterial.
Resumen
Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores y los vasodilatadores. Contribuyen a lo anterior, de modo importante, diversos factores hormonales, como el sistema captación y descarboxilación de los precursores de grupos amino (APUD) digestivo y el síndrome anémico.

Palabras clave: Hipertensión, fisiopatología; sistema renina angiotensina; hidrolasas diester fosforicas; anemia.
Abstract
Several factors are implicated in the pathophysiology of essential hypertension. The basic element is endothelial dysfunction and imbalance between vasoconstrictor and vasodilator factors. Various hormonal factors contribute importantly to this, such as the digestive amine precursor uptake decarboxylase (APUD) system and certain enzymes contributing to the anemic syndrome.

Keywords: Hypertension, pathophysiology; renin angiotensin system; phosphoric diester hydrolases; anemia.

La hipertensión arterial (HTA) se caracteriza básicamente por la existencia de una disfunción endotelial (DE), con ruptura del equilibrio entre los factores relajantes del vaso sanguíneo (óxido nítrico –NO-, factor hiperpolarizante del endotelio -EDHF) y los factores vasoconstrictores (principalmente endotelinas). Es conocida la disminución a nivel del endotelio de la prostaciclina-PGI2 vasodepresora y el aumento relativo del tromboxano-TXA2 intracelular vasoconstrictor (1).

Revisaremos algunos de los principales factores.

Las endotelinas (ETs) son factores vasoconstrictores locales muy potentes, cerca de 10 a 100 veces más poderosos que la angiotensina II (2). Se sabe actualmente que se trata de un sistema complejo: pre–proendotelina ð proendotelina ð ET1. A nivel de la proendotelina actúa una enzima convertidora de la endotelina (ECE), formándose principalmente ET1, pero también en menor proporción, ET2 y ET3 (3). Solo la ET1 parece poseer acción vasoconstrictora sistémica.

La ET1 ejerce diversas acciones: sobre el tono vascular (4), la excreción renal de sodio y agua (5) y la producción de la matriz extracelular (6). Se ha descrito disfunción del sistema ET1 en estados de proteinuria crónica, en la acumulación de matriz extracelular glomerular e intersticial, así como en la nefropatía diabética, en la glomerulopatía hipertensiva y en otros tipos de glomerulonefritis (7,8).

El endotelio es la principal fuente de ET1, pero no es la única. ET1 es sinterizada por las células epiteliales, las células musculares lisas vasculares, los macrófagos y en el seno de numerosos tejidos en los que se liga a sus receptores para ejercer su efecto. Sus dos receptores específicos, ETA y ETB, son capaces de iniciar efectos biológicos sinérgicos o diferentes, en el seno de una misma célula o entre tipos celulares distintos.

La concentración extracelular local de ET1 es regulada en su mayor parte por su internalización, y su aclaramiento por el receptor ETB endotelial (8-11), así como por su secreción mayormente abluminal, hacen que ella (la ET1) actúe principalmente de manera autocrina o paracrina, permitiendo efectos confinados al microambiente local. Una gran variedad de factores modula su expresión, incluyendo la localización de las enzimas de su vía de biosíntesis, diversos agentes vasoactivos, citoquinas, factores de crecimiento o varias sustancias inflamatorias ( figura 1).

Sus efectos biológicos difieren de acuerdo a su concentración en el seno de cada tejido.

La ET1 es de vida media muy breve, a causa de la captura por su receptor, no por su degradación. Su concentración plasmática varía de 0,5 a 2,0 pg/mL, la que no revela verdaderamente su actividad.

La ET1 está implicada, de modo importante, en el proceso de remodelamiento vascular y de regulación de la proliferación celular. Se trata, en efecto, de una sustancia mitogénica extraordinariamente potente, que produce hiperplasia e hipertrofia del músculo liso vascular (10,11).
EL SISTEMA RENINA - ANGIOTENSINA - ALDOSTERONA (SRAA)
Se trata de un sistema sumamente complejo, que comprende una serie de proteínas y 4 angiotensinas (I, II, III y IV) con actividades propias y específicas ( figura 2).

El SRAA, además de sus acciones propiamente vasculares, induce estrés oxidativo a nivel tisular, el que produce tanto cambios estructurales como funcionales, especialmente disfunción endotelial, que configuran la patología hipertensiva ( figura 3).

Las acciones de la angiotensina II incluyen: contracción del músculo liso vascular arterial y venoso, estimulación de la síntesis y secreción de aldosterona (¿por acción de la AIII?), liberación de noradrenalina en las terminaciones simpáticas, modulación del transporte del sodio (Na) por las células tubulares renales, aumento del estrés oxidativo por activación de oxidasas NADH y NADPH dependientes, estimulación de la vasopresina/ ADH, estimulación del centro dipsógeno en el sistema nervioso central, antagonismo del sistema del péptido atrial natriurético-natural (BNP) y tipo C (CNP)-(12), incremento de la producción de endotelina (ET1) y de prostaglandinas vasoconstrictoras (TXA2, PgF2α).

La AII y la aldosterona poseen, asimismo, acciones no hemodinámicas: aumento del VEGF con actividad proinflamatoria, estimulación de la producción de especies reactivas de oxígeno (ROS) nefrotóxicas, incremento de la proliferación celular y de la remodelación tisular, con aumento de la síntesis de citoquinas profibróticas y factores de crecimiento y reducción de la síntesis del NO y del BNP (12).

Además, ambas (AII y aldosterona) incrementan el tejido colágeno a nivel cardiaco y vascular, por inhibición de la actividad de la metaloproteinasa (MMP1) que destruye el colágeno e incremento de los inhibidores tisulares específicos de la MMP1 (TIMPs). El resultado es el incremento del colágeno 3 en el corazón y vasos sanguíneos de los pacientes hipertensos. Estos efectos son mediados por el aumento de la expresión del factor de crecimiento de tumor TGFβ1 (13). Finalmente, ambas sustancias poseen acción estimulante sobre el factor de crecimiento del tejido conectivo (CTGF) (13).

Existen por lo menos 4 receptores de la AII, cada uno de ellos con características propias: AT1, AT2, AT3 y AT4 ( figura 4).

En las tablas 1 y 2 se detalla los diversos efectos de la AII mediados por los receptores AT1 y AT2.

Se describe actualmente nuevas angiotensinas de acción vasodepresora, que provienen de la A1-7, que es una proteína esencialmente vasodilatadora y antiproliferativa. La A1–9 es de actividad intermedia entre la A1 y la A1-7. La A1–9 se convierte en A1-7 y nunca en A II (14). La A1–9 se convierte en A1-7 por acción de una endopeptidasa tisular, la neprilisina, de alta concentración en el endotelio vascular. Una nueva angiotensina, la A1–12, posee también acción vasodepresora (15).

Se ha descrito dos enzimas convertidoras de angiotensina (ECAs): la ECA1, que es la enzima fisiológica clásica, y la ECA2, que es la enzima que lleva a la formación de la A1–7, deprimida en algunos pacientes con HTA (14).

El remodelamiento vascular, estimulado por el SRAA, es diferente en las arterias grandes y en las pequeñas. En el primer caso, se trata de una remodelación hipertrófica; en el segundo, de una remodelación eutrófica ( figura 5).

EL FACTOR DIGITÁLICO ENDÓGENO (FDE)
Factor ouabaíno–sensible. Se trata de un factor hormonal, descrito hace varios años, que inhibe a la bomba Na – K – Mg – ATPasa (16), con intensa actividad vasoconstrictora, de acción natriurética. Tiene un PM de 500–1000 D y es de probable origen hipotalámico. Su concentración se halla elevada en cerca de 50% de pacientes hipertensos esenciales (16).

Su efecto natriurético se expresa de modo evidente e importante después de un aporte de sodio por vía oral ( figura 6).

Resulta posible establecer un rol fisiopatológico en la HTA por incremento de la actividad plasmática del FDE, tal como se expresa en la figura 7.

HORMONAS GASTROINTESTINALES DEL SISTEMA – Captación y descarboxilación de los precursores de grupos amino ( Amine precursor uptake descarboxilase - APUD)

Muchas de estas hormonas, secretadas por diversas células especializadas del aparato digestivo, poseen una intensa acción vascular. Así, p ej., el péptido intestinal vasoactivo (VIP) es intensamente vasodilatador, la coherina es vasoconstrictora, la colecistokinina (CCK) es vasodilatadora, la sustancia P también es vasodilatadora. Lo mismo, la bombesina, las endorfinas y los eicosanoides (17).

Existe la posibilidad de que estas hormonas contribuyan a la regulación de la presión arterial, regulación que se perdería en la HTA esencial.

Podría, entonces, existir una cierta asociación entre las patologías funcionales digestivas con la HTA.

Se especula acerca de la existencia de un eje hipotálamo–hipófiso–reno– suprarrenal–intestinal de regulación de la presión arterial, que pudiera alterarse en algunos casos de HTA esencial (17). Rol de la anemia en la HTA

La hemoglobina es renoprotectora. La disminución de la hemoglobina promueve fibrosis intersticial renal, que puede llevar a una enfermedad renal crónica (ERC) hipertensiva.

Existe una probable estimulación del SRAA a la vía de las caspasas, que son enzimas proapoptóticas sobre las células eritropoyéticas y vasoconstrictoras, por un bloqueo de la PGI2 y el NO (18).
REFERENCIAS BIBLIOGRÁFICAS
1. Hickey KA, Rubanyi G, Paul 1. RJ, Highsmith RF. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol. 1985;248(5 Pt 1):C550-6.

2. Yanagisawa M. Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5.

3. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA. 1989;86(8):2863-7.

4. Ar ai H, Hori S, Ar amori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990:348(6303):730–2.

5. Sakamoto A, Yanagisawa M, Sakurai T, Takuwa Y, Yanagisawa H, Masaki T. Cloning and functional expression of human cDNA for the ETB endothelin receptor. Biochem Biophys Res Commun. 1991;178:656–63.

6. Schiffrin EL. Vascular endothelin in hypertension. Vascul Pharmacol. 2005;43:19–29.

7. Kotelevtsev Y, Webb DJ. Endothelin as a natriuretic hormone: the case for a paracrine action mediated by nitric oxide. Cardiovasc Res. 2001;51(3):481–8.

8. Dussaule JC, Boffa JJ, Tharaux PL, Fakhouri F, Ardaillou R, Chatziantoniou C. Endothelin, renal diseases and hypertension. Adv Nephrol Necker Hosp. 2000;30:281–303.

9. Fukuroda T, Fujikawat, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun. 1994;199(3):1461-5.

10. Ozaki S, Ohwaki K, Ihara M, Fukuroda T, Ishikawa K, Yano M. ETB-mediated regulation of extracellular levels of endothelin-1 in cultured human endothelial cells. Biochem Biophys Res Commun. 1995;209(2):483–9.

11. Dupuis J, Stewart DJ, Cernacek P, Gosselin G. Human pulmonary circulation is an important site for both clearance and production of endothelin in the anesthetized dog. Circulation. 1996;94(7):1578–84.

12. Pagliaro P, Penna C. Rethinking the 12. renin-angiotensin system and its role in cardiovascular regulation. Cardiovasc Drugs Ther. 2005;19(1):77–87.

13. Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA. 1996;275(19):1507–13.

14. Dzau VJ, Re T. Tissue angiotensin system in cardiovascular system. Basic Res Cardiol. 2008;93(suppl 2):7–14.

15. Jessup JA, Trask AJ, Chappell MC, Nagata S, Kato J, Kitamura K, Ferrario CM. Localization of the novel angiotensin peptide, angiotensin-(1- 12), in heart and kidney of hypertensive and normotensive rats. Am J Physiol Heart Circ Physiol. 2008;294(6):H2614-H2618,

16. Wagner P. El factor digitálico endógeno. Hipertensión. 1996;2(3):111.

17. Wagner P. La anemia, consider aciones fisiopatológicas, clínicas y terapéuticas. Capítulo 7. 4ª edición. 2008:160.

18. Kurella Tamura M, Xie D, Yaffe K, Cohen DL, Teal V, Kasner SE, Messé SR, Sehgal AR, Kusek J, Desalvo KB, Cornish-Zirker D, Cohan J, Seliger SL, Chertow GM, Go AS. Vascular Risk Factors and Cognitive Impairment in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study. Clin J Am Soc Nephrol. 2010 Oct 28. [Publicación electrónica antes de la impresión].
Correspondencia:
Patrick Wagner-Grau
pwagner2310@yahoo.es

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Fisiopatología de la hipertensión arterial

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Citado por SciELO Similares en SciELO Fisiopatología de la hipertensión arterial Pathophysiology of arterial hypertension Patrick Wagner-Grau1 1 Presidente, Sociedad Peruana de Hipertensión Arterial. Resumen Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores y los vasodilatadores.

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La Hipertensión Arterial está caracterizada por la existencia de una disfunción endotelial, ruptura del equilibrio entre los factores relajantes del vaso sanguíneo (Oxido nítrico y factor hiperpolarizante del endotelio) y los factores vasoconstrictores. Siendo el sistema renina-angiotensina-aldosterona el de más interés porque condiciona la acción de distintos factores humorales y neurales, como la producción de endotelina, la inhibición del óxido nítrico o de prostaciclina, interviene en la acción de catecolaminas o de vasopresina y del tromboxano A2 como también de las sustancias vasopresoras endógenas.

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La hipertensión arterial (HTA) se caracteriza básicamente por la existencia de una disfunción endotelial (DE), con ruptura del equilibrio entre los factores relajantes del vaso sanguíneo (óxido nítrico –NO-, factor hiperpolarizante del endotelio -EDHF) y los factores vasoconstrictores (principalmente endotelinas). Es conocida la disminución a nivel del endotelio de la prostaciclina-PGI2 vasodepresora y el aumento relativo del tromboxano-TXA2 intracelular vasoconstrictor

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Citado por SciELO

Similares en SciELO
Fisiopatología de la hipertensión arterial Pathophysiology of arterial hypertension Patrick Wagner-Grau¹
1 Presidente, Sociedad Peruana de Hipertensión Arterial.
Resumen
Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores y los vasodilatadores. Contribuyen a lo anterior, de modo importante, diversos factores hormonales, como el sistema captación y descarboxilación de los precursores de grupos amino (APUD) digestivo y el síndrome anémico.

Palabras clave: Hipertensión, fisiopatología; sistema renina angiotensina; hidrolasas diester fosforicas; anemia.
Abstract
Several factors are implicated in the pathophysiology of essential hypertension. The basic element is endothelial dysfunction and imbalance between vasoconstrictor and vasodilator factors. Various hormonal factors contribute importantly to this, such as the digestive amine precursor uptake decarboxylase (APUD) system and certain enzymes contributing to the anemic syndrome.

Keywords: Hypertension, pathophysiology; renin angiotensin system; phosphoric diester hydrolases; anemia.

La hipertensión arterial (HTA) se caracteriza básicamente por la existencia de una disfunción endotelial (DE), con ruptura del equilibrio entre los factores relajantes del vaso sanguíneo (óxido nítrico –NO-, factor hiperpolarizante del endotelio -EDHF) y los factores vasoconstrictores (principalmente endotelinas). Es conocida la disminución a nivel del endotelio de la prostaciclina-PGI2 vasodepresora y el aumento relativo del tromboxano-TXA2 intracelular vasoconstrictor (1).

Revisaremos algunos de los principales factores.

Las endotelinas (ETs) son factores vasoconstrictores locales muy potentes, cerca de 10 a 100 veces más poderosos que la angiotensina II (2). Se sabe actualmente que se trata de un sistema complejo: pre–proendotelina ð proendotelina ð ET1. A nivel de la proendotelina actúa una enzima convertidora de la endotelina (ECE), formándose principalmente ET1, pero también en menor proporción, ET2 y ET3 (3). Solo la ET1 parece poseer acción vasoconstrictora sistémica.

La ET1 ejerce diversas acciones: sobre el tono vascular (4), la excreción renal de sodio y agua (5) y la producción de la matriz extracelular (6). Se ha descrito disfunción del sistema ET1 en estados de proteinuria crónica, en la acumulación de matriz extracelular glomerular e intersticial, así como en la nefropatía diabética, en la glomerulopatía hipertensiva y en otros tipos de glomerulonefritis (7,8).

El endotelio es la principal fuente de ET1, pero no es la única. ET1 es sinterizada por las células epiteliales, las células musculares lisas vasculares, los macrófagos y en el seno de numerosos tejidos en los que se liga a sus receptores para ejercer su efecto. Sus dos receptores específicos, ETA y ETB, son capaces de iniciar efectos biológicos sinérgicos o diferentes, en el seno de una misma célula o entre tipos celulares distintos.

La concentración extracelular local de ET1 es regulada en su mayor parte por su internalización, y su aclaramiento por el receptor ETB endotelial (8-11), así como por su secreción mayormente abluminal, hacen que ella (la ET1) actúe principalmente de manera autocrina o paracrina, permitiendo efectos confinados al microambiente local. Una gran variedad de factores modula su expresión, incluyendo la localización de las enzimas de su vía de biosíntesis, diversos agentes vasoactivos, citoquinas, factores de crecimiento o varias sustancias inflamatorias ( figura 1).

Sus efectos biológicos difieren de acuerdo a su concentración en el seno de cada tejido.

La ET1 es de vida media muy breve, a causa de la captura por su receptor, no por su degradación. Su concentración plasmática varía de 0,5 a 2,0 pg/mL, la que no revela verdaderamente su actividad.

La ET1 está implicada, de modo importante, en el proceso de remodelamiento vascular y de regulación de la proliferación celular. Se trata, en efecto, de una sustancia mitogénica extraordinariamente potente, que produce hiperplasia e hipertrofia del músculo liso vascular (10,11).
EL SISTEMA RENINA - ANGIOTENSINA - ALDOSTERONA (SRAA)
Se trata de un sistema sumamente complejo, que comprende una serie de proteínas y 4 angiotensinas (I, II, III y IV) con actividades propias y específicas ( figura 2).

El SRAA, además de sus acciones propiamente vasculares, induce estrés oxidativo a nivel tisular, el que produce tanto cambios estructurales como funcionales, especialmente disfunción endotelial, que configuran la patología hipertensiva ( figura 3).

Las acciones de la angiotensina II incluyen: contracción del músculo liso vascular arterial y venoso, estimulación de la síntesis y secreción de aldosterona (¿por acción de la AIII?), liberación de noradrenalina en las terminaciones simpáticas, modulación del transporte del sodio (Na) por las células tubulares renales, aumento del estrés oxidativo por activación de oxidasas NADH y NADPH dependientes, estimulación de la vasopresina/ ADH, estimulación del centro dipsógeno en el sistema nervioso central, antagonismo del sistema del péptido atrial natriurético-natural (BNP) y tipo C (CNP)-(12), incremento de la producción de endotelina (ET1) y de prostaglandinas vasoconstrictoras (TXA2, PgF2α).

La AII y la aldosterona poseen, asimismo, acciones no hemodinámicas: aumento del VEGF con actividad proinflamatoria, estimulación de la producción de especies reactivas de oxígeno (ROS) nefrotóxicas, incremento de la proliferación celular y de la remodelación tisular, con aumento de la síntesis de citoquinas profibróticas y factores de crecimiento y reducción de la síntesis del NO y del BNP (12).

Además, ambas (AII y aldosterona) incrementan el tejido colágeno a nivel cardiaco y vascular, por inhibición de la actividad de la metaloproteinasa (MMP1) que destruye el colágeno e incremento de los inhibidores tisulares específicos de la MMP1 (TIMPs). El resultado es el incremento del colágeno 3 en el corazón y vasos sanguíneos de los pacientes hipertensos. Estos efectos son mediados por el aumento de la expresión del factor de crecimiento de tumor TGFβ1 (13). Finalmente, ambas sustancias poseen acción estimulante sobre el factor de crecimiento del tejido conectivo (CTGF) (13).

Existen por lo menos 4 receptores de la AII, cada uno de ellos con características propias: AT1, AT2, AT3 y AT4 ( figura 4).

En las tablas 1 y 2 se detalla los diversos efectos de la AII mediados por los receptores AT1 y AT2.

Se describe actualmente nuevas angiotensinas de acción vasodepresora, que provienen de la A1-7, que es una proteína esencialmente vasodilatadora y antiproliferativa. La A1–9 es de actividad intermedia entre la A1 y la A1-7. La A1–9 se convierte en A1-7 y nunca en A II (14). La A1–9 se convierte en A1-7 por acción de una endopeptidasa tisular, la neprilisina, de alta concentración en el endotelio vascular. Una nueva angiotensina, la A1–12, posee también acción vasodepresora (15).

Se ha descrito dos enzimas convertidoras de angiotensina (ECAs): la ECA1, que es la enzima fisiológica clásica, y la ECA2, que es la enzima que lleva a la formación de la A1–7, deprimida en algunos pacientes con HTA (14).

El remodelamiento vascular, estimulado por el SRAA, es diferente en las arterias grandes y en las pequeñas. En el primer caso, se trata de una remodelación hipertrófica; en el segundo, de una remodelación eutrófica ( figura 5).

EL FACTOR DIGITÁLICO ENDÓGENO (FDE)
Factor ouabaíno–sensible. Se trata de un factor hormonal, descrito hace varios años, que inhibe a la bomba Na – K – Mg – ATPasa (16), con intensa actividad vasoconstrictora, de acción natriurética. Tiene un PM de 500–1000 D y es de probable origen hipotalámico. Su concentración se halla elevada en cerca de 50% de pacientes hipertensos esenciales (16).

Su efecto natriurético se expresa de modo evidente e importante después de un aporte de sodio por vía oral ( figura 6).

Resulta posible establecer un rol fisiopatológico en la HTA por incremento de la actividad plasmática del FDE, tal como se expresa en la figura 7.

HORMONAS GASTROINTESTINALES DEL SISTEMA – Captación y descarboxilación de los precursores de grupos amino ( Amine precursor uptake descarboxilase - APUD)

Muchas de estas hormonas, secretadas por diversas células especializadas del aparato digestivo, poseen una intensa acción vascular. Así, p ej., el péptido intestinal vasoactivo (VIP) es intensamente vasodilatador, la coherina es vasoconstrictora, la colecistokinina (CCK) es vasodilatadora, la sustancia P también es vasodilatadora. Lo mismo, la bombesina, las endorfinas y los eicosanoides (17).

Existe la posibilidad de que estas hormonas contribuyan a la regulación de la presión arterial, regulación que se perdería en la HTA esencial.

Podría, entonces, existir una cierta asociación entre las patologías funcionales digestivas con la HTA.

Se especula acerca de la existencia de un eje hipotálamo–hipófiso–reno– suprarrenal–intestinal de regulación de la presión arterial, que pudiera alterarse en algunos casos de HTA esencial (17). Rol de la anemia en la HTA

La hemoglobina es renoprotectora. La disminución de la hemoglobina promueve fibrosis intersticial renal, que puede llevar a una enfermedad renal crónica (ERC) hipertensiva.

Existe una probable estimulación del SRAA a la vía de las caspasas, que son enzimas proapoptóticas sobre las células eritropoyéticas y vasoconstrictoras, por un bloqueo de la PGI2 y el NO (18).
REFERENCIAS BIBLIOGRÁFICAS
1. Hickey KA, Rubanyi G, Paul 1. RJ, Highsmith RF. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol. 1985;248(5 Pt 1):C550-6.

2. Yanagisawa M. Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5.

3. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA. 1989;86(8):2863-7.

4. Ar ai H, Hori S, Ar amori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990:348(6303):730–2.

5. Sakamoto A, Yanagisawa M, Sakurai T, Takuwa Y, Yanagisawa H, Masaki T. Cloning and functional expression of human cDNA for the ETB endothelin receptor. Biochem Biophys Res Commun. 1991;178:656–63.

6. Schiffrin EL. Vascular endothelin in hypertension. Vascul Pharmacol. 2005;43:19–29.

7. Kotelevtsev Y, Webb DJ. Endothelin as a natriuretic hormone: the case for a paracrine action mediated by nitric oxide. Cardiovasc Res. 2001;51(3):481–8.

8. Dussaule JC, Boffa JJ, Tharaux PL, Fakhouri F, Ardaillou R, Chatziantoniou C. Endothelin, renal diseases and hypertension. Adv Nephrol Necker Hosp. 2000;30:281–303.

9. Fukuroda T, Fujikawat, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun. 1994;199(3):1461-5.

10. Ozaki S, Ohwaki K, Ihara M, Fukuroda T, Ishikawa K, Yano M. ETB-mediated regulation of extracellular levels of endothelin-1 in cultured human endothelial cells. Biochem Biophys Res Commun. 1995;209(2):483–9.

11. Dupuis J, Stewart DJ, Cernacek P, Gosselin G. Human pulmonary circulation is an important site for both clearance and production of endothelin in the anesthetized dog. Circulation. 1996;94(7):1578–84.

12. Pagliaro P, Penna C. Rethinking the 12. renin-angiotensin system and its role in cardiovascular regulation. Cardiovasc Drugs Ther. 2005;19(1):77–87.

13. Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA. 1996;275(19):1507–13.

14. Dzau VJ, Re T. Tissue angiotensin system in cardiovascular system. Basic Res Cardiol. 2008;93(suppl 2):7–14.

15. Jessup JA, Trask AJ, Chappell MC, Nagata S, Kato J, Kitamura K, Ferrario CM. Localization of the novel angiotensin peptide, angiotensin-(1- 12), in heart and kidney of hypertensive and normotensive rats. Am J Physiol Heart Circ Physiol. 2008;294(6):H2614-H2618,

16. Wagner P. El factor digitálico endógeno. Hipertensión. 1996;2(3):111.

17. Wagner P. La anemia, consider aciones fisiopatológicas, clínicas y terapéuticas. Capítulo 7. 4ª edición. 2008:160.

18. Kurella Tamura M, Xie D, Yaffe K, Cohen DL, Teal V, Kasner SE, Messé SR, Sehgal AR, Kusek J, Desalvo KB, Cornish-Zirker D, Cohan J, Seliger SL, Chertow GM, Go AS. Vascular Risk Factors and Cognitive Impairment in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study. Clin J Am Soc Nephrol. 2010 Oct 28. [Publicación electrónica antes de la impresión].
Correspondencia:
Patrick Wagner-Grau
pwagner2310@yahoo.es

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Fisiopatología de la hipertensión arterial

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Citado por SciELO Similares en SciELO Fisiopatología de la hipertensión arterial Pathophysiology of arterial hypertension Patrick Wagner-Grau1 1 Presidente, Sociedad Peruana de Hipertensión Arterial. Resumen Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores y los vasodilatadores.

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La fisiopatología de la hipertensión arterial es compleja, pues intervienen múltiples factores que, en su mayoría, tienen una base genética. Se ha podido mostrar que es el sistema renina-angiotensina-aldosterona (SRAA) el que tiene mayor importancia, puesto que condiciona la acción de otros factores humorales y/o neurales, tales como producción de endotelina, la inhibición del óxido nítrico o de la prostaciclina, la acción de catecolaminas o de vasopresina, del factor ouabaína-sensible o FDE, del tromboxano A2 (TxA2) y de diversas sustancias vasopresoras endógenas.

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Fisiopatología de la hipertensión arterial: nuevos conceptos

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SIMPOSIO redefinición de la hipertensión arterial

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Tolentino Lavado Christopher Marck (Grupo 5)

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Tolentino Lavado Christopher Marck (Grupo 5)

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http://www.fepreva.org/curso/curso_conjunto_abcba/ut_16.pdf

La hipertensión arterial tiene diversos factores entre los cuales están:
_ El sodio
_ Sistema Renina Angiotensina Aldosterona
_ Sistema Nervioso Simpático y Estrés
_ Endotelio
_ Cambios vasculares y edad

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La fisiopatología de la hipertensión es muy compleja ya que la PA dispone de varios mecanismos de control que actúan integradamente. Esta complejidad se origina en la necesidad del organismo de mantener una adecuada presión de perfusión a nivel de cada célula.  La Figura 3 muestra esquemáticamente los elementos de control de la HA. En forma simple, la PA es una resultante del volumen sistólico y la resistencia periférica, o sea la relación entre contenido y continente en un sistema cerrado.
Los sistemas reguladores de la PA actúan en diferentes tiempos. Los baro y quimiorreceptores son de respuesta inmediata a través del sistema nervioso simpático, en tanto las respuestas hormonales y renales demoran más tiempo en expresarse.

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La hipertensión arterial se caracteriza básicamente por la existencia de una disfunción endotelial, con ruptura del equilibrio entre los factores relajantes del vaso sanguíneo (óxido nítrico –NO-, factor hiperpolarizante del endotelio -EDHF) y los factores vasoconstrictores (principalmente endotelinas). Es conocida la disminución a nivel del endotelio de la prostaciclina vasodepresora y el aumento relativo del tromboxano intracelular vasoconstrictor.
http://www.scielo.org.pe/pdf/afm/v71n4/a03v71n4.pdf

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La presión arterial elevada, es resultado de un gasto cardiaco y una resistencia vascular elevada, que están regulados por procesos hemodinámicos, neurales, humorales y renales. https://dx.doi.org/10.3238%2Farztebl.2018.0557

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Background: Essential arterial hypertension is one of the main treatable cardiovascular risk factors. In Germany, approximately 13% of women and 18% of men have uncontrolled high blood pressure (≥ 140/90 mmHg).

This review is based on pertinent publications retrieved by a selective literature search in PubMed.

Arterial hypertension is diagnosed when repeated measurements in a doctor's office yield values of 140/90 mmHg or higher. The diagnosis should be confirmed by 24-hour ambulatory blood pressure monitoring or by home measurement. Further risk factors and end-organ damage should be considered as well. According to the current European guidelines, the target blood pressure for all patients, including those with diabetes mellitus or renal failure, is <140/90 mmHg. If the treatment is well tolerated, further lowering of blood pressure, with a defined lower limit, is recommended for most patients. The main non-pharmacological measures against high blood pressure are reduction of salt in the diet, avoidance of excessive alcohol consumption, smoking cessation, a balanced diet, physical exercise, and weight loss. The first-line drugs for arterial hypertension include long-acting dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and thiazide-like diuretics. Mineralocorticoid-receptor blockers are effective in patients whose blood pressure cannot be brought into acceptable range with first-line drugs.

Conclusion: In most patients with essential hypertension, the blood pressure can be well controlled and the cardiovascular risk reduced through a combination of lifestyle interventions and first-line antihypertensive drugs.

The World Health Organization estimates that 54% of strokes and 47% of cases of ischemic heart disease are the direct consequence of high blood pressure, which thus takes its place among the main risk factors for cardiovascular morbidity and mortality ( 1). The declining incidence of stroke in recent decades is accounted for in large measure by the reduction of blood pressure ( 2). Even though the epidemiological association between high blood pressure and cardiovascular morbidity and mortality is well known, and despite the fact that sufficient evidence exists to justify antihypertensive treatment ( 3), blood pressure is often not adequately controlled. Either the blood pressure is not measured, or the physician fails to react in the face of elevated blood pressure values ( 4), or treatment is not provided optimally, or the patient fails to take the necessary medication regularly ( 5). In patients who suffer from treatment-resistant arterial hypertension, the blood pressure cannot be adequately controlled even if the patient does take the prescribed medication regularly. In patients with essential hypertension, none of the currently available clinical methods can detect a specific cause of the elevated blood pressure. Causes of secondary hypertension such as renal artery stenosis, hyperaldosteronism, or pheochromocytoma, must be considered in the differential diagnosis, particularly in younger patients and those whose blood pressure is hard to control. Secondary types of hypertension call for specific diagnostic and therapeutic approaches (e.g., a pheochromocytoma must be resected) and will not be discussed here. In what follows, we provide an overview of the epidemiology and pathophysiology of essential arterial hypertension and derive recommendations for the treatment of the affected patients.

Learning objectives

This article should enable the reader to

diagnose arterial hypertension and treat this leading cardiovascular risk factor,

be familiar with the definition of blood pressure target values for treatment, and

know how to treat patients in conformity with the current guidelines.

Methods

A selective search for original articles and reviews was carried out in PubMed with special attention to current guidelines and meta-analyses, which are given here as references. This article is also based on the authors' scientific and clinical experience.

Epidemiology

In the 1990s, the prevalence of arterial hypertension in Germany was still higher than the mean value among other Western countries. German epidemiological data from the years 2008-2011 reveal a decline in the frequency of uncontrolled hypertension from 22% to 13% in women and from 24% to 18% in men (Figure 1) ( 6). Meanwhile, however, the prevalence among men aged 18 to 29 rose from 4.1% to 8.5%.

Pathophysiology

Elevated blood pressure must be due to elevated cardiac output, elevated peripheral vascular resistance, or a combination of both. Each of these mechanisms is regulated, in turn, by hemodynamic, neural, humoral, and renal processes, all of which vary in their contribution from one individual to another (Figure 2). As persons grow older, the predominant cause of hypertension tends to be elevated peripheral vascular resistance, often in combination with increased stiffness of the vessels, which manifests itself clinically as isolated systolic hypertension ( 7). Familial clustering implies a genetic predisposition whose interaction with environmental factors, such as the intake of salt and calories and the degree of physical exercise, ultimately determines how severe the rise of blood pressure will be.

Diagnostic evaluation and screening

In their current, updated joint guidelines on the diagnosis and treatment of arterial hypertension ( 8), the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) retain the threshold value of ≥ 140/90 mm Hg for the definition of high blood pressure when measured in a doctor's office. At least three measurements should be made on each of several days, with 1-2 minutes between measurements and with a 3-5 minute pause before blood pressure is measured with the patient sitting. The optimal conditions for blood pressure measurement should be maintained (Box 1). Measurements from the arm in patients with an arm circumference of 22-32 cm are made with a standard cuff (12-13 cm wide, 35 cm long); for larger upper arms, cuffs that are 15-18 cm wide are available. When the blood pressure is first measured, it should be measured on both sides. If the difference in the values obtained on the two sides is >20 mmHg systolic or >10 mmHg diastolic, the following potential causes must be ruled out, and, if the blood pressure is lower on the left side, the possibility of an aortic isthmus stenosis should be considered:

Aortic arch syndrome due to atherosclerosis, or, rarely, vasculitis;

Unilateral subclavian artery stenosis;

Aortic dissection.

Further measurements are subsequently always made on the arm with the higher values. Orthostatic hypotension is defined as a fall in blood pressure by more than 20 mmHg systolic and/or more than 10 mmHg diastolic after the patient has been standing for three minutes ( 9). If orthostatic hypotension is suspected, particularly in an elderly or diabetic patient, two further measurements should be made 1 and 3 minutes later, with the patient still standing.

The diagnosis should be confirmed by a 24-hour ambulatory measurement or by automated home blood pressure measurements. The values obtained by these methods are usually lower than those obtained in the doctor's office. This fact is taken into account by the lower recommended cutoff values ( 8). A 24-hour ambulatory measurement is also particularly helpful for ascertaining the presence of white-coat hypertension or of masked hypertension.

A patient with white-coat hypertension regularly has an elevated blood pressure in the doctor's office, but normal values when measured at home. The prevalence of this phenomenon in the general population is approximately 13% ( 10). The long-term risk of cardiovascular events may be slightly higher in persons with white-coat hypertension than in persons without it ( 11).

In contrast, masked hypertension is the situation in which the measured blood pressure values are normal in the doctor's office, but elevated at home. It is more common in young people, males, smokers, overweight or diabetic persons, and those suffering from anxiety or stress ( 12). The incidence of cardiovascular events in persons with masked hypertension is similar to that of persons with persistently elevated blood pressure ( 13).

10-15% of persons with hypertension have secondary hypertension due to a potentially treatable cause. If the history and basic diagnostic assessment suggest this possibility (Box 2), a targeted supplementary evaluation should be performed (Table 1). The patient should be asked about his or her intake of substances that elevate blood pressure, including licorice, amphetamines, cocaine, oral contraceptive drugs, mineralo- and glucocorticoids, nonsteroidal anti-inflammatory drugs, erythropoietin, and cyclosporine. Anticancer drugs, particularly angiogenesis inhibitors and tyrosine kinase inhibitors, can also elevate blood pressure.

High blood pressure is usually accompanied by other cardiovascular risk factors that further potentiate the risk. It follows that an evaluation of the patient's overall risk should always be the first objective (Box 3).

According to the current recommendation, the higher the patient's overall cardiovascular risk, the more strictly the blood pressure should be controlled and the earlier drug treatment should be initiated (Figure 4) ( 8). Moreover, before any treatment is given, the potential causes of secondary hypertension should be excluded (Table 1). The possibility of pseudoresistance to treatment due to white-coat hypertension or suboptimal drug compliance should be borne in mind. Compliance can be checked by blood pressure measurement after supervised drug intake, or else by measurement of the active substance(s) in the patient's serum or urine. These factors are too often left out of consideration, even by specialists ( 14). In one study, out of 731 patients carrying the diagnosis of treatment-resistant hypertension, 26.5% actually had either pseudoresistant essential hypertension or a secondary type of hypertension. In 47% of cases, blood pressure became normal after a suitable change in the drug regimen ( 14).

Treatment

Target values for blood pressure

According to the update of the European ESH/ESC guidelines (2 018), all patients, including those with renal failure or diabetes, should have their blood pressure reduced to less than 140/90 mmHg (as measured in the doctor's office) at the beginning of their treatment ( 8). Most patients will tolerate this well; for those who do, a further reduction of blood pressure is recommended. A target blood pressure range is defined, including a lower limit ( 8). For patients aged 18-65, a target systolic blood pressure below 130 mmHg, but no less than 120 mmHg is suggested. The same holds for diabetic patients, whereas the recommendation for patients with renal failure is a somewhat higher target systolic blood pressure range (below 140 mmHg, but no less than 130 mmHg). For patients over age 65, the recommended target systolic blood pressure range is also below 140 mmHg, but no less than 130 mmHg. The target diastolic blood pressure range for all patients, regardless of age, is below 80 mmHg, but no less than 70 mmHg. In elderly patients in particular, attention must be paid to side effects, and the blood pressure target may have to be reset. The available scientific evidence on the treatment of high blood pressure in the elderly is limited, because the elderly are often excluded from clinical trials ( 15).

The German High Blood Pressure League recommends the reduction of blood pressure to less than 135/85 mmHg only in patients who have a high cardiovascular risk ( 16), stating that the advantage of low systolic blood pressure has not yet been demonstrated for hypertensive patients who suffer from diabetes mellitus, have already sustained a stroke, or are physically handicapped or dependent on nursing care.

The U.S. American cardiological societies, in the most recent update of their guidelines, classify blood pressure values in the range of 130-139/85-89 mmHg as grade I hypertension, but state that this should initially be treated without drugs in most cases (Figure 3)( 17, 18). In the updated European guidelines, this is designated as the upper range of normal blood pressure, and it is recommended that drug treatment be considered for patients with blood pressure in this range only if their cardiovascular risk is very high (Figure 4) ( 8). More liberal cutoff values for high blood pressure are set by the United Kingdom's National Institute for Health and Care Excellence (NICE) ( 19), which defines hypertension as an initial measurement ≥ 140/90 mm Hg with subsequent measurements ≥ 135/85 mm Hg (Figure 3).

The association of blood pressure with the occurrence of cardiovascular events in patients at high risk can be depicted by a J-shaped curve: over-aggressive blood pressure reduction (to <120 mmHg systolic or <70 mmHg diastolic) only causes more side effects without any further reduction of cardiovascular events ( 20). On the other hand, the findings of the Systolic Pressure Intervention Trial (SPRINT) contributed to a downward trend in blood pressure cutoff values in the U.S. American and European guidelines. In this trial, 9361 patients over age 50 with a high cardiovascular risk, but without diabetes mellitus, were randomized to systolic blood pressure reduction to either <120 mmHg or <140 mm Hg ( 21). Over a mean follow-up time of 3.26 years, the patients with the lower blood pressure target had a lower incidence of a combined cardiovascular endpoint (hazard ratio [HR]: 0.75, 95% confidence interval: [0.64; 0.89]) and a lower risk of death from a cardiovascular cause (HR: 0.57 [0.38; 0.85]. The patients with the lower blood pressure target achieved a mean systolic blood pressure of 121 mmHg over a three-year period by taking a mean of 2.8 antihypertensive drugs, while those with the lower target achieved a mean systolic blood pressure of 134 mmHg by taking a mean of 1.8 antihypertensive drugs. The automated blood-pressure measurements in this trial were carried out after a five-minute rest period and without medical supervision, resulting in values that were a mean of 12.7/12.0 mmHg lower than those obtained in a conventional doctor's office setting ( 22). It follows that these findings are not directly applicable to routine outpatient care.

A somewhat different picture arose from a Cochrane Review concerning the question whether a reduction of blood pressure by 9.5/4.9 mmHg (down to ≤ 135/85 mmHg from starting values of 140-160/90-100 mmHg) might lower morbidity and mortality in patients already suffering from cardiovascular disease ( 23). Data derived from 9795 subjects, including data from SPRINT, were evaluated; no difference was seen either in overall mortality (relative risk [RR] 1.05 [0.90; 1.22]) or in cardiovascular mortality (RR 0.96 [0.77; 1.21]). Lower blood pressure did, however, lead to a 1.6% absolute risk reduction for fatal and non-fatal cardiovascular events. A further meta-analysis concerned the effects of reducing blood pressure from 150-160/95-105 mmHg to <140/90 mmHg in elderly patients with a mean age of 75 years ( 24). A total of 8221 patients from three different trials were included in this meta-analysis, with SPRINT patients excluded for methodological reasons. There was no statistically significant effect on overall mortality, stroke, or serious cardiovascular events. Overall, it was concluded that there is an individual, relatively narrow blood pressure corridor that can be recommended for each patient on the basis of his or her age, comorbidities, and ability to tolerate the treatment. It remains to be seen whether this concept can be practically applied in routine clinical situations.

Non-pharmacological treatment

The two pillars of antihypertensive treatment are non-pharmacological treatment and drug treatment (Figure 4). Lifestyle changes are always to be considered first as a means of lowering blood pressure ( 8), and it makes sense to maintain these changes even after the later initiation of drug treatment. The most important measures are a low-salt diet, adequate potassium intake, avoidance of excessive alcohol consumption, smoking cessation, a healthy, balanced diet, physical exercise, and weight loss.

In a meta-analysis, the reduction of salt intake from 201 mmol/day (a fairly typical value for the German population) to 66 mmol/day lowered blood pressure by a mean of 5.5/2.9 mmHg in white hypertensive patients ( 25). The effect is variable, however: not every patient benefits from a low-salt diet. Some antihypertensive drugs, particularly inhibitors of the renin-angiotensin-aldosterone system, tend to be more effective if the patient is on a low-salt diet ( 26). According to the ESH/ESC guidelines, daily salt intake should not exceed 5 g ( 8). Potassium intake can be increased by increased consumption of vegetables and fruit.

In randomized controlled trials, regular endurance training lowered blood pressure by a mean of 11/5 mmHg ( 27, 28). The strongest effect was found in patients who exercised during 40- to 60-minute periods at least three times per week. A meta-analysis revealed that regular dynamic strength training can also positively affect blood pressure ( 29, 30).

Overweight and obese persons are at higher risk for arterial hypertension, need more antihypertensive medication, and are more commonly resistant to treatment than patients with normal weight ( 31, 32). It is currently recommended that all persons should have a body-mass index between 20 and 25 kg/m ², with a waist circumference less than 94 cm in men and 80 cm in women ( 14). The value of weight-reducing drugs for obese hypertensive patients is unclear ( 33, 34). The massive weight reduction brought about by bariatric surgery is associated with an initial marked improvement in blood pressure ( 35). Over the long term, however, this effect seems to diminish, and persistent weight reduction by at least 10 kg is needed to lower systolic blood pressure by 6 mmHg [−10.66; −1.38 mmHg] ( 36).

Antihypertensive pharmacotherapy

Drug treatment can be initiated with a single drug or a combined preparation ( 13, 37). The ESC and ESH, in their updated joint guideline, recommend that most patients should take two antihypertensive drugs at the start of pharmacotherapy, preferably combined in a single tablet ( 8). The recommended first line of treatment consists of preparations that are constituted from the following four drug classes: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor subtype 1 (AT1) blockers (sartans), long-acting calcium channel blockers of the dihydropyridine type, and thiazide-like diuretics (Table 2). Even though beta-adrenoreceptor blockers are inferior to these substance classes with respect to cardiovascular protection ( 38), they are considered a suitable component of first-line treatment in some countries. Beta-blockers are used in patients who suffer from angina pectoris, have sustained a myocardial infarction in the past, or have heart failure, or else for the control of heart rate ( 8). On the one hand, the choice of antihypertensive drug is based on individual efficacy and tolerability, for which there are still no good predictors; on the other hand, certain antihypertensive drugs improve outcomes in patients with certain underlying diseases and should, therefore, be used preferentially in these patients (Figure 5). Preparations with a long half-life that can be given once per day are preferable for reasons of compliance. In view of the circadian rhythms of circulatory regulation, it may be better for patients to take long-acting antihypertensive drugs in the evening ( 39), but it remains unclear whether this has any positive effect on cardiovascular events.

ACE inhibitors and AT1 receptor antagonists have been extensively studied in large-scale clinical trials ( 40). They improve the survival of patients with heart failure and have a beneficial effect on diabetic nephropathy, and should therefore be given preferentially to patients with these conditions (Figure 5). They may also lower the risk of developing type 2 diabetes mellitus ( e1). Rising creatinine values and a corresponding drop in the estimated glomerular filtration rate (eGFR) by as much as 30% after the initiation of treatment with an ACE inhibitor or an AT1 receptor antagonist are not infrequently seen, particularly in patients with diabetic nephropathy, and should not necessarily prompt the physician to discontinue these drugs. This phenomenon is due to the desired reduction of the blood pressure faced by the renal glomeruli, resulting in a functional reduction of the eGFR. AT1 receptor antagonists carry a much lower risk of inducing cough and angioedema, but their side-effect profile is similar to that of ACE inhibitors in other respects ( e2).

Calcium channel blockers of the dihydropyridine type are effective antihypertensive drugs and can, in principle, be combined with any other type of first-line antihypertensive drug. Peripheral edema due to peripheral vasodilatation is a common side effect and sometimes leads to discontinuation of the drug ( 18). In a Cochrane analysis, the incidence of peripheral edema was 38% lower when the calcium channel blocker was given in combination with an ACE inhibitor or an AT1 receptor antagonist, probably because of the relaxation of post-capillary resistance vessels brought about by the second drug ( e3). calcium channel blockers can cause or worsen constipation, particularly in elderly and immobile patients. They can also cause clinically significant drug interactions by inhibiting the enzyme cytochrome P450 3A4.

Thiazide-like diuretics have been a mainstay of antihypertensive treatment for decades ( e4). Hydrochlorothiazide is the one most commonly prescribed around the world, even though it seems to be less effective than indapamide or chlorthalidone ( e5). Electrolyte disturbances are a common side effect, especially in elderly patients ( e6); the main types are hyponatremia and hypokalemia. 4.1% of elderly hypertensive patients treated with chlorthalidone had a serum sodium concentration below 130 mmol/L ( e7). The risk of hypokalemia is lower when a thiazide diuretic is given in combination with an ACE inhibitor, an AT1 receptor antagonist, or a potassium-sparing diuretic.

Beta-blockers are inferior to other first-line antihypertensive drugs for the reduction of blood pressure ( 13, e8). They can cause weight gain ( e9). Non-vasodilating beta-blockers have a deleterious effect on glucose metabolism ( e10). Beta-blockers may worsen bronchoconstriction in patients with asthma. Nor should they be combined with verapamil or diltiazem, two drugs that can slow the sinus rhythm or prolong atrioventricular conduction. Beta-blockers do improve the prognosis of patients who have sustained an acute myocardial infarction and/or suffer from chronic congestive heart failure, and they are, therefore, indicated for patients with these conditions, independently of their antihypertensive effect ( 8).

ACE inhibitors and AT1 receptor antagonists are contraindicated during pregnancy. Pregnant women may take older antihypertensive drugs such as dihydralazine and alpha-methyldopa; they may also take beta-blockers, such as metoprolol, and extended-release nifedipine. Dihydralazine and nifedipine, however, should not be given during the first trimester ( e11).

Treatment-resistant hypertension

Even when all of these measures are taken, some 10% of hypertensive patients treated in routine clinical practice do not achieve adequate blood pressure control ( e12, e13). The definition of treatment-resistant hypertension is blood pressure that persistently remains over 140/90 mmHg despite treatment with three antihypertensive drugs in optimal doses, one of which is a diuretic. The definition also requires the exclusion of potential causes of secondary hypertension. Treatment-resistant hypertension often turns out to be treatable once the matter of patient compliance and the potential for further improvement of the drug regimen have been properly addressed; in our experience, the true prevalence of treatment-resistant hypertension is closer to 4-5%. In these patients, the therapeutic spectrum must be widened in order to counteract the still unaltered, high cardiovascular risk.

The treatment should be directed against two main pathophysiological mechanisms: overactivity of the sympathetic nervous system and volume excess due to excessive sodium retention, renal failure, or an excessively high aldosterone level. Hypervolemia can be countered with high-dose diuretics or with supplementary treatment with a mineralocorticoid-receptor antagonist. This was confirmed in the Pathway 2 trial ( e14): 285 hypertensive patients whose mean blood pressure, measured in the doctor's office, was 157/90 mmHg under standard treatment with an ACE inhibitor or AT1 blocker, a calcium antagonist, and a diuretic at the highest tolerated doses were given either spironolactone (25-50 mg), doxazosine (4-8 mg), bisoprolol (5-10 mg), or placebo for a period of 12 weeks in a double-blind crossover trial. If tolerated, the dose was doubled at 6 weeks. Absolute reduction of blood pressure was most pronounced with spironolactone (values of −12.8 mm Hg, −8.7 mm Hg, −8.3 mm Hg, and -4.1 mmHg, respectively). Blood pressure became normal under this treatment in 58% of patients. The frequency of serious side effects and the treatment discontinuation rate did not differ among treatment groups. Elevated activity of the sympathetic nervous system ( e15) also provides the rationale for some of the interventional techniques that have been developed for this group of patients.

Conclusion

The treatment of arterial hypertension with a combination of lifestyle interventions and drugs can markedly lower cardiovascular risk. In most patients, blood pressure can be lowered effectively with first-line antihypertensive drugs, but monotherapy often does not suffice. With regard to blood pressure target values, many questions remain open. We expect that the newly altered target values will give rise to a lively discussion of their advantages and potential risks in the very near future.

Conflict of interest statement
Prof. Jordan has served as a paid scientific consultant for Bayer, Eternygen, Johnson & Johnson, Novartis, Novo-Nordisk, and Theravance. He is a co-founder of Eternygen GmbH.

Prof. Reuter has received lecture fees from, and has served as a paid consultant for, Bayer, Cordis, CVRx, Medtronic, and Servier.

Prof. Kurschat states that he shas no conflict of interest.

Corresponding author
Prof. Dr. med. Jens Jordan

Institut für Luft- und Raumfahrtmedizin
Deutsches Zentrum für Luft- und Raumfahrt (DLR)

Linder Höhe,D-51147 Cologne, Germany
jens.jordan@dlr.de

► Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref3318

8.

Williams B, Mancia G, et al.: 2018 ESC/ESH guidelines on hypertension. J Hypertens 2018; in press.

18.

National Institute for Health and Care Excellence: Hypertension in adults: diagnosis and management. www.nice.org.uk/guidance/CG127 (last accessed on 13 July 2018).

35.

Schiavon CA, Bersch-Ferreira AC, Santucci EV, et al.:
Effects of bariatric surgery in obese patients with hypertension: The GATEWAY randomized trial. Circulation 2018; 137: 1132-42 CrossRef MEDLINE PubMed Central

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Deutscher Ärzteverlag GmbH, Redaktion Deutsches Ärzteblatt

# data[].attributes.attachment_link.description
Background: Essential arterial hypertension is one of the main treatable cardiovascular risk factors. In Germany, approximately 13% of women and 18% of men have uncontrolled high blood pressure (≥ 140/90 mmHg). This review is based on pertinent publications retrieved by a selective literature search in PubMed.

# data[].attributes.body
http://www.scielo.org.pe/scielo.php?script=sci_arttext&pid=S2304-51322018000200004La fisiopatologia de la HTA esta dada por distintos mecanismos, en las cuales intervienen el Sistema renina-angiotensina-aldosterona (el que tiene mayor importancia puesto que, de algún modo, condiciona la acción de otros factores humorales y/o neurales, tales como producción de endotelina, la inhibición del óxido nítrico (NO) o de la prostaciclina (PGI2), la acción de catecolaminas o de vasopresina (AVP), del factor ouabaína-sensible o FDE, del tromboxano A2 (TxA2) y de diversas sustancias vasopresoras endógenas.

# data[].attributes.attachment_link.title
Fisiopatología de la hipertensión arterial: nuevos conceptos

# data[].attributes.attachment_link.description
SIMPOSIO redefinición de la hipertensión arterial

# data[].attributes.body
Diversos factores están implicados en la fisiopatología de la hipertensión arterial esencial. El elemento básico es la disfunción endotelial y la ruptura del equilibrio entre los factores vasoconstrictores (principalmente endotelinas) y los vasodilatadores (principalmente óxido nítrico).  La modulación de la función endotelial es una opción terapéutica atractiva para intentar minimizar algunas de las complicaciones importantes de la hipertensión.

# data[].attributes.body
La acción de la renina producida por el riñón, actuando sobre angiotensinógeno produce angiotensina I, la cual es a su vez catalizada por la enzima de conversión de la angiotensina (ECA) en angiotensina II. La angiotensina II estimula en las glándulas suprarrenales la producción y liberación de aldosterona, la cual favorece la reabsorción de sodio en el túbulo renal, incrementando el intercambio sodio-potasio.
http://www.scielo.org.pe/scielo.php?script=sci_arttext&pid=S2304-51322018000200004

# data[].attributes.attachment_link.title
Fisiopatología de la hipertensión arterial: nuevos conceptos

# data[].attributes.attachment_link.description
SIMPOSIO redefinición de la hipertensión arterial

# data[].attributes.body
La fisiopatología de la hipertensión arterial es compleja, pues intervienen múltiples factores que, en su mayoría, tienen una base genética. Se ha podido mostrar que es el sistema renina–angiotensina–aldosterona (SRAA) el que tiene mayor importancia, puesto que condiciona la acción de otros factores humorales y/o neurales, tales como producción de endotelina, la inhibición del óxido nítrico o de la prostaciclina, la acción de catecolaminas o de vasopresina, del factor ouabaína–sensible o FDE, del tromboxano A2 (TxA2) y de diversas sustancias vasopresoras endógenas. Se presenta en este artículo una revisión exhaustiva de lo que conocemos hoy acerca del SRAA. Y se incluye algunas novedades de la investigación del SRAA.

# data[].attributes.body
La fisiopatología arterial intervienen múltiples factores, pero se ha podido mostrar que es el sistema renina-angiotensina-aldosterona (SRAA) es el que tiene mayor importancia, puesto que condiciona la acción de otros factores humorales y/o neurales, tales como producción de endotelina, la inhibición del óxido nítrico o de la prostaciclina, la acción de catecolaminas o de vasopresina, , del tromboxano A2 (TxA2) y de diversas sustancias vasopresoras endógenas.

# data[].attributes.attachment_link.title
Fisiopatología de la hipertensión arterial: nuevos conceptos

# data[].attributes.attachment_link.description
SIMPOSIO redefinición de la hipertensión arterial

# data[].attributes.body
La HTA está determinada por varios parámetros, los cuales son:
- Sistema renina-angiotensina-aldosterona
- Papel de los péptidos natriuréticos
- El endotelio
- Sistema nervioso simpático.
- Sistema inmunitario.

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Nat Rev Dis Primers. Author manuscript; available in PMC 2019 Apr 23.

Published in final edited form as:

Suzanne Oparil, ¹ Maria Czarina Acelajado, ² George L. Bakris, ³ Dan R. Berlowitz, 4, ⁵ Renata Cífková, ⁶ Anna F. Dominiczak, ⁷ Guido Grassi, 8, ⁹ Jens Jordan, ¹⁰ Neil R. Poulter, ¹¹ Anthony Rodgers, ¹² and Paul K. Whelton ¹³

Abstract

Systemic arterial hypertension is the most important modifiable risk factor for all-cause morbidity and mortality worldwide and is associated with increased risk of cardiovascular disease (CVD). Fewer than half of those with hypertension are aware of their condition, and many others are aware but not treated or inadequately treated, although successful treatment of hypertension reduces the global burden of disease and mortality. The aetiology of hypertension involves the complex interplay of environmental and pathophysiological factors that affect multiple systems, as well as genetic predisposition. Evaluation of patients with hypertension includes accurate standardized blood pressure (BP) measurement, assessing patients' predicted risk of atherosclerotic CVD, evidence of target organ damage, detection of secondary causes of hypertension and presence of comorbidities, including CVD and kidney disease. Lifestyle changes, including dietary modifications and increased physical activity, are effective in lowering BP and preventing hypertension and its CVD sequelae. Pharmacological therapy is very effective in lowering BP and preventing CVD outcomes in most patients; first line antihypertensive medications include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, dihydropyridine calcium channel blockers and thiazide diuretics.

INTRODUCTION

Systemic arterial hypertension (hereafter referred to as hypertension) is characterized by persistently high blood pressure (BP) in the systemic arteries. BP is commonly expressed as the ratio of the systolic BP (that is, the pressure that the blood exerts on the arterial walls when the heart contracts) and the diastolic BP (the pressure when the heart relaxes). The BP thresholds that define hypertension depend on the measurement method ( Table 1 ). Several aetiologies can underlie hypertension. The majority (90-95%) of patients have a highly heterogeneous 'essential' or primary hypertension with a multifactorial gene-environment aetiology. A positive family history is a frequent occurrence in patients with hypertension, with the heritability (a measure of how much of the variation in a trait is due to variation in genetic factors) estimated between 35% and 50% in the majority of studies1,2. Genome-wide association studies (GWAS) have identified ~120 loci that are associated with BP regulation and together explain 3.5% of the trait variance3,4,5. These findings are becoming increasingly important as we search for new pathways and new biomarkers to develop more-modern 'omics'-driven diagnostic and therapeutic modalities for hypertension in the era of precision medicine6.

Table 1 -

Category

Subtype

Systolic BP (mmHg)

Diastolic BP (mmHg)

Office BP

NA

≥ 140

≥ 90

Ambulatory BP

Daytime (awake)

≥ 135

≥ 85

Night time (asleep)

≥ 120

≥ 70

24hr

≥ 130

≥ 80

Home BP

NA

≥ 135

≥ 85

Several rare, monogenic forms of hypertension have been described (for example, the Liddle syndrome, glucocorticoid-remediable aldosteronism (a mineralocorticoid excess state) and mutations in PDE3A (which encodes cGMP-inhibited 3',5'-cyclic phosphodiesterase A)), in which a single gene mutation fully explains the pathogenesis of hypertension and indicates the best treatment modality7,8,9. If hypertension is caused by another condition (for example, primary aldosteronism, pheochromocytoma (a neuroendocrine tumour of the adrenal glands or other neuroendocrine tissues) or renal artery stenosis), it is referred to as secondary hypertension.

Hypertension is the most common preventable risk factor for cardiovascular disease (CVD; including coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation and peripheral artery disease), chronic kidney disease (CKD) and cognitive impairment, and is the leading single contributor to all-cause death and disability worldwide10. The relationship between BP and the increased risk of CVD is graded and continuous, starting as low as 115/75 mmHg, well within what is considered to be the normotensive range. Successful prevention and treatment of hypertension are key in reducing disease burden and promoting longevity in the world's population. In treating hyperteinsion, it is important to consider a person's predicted atherosclerotic CVD (ASCVD) risk more than the level of BP alone, as persons with high CVD risk derive the greatest benefit from BP lowering treatment11.

This Primer will discuss the epidemiology and pathophysiology of primary hypertension, prevention strategies for slowing the progression of BP elevation, management strategies (including optimal BP targets) for lowering BP and preventing CVD outcomes in patients with established hypertension and the effects of antihypertensive treatment on quality of life; finally, we will explore knowledge gaps, future trends and the outlook for hypertension research and treatment over the next decade.

EPIDEMIOLOGY

As economic development progresses, hypertension initially affects those with a high socioeconomic status, but at later stages of economic development, the prevalence of hypertension and its consequences are greatest in those with lower socioeconomic status; this phenomenon is seen both within and between countries. Further, the speed of change prevalence of hypertension since 2000 to 2010 has been much more rapid than in previous epidemiological transitions15.

Disease burden

Globally, 3.5 billion adults now have non-optimal systolic BP levels (that is, >110-115 mmHg) and 874 million adults have systolic BP ≥140 mmHg. Thus, approximately one in four adults has hypertension16. Between 1990 and 2015 there was a 43% increase in the total global number of healthy life years lost to non-optimal BP, driven by population increase, population aging and a 10% increase in the age-standardized prevalence of hypertension16. The Global Burden of Disease study has shown that non-optimal BP continues to be the biggest single risk factor contributing to the global burden of disease and to global all-cause mortality, leading to 9.4 million deaths and 212 million lost healthy life years (8.5% of the global total) each year10.

CVD risk

Prospective observational studies have repeatedly demonstrated a strong, continuous positive relationship between BP and CVD, with no evidence of a threshold for risk throughout the usual range of BP observed in clinical practice. The relationship between BP and CVD applies to both systolic BP and diastolic BP, but is somewhat more robust for systolic BP in adults19. It is noted in both sexes, at all ages throughout adulthood and for all major manifestations of CVD, including stroke (ischaemic and haemorroagic), coronary artery disease, heart failure, peripheral vascular disease and end stage renal disease (although there are variations in the strength of the associations and the slopes of the curves)17,18,19,20 ( Figure 1 ). The relationship is independent of other CVD risk factors, and level of BP has proven to be a major component of CVD risk in all prediction models21. Approximately two-thirds of all adults who have hypertension or receive treatment with BP lowering medication at 30 years of age have a ~40 % higher risk of experiencing a CVD event than their age-matched and sex-matched counterparts with a lower level of BP18. In addition, CVD events in individuals with hypertension tend to manifest about five years earlier than in individuals with a lower level of BP18.

In individuals of 40-69 years of age, a 20 mmHg rise of systolic BP or a 10 mmHg rise of diastolic BP regardless of baseline values is associated with more than a doubling of the risk for stroke or ischaemic heart disease mortality17, whereas a systolic BP reduction of 5 mmHg can decrease stroke mortality by 14% and CVD mortality by 9%. At older ages (≥80 years), the corresponding relative risk is slightly lower, but the absolute risk is far greater than earlier in life17. For example, a 20 mm Hg difference in systolic BP between 120 and 140 mmHg is associated with an annual difference in absolute risk that is nearly ten times larger at ages 80-89 years than that at ages 50-59 years17.

MECHANISMS/PATHOPHYSIOLOGY

BP regulation

BP is determined by several parameters of the cardiovascular system, including blood volume and cardiac output (the amount of blood pumped by the heart per minute) as well as the balance of arterial tone that is affected by both intravascular volume and neurohumoral systems (discussed in the following sections). The maintenance of physiological BP levels involves a complex interplay of various elements of an integrated neurohumoral system that includes the renin-angiotensin-aldosterone system (RAAS), the role of natriuretic peptides and the endothelium, the sympathetic nervous system (SNS) and the immune system ( Figure 2 ). Malfunction or disruption of factors involved in BP control in any of these systems can directly or indirectly lead to increases in mean BP, BP variability or both, over time resulting in target organ damage (for example, left ventricular hypertrophy and CKD) and CVD outcomes22.

The pathophysiological mechanisms responsible for hypertension are complex and act on a genetic background. Primary hypertension involves multiple types of genes; some allelic variants of several genes are associated with an increased risk of developing primary hypertension and are linked in almost all cases to a positive family history ( Box 1) This genetic predisposition, along with a host of environmental factors, such as high Na⁺ intake, poor sleep quality or sleep apnoea, excess alcohol intake and high mental stress, contribute to the development of hypertension. Finally, the probability of developing hypertension increases with aging, owing to progressive stiffening of the arterial vasculature caused by, among other factors, slowly developing changes in vascular collagen and increases in atherosclerosis. Immunological factors can also play a major part, especially on the background of infectious or rheumatological diseases such as rheumatoid arthritis. The mosaic theory of hypertension describes its multifaceted pathophysiology28,29.

Box 1.

A large GWAS of 2.5 million genotyped single nucleotide polymorphisms (SNPs) in >69,000 individuals of European ancestry from 29 studies demonstrated that most SNPs related to BP regulation and CVD risk involved natriuretic peptides198. SNPs in genes that encode precursors for ANP and BNP had been previously identified199, and two other loci were identified in this study, containing genes involved in natriuretic peptide and NO signalling pathways; both these pathways regulate cyclic guanosine monophosphate, which promotes vasodilation. A 2016 study identified 66 BP-associated loci, which were enriched for cis-regulatory elements in vascular endothelial cells, consistent with a role in BP control through modulation of vascular tone. This information prompted development of a genetic risk score to predict target organ damage4.

Gene deletion studies in rodent models have evaluated cardiac ANP and BNP as paracrine regulators of vascular regeneration. Deletion of the genes encoding ANP and BNP exaggerates cardiac fibrosis and increase adverse left ventricular (LV) remodelling38, and natriuretic peptide receptor A (NPRA) deficiency leads to increased BP, severe fibrosis and LV dysfunction. Further, deletion of the gene encoding the endothelial guanylyl cyclase-A (GC-A) receptor, a cell surface receptor for natriuretic peptides, leads to diminished vascular regeneration and angiogenesis in response to critical hind limb ischemia, as well as cardiac fibrosis and diastolic dysfunction.

Further, clinical studies have observed an association between certain corin gene polymorphisms and risk of pre-eclampsia and hypertension, particularly among African-American but not Chinese populations200.

Sodium homeostasis regulation

Sodium (Na⁺) is a crucial regulator of blood volume: high serum Na⁺ concentration promotes fluid (water) retention, thereby increasing blood volume and BP. When dietary Na⁺ increases in normotensive individuals, compensatory haemodynamic changes occur to maintain constant BP. These changes include reduction in renal and peripheral vascular resistance and increased production of nitric oxide (a vasodilator) from the endothelium. However, if the effect of nitric oxide is impaired or absent, an increase in BP occurs. Endothelial dysfunction is a risk factor for the development of salt sensitivity and subsequent hypertension. Salt sensitivity is defined as a marked elevation in BP following a Na⁺ load of ≥5 g and is characterized by an elevation of systolic BP of at least 10 mmHg within a few hours of ingestion. Salt sensitive individuals have underlying endothelial dysfunction due to genetic or environmental influences. In response to a high salt load these individuals generally manifest overproduction of transforming growth factor β (TGF-β), which increases the risk of fibrosis, and oxidative stress, and have limited bioavailable nitric oxide. Chronic high salt ingestion can result in endothelial dysfunction, even in salt-resistant individuals30, and also affects the gut microbiota, with resultant changes that contribute to increased salt sensitivity and the development of hypertension31. High salt intake also appears to drive autoimmunity by inducing T helper 17 (T H17) cells31. High salt intake in mice has been shown to deplete Lactobacillus murinus in the gut microbiota. Treatment of mice with L. murinus prevented salt-induced exacerbation of salt-sensitive hypertension by modulating T H17 cells31. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased the activity of T H17 cells and increased BP31. Thus, the gut microbiota appears to contribute to salt sensitivity of BP and the pathogenesis of hypertension.

Renin-Angiotensin-Aldosterone System

The RAAS has wide-ranging effects on BP regulation, mediating Na⁺ retention, pressure natriuresis (that is, the mechanism whereby increases in renal perfusion pressure (the gradient between renal arterial and venous blood pressure) lead to decreased Na⁺ reabsorption and increased Na⁺ excretion), salt sensitivity, vasoconstriction, endothelial dysfunction and vascular injury, and plays an important part in the pathogenesis of hypertension22. The RAAS is present at the cellular level in many organs, but its most crucial role is to help regulate pressure-volume homeostasis in the kidney, where it maintains perfusion in volume depleted states (that is, when there is a reduction in extracellular fluid volume as a result of sodium and fluid loss) and is suppressed in volume expanded (fluid overload) conditions. Renin and its precursor pro-renin are synthesized and stored in the juxtaglomerular cells of the kidney and are released in response to various stimuli ( Figure 3 ). The main function of renin is to cleave angiotensinogen to form angiotensin I. Angiotensin-converting enzyme (ACE) cleaves angiotensin I to form angiotensin II, which is at the center of the pathogenetic role of the RAAS in hypertension ( Figure 3 )32..

Angiotensin II enhances Na⁺ reabsorption in the proximal tubule by increasing the activity of the sodium-hydrogen exchanger (NHE3), sodium-bicarbonate exchanger and sodium-potassium ATPase, and by inducing aldosterone synthesis and release from the adrenal glomerulosa22. Angiotensin II is also associated with endothelial dysfunction and has pro-fibrotic and pro-inflammatory effects, mediated in large part by increased oxidative stress, resulting in renal, cardiac and vascular injury. Angiotensin II is tightly linked to target organ damage in hypertension via these mechanisms22..

Angiotensin-converting enzyme 2 (ACE2) has emerged as an important modulator in the pathophysiology of hypertension, CVD and renal disease, owing to its role in metabolizing angiotensin II into angiotensin-(1-7)33. Ang-(1-7) induces systemic and regional vasodilation, diuresis and natriuresis, and exerts antiproliferative and antigrowth effects on vascular smooth muscle cells, cardiac myocytes and fibroblasts as well as glomerular and proximal tubular cells33. Ang-(1-7) also has cardiorenal protective effects that are mediated by the proto-oncogene Mas receptor through signalling pathways that include mitogen-activated protein kinases (MAPK), PI3K-AKT, NADPH oxidase, TGF-β1, the EGF receptor, and NF-κB activity.

Aldosterone plays a crucial part in hypertension: by binding to the mineralocorticoid receptor, it induces non-genomic effects (that is, without directly modifying gene expression) that include activation of the amiloride-sensitive sodium channel, commonly known as the epithelial sodium channel (ENaC) and result in the stimulation of renal Na⁺ reabsorption in the cortical collecting duct36. Aldosterone also has many non-epithelial effects that contribute to endothelial dysfunction, vasoconstriction and hypertension36,37. These include vascular smooth muscle cell proliferation, vascular extracellular matrix deposition, vascular remodeling, fibrosis, and increased oxidative stress36,37.

Natriuretic Peptides

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) play an important part in salt sensitivity and hypertension. They have important natriuretic and vasodilator properties that allow maintenance of Na⁺ balance and BP during Na⁺ loading38,39. Upon administration of a Na⁺ load, atrial and ventricular stretch leads to release of ANP and BNP, respectively, which leads to systemic vasodilation and decreased plasma volume (owing to fluid shifts from the intravascular to the interstitial compartment) and results in BP lowering40. Natriuretic peptides increase glomerular filtration rate via an increase in efferent arteriolar tone in volume-expanded states and inhibit renal Na⁺ reabsorption through both direct and indirect effects. Direct effects include decreased activity of Na⁺-K⁺-ATPase and the sodium-glucose co-transporter in the proximal tubule and inhibition of the epithelial sodium channel in the distal nephron. Indirect effects include inhibition of renin and aldosterone release39.

Natriuretic peptide deficiency promotes hypertension. Corin is a serine protease that is largely expressed in the heart and converts the ANP and BNP precursors pro-ANP and pro-BNP to their active forms. Corin deficiency has been associated with volume overload, heart failure and salt-sensitive hypertension41. Natriuretic peptide deficiency also predisposes to insulin resistance and type 2 diabetes mellitus. Obesity is associated with natriuretic peptide deficiency, probably through upregulation of the natriuretic peptide scavenger receptor NPR-C in adipose tissue42. Natriuretic peptides have therapeutic potential for the metabolic syndrome; the metabolic syndrome is a cluster of conditions (including high BP, high fasting glucose levels, abdominal obesity, high triglycerides and microalbuminuria) that occur together, increasing the risk of CVD and diabetes mellitus42.

The Endothelium

The endothelium is a major regulator of vascular tone and major contributor to salt sensitivity through NO. Endothelial cells produce a host of vasoactive substances, of which NO is the most important in BP regulation43,44. NO is continuously released by endothelial cells in response to flow-induced shear stress, leading to vascular smooth muscle relaxation through activation of guanylate cyclase and generation of intracellular cyclic guanosine monophosphate45. Interruption of NO production via inhibition of constitutively expressed endothelial NO synthase (eNOS) causes BP elevation and development of hypertension in animals and humans46. Studies to evaluate NO activity in humans have demonstrated decreased whole-body production of NO in patients with hypertension compared with normotensive controls46,47.

Endothelial cells also secrete a variety of other vasoregulatory substances, including vasodilators such as prostacyclin and endothelium-derived hyperpolarizing factors, and vasoconstrictors such as endothelin 1 (ET-1), locally generated angiotensin II and the prostanoids thromboxane A2 and prostaglandin A2. ET-1 is a potent vasoconstrictor that activates ET-A receptors in vascular smooth muscle48. Other vasodilating substances, secreted by a variety of cells types, such as calcitonin gene related peptide, adrenomedullin and substance P act primarily through increases in NO release from endothelial cells49,50. The glucose-regulating gut hormone glucagon-like peptide-1 (GLP-1) also has vasodilating properties51. The balance between these factors, along with NO and ET-1, determines the final effect of the endothelium on vascular tone52,48,53,51. Circulating ET-1 levels are not consistently increased in hypertension, but there is a trend toward increased sensitivity to the vasoconstrictor and hypertensive effects of ET-1 in individuals with hypertension53. ET-A receptor antagonists attenuate or abolish hypertension in a variety of experimental models and are effective in lowering BP in humans48,53.

Endothelial dysfunction plays a seminal part in the pathogenesis of hypertension. Normotensive offspring of parents with hypertension often have impaired endothelium-dependent vasodilation, which implies a genetic component in the development of endothelial dysfunction47. Endothelial dysfunction in the setting of chronic hypertension is related to a combination of direct pressure-induced injury and increased oxidative stress. Several enzyme systems, including NADPH oxidase, xanthine oxidase and cyclooxygenase, as well as decreased activity of superoxide dismutase generate reactive oxygen species47,54. Excess superoxide anions bind to NO, decreasing NO bioavailability and generating the pro-inflammatory oxidant, peroxynitrite. Decreased NO bioavailability is the central factor that links oxidative stress to endothelial dysfunction and hypertension47. Salt-sensitive individuals may be very sensitive to the hemodynamic stress of increased blood volume, leading to overproduction of TGF-beta, oxidative stress, and limiting bioavailable NO30. Angiotensin II, along with other factors, including cyclic vascular stretch as a result of BP changes, endothelin-1 (ET-1), uric acid, systemic inflammation, norepinephrine, free fatty acids, and tobacco smoking, enhances NADPH oxidase activity and plays a central part in the generation of oxidative stress in hypertension52.

Sympathetic Nervous System

Baroreceptors, mechanoreceptors that sense pressure changes of the circulatory system, are housed in various locations in the arterial tree, a key place being the carotid sinus, a dilated area at the base of the internal carotid artery just superior to bifurcation of the common carotid artery. When this artery is stretched by elevated BP, nerve bundles projecting from the baroreceptors in the carotid sinus send messages to the brain to reduce sympathetic outflow of nerve impulses or nerve traffic and, thereby, BP. The SNS is generally more activated in persons with hypertension than in normotensive individuals.58,59 SNS activity is also greater in individual with obesity, in men than in women, in younger than in older persons, and in those with advanced kidney disease.60,61 Many patients with hypertension are in a state of autonomic imbalance with increased sympathetic and decreased parasympathetic activity59,62. SNS hyperactivity is relevant to both the generation and maintenance of hypertension. Studies in humans have also identified markers (such as increased catecholamine spillover and sural nerve activity assessed by microneurography) of sympathetic overactivity in normotensive individuals with a family history of hypertension63. Among patients with hypertension, increasing severity of hypertension is associated with increasing levels of sympathetic activity measured by microneurography64,65. Plasma catecholamine levels, microneurographic recordings and systemic catecholamine spillover (the amount of catecholamines released from sympathetic nerves innervating blood vessels that enter the bloodstream) studies have given evidence of increased sympathetic activity in patients with hypertension who are obese, in those with the metabolic syndrome, and in those whose hypertension is complicated by heart failure or kidney disease65.

The importance of the SNS in the pathogenesis of hypertension has been defined in a variety of experimental models. Models of obesity-related hypertension demonstrate that increased renal sympathetic nerve activity and its attendant increase in renal sodium reabsorption are key factors in the maintenance of sustained hypertension62. In another animal model, rats that received daily infusions of phenylephrine for 8 weeks developed hypertension during the infusions; their BP normalized under a low salt diet after discontinuation of phenylephrine, but once re-challenged with a high salt diet, the animals became hypertensive again30. The degree of BP elevation on the high salt diet was directly related to the degree of renal tubulo-interstitial fibrosis and decrease in glomerular filtration rate, suggesting that catecholamine-induced hypertension causes renal interstitial injury and a salt-sensitive phenotype that persists even after sympathetic overactivity is no longer present. In addition, enhanced SNS activity results in alpha-1 adrenergic receptor mediated endothelial dysfunction, vasoconstriction, vascular smooth muscle proliferation and increased arterial stiffness, which contribute to the development and maintenance of hypertension66. Finally, there is evidence that sympathetic overactivity enhances salt-sensitivity owing to a reduction in activity of the WNK lysine deficient protein kinase 4 ( WNK4) gene, which encodes a serine/threonine kinase that inhibits the thiazide-sensitive-Na-Cl co-transporter, resulting in increased distal tubular Na⁺ retention67. These mechanisms have been reviewed recently66.

Inflammation and the immune system

Inflammation makes an important contribution to the genesis of hypertension and related target organ damage. Inflammation is associated with increased vascular permeability and release of potent mediators, such as reactive oxygen species, NO, cytokines and metalloproteinases. Cytokines mediate the formation of neo-intima (a new or thickened layer of arterial intima), thereby decreasing the lumen diameter of resistance vessels (small arteries and arterioles highly innervated by autonomic nerves and the primary vessels involved in the regulation of BP), and promoting vascular fibrosis, leading to increased vascular resistance and stiffness. Cytokines also affect renal tubular function by increasing local synthesis of angiotensinogen and angiotensin II, as well as promoting sodium and volume retention in hypertension68. Matrix metalloproteinases stimulate the degradation of the extracellular matrix, allowing infiltration of immune cells through the vessel wall into the interstitium of the affected organs, promoting apoptosis and enhancing collagen synthesis and matrix deposition, leading to target organ damage68.

While animal data are clear about the relationship between inflammation and hypertension, the data in humans are limited. There are associations between C-reactive protein, TNF-alpha and various interleukins and hypertension, but no direct link68. GWASs have identified a single nucleotide polymorphism of SH2B3 (SNP rs3184504), which results in an amino acid substitution in SH2B adapter protein 3 (a protein involved in T cell receptor activation and signalling), that is associated with many autoimmune and cardiovascular disorders, including hypertension69. Further, drugs that are used to treat inflammation, such as non-steroidal anti-inflammatory drugs and cyclosporine, raise rather than lower BP in hypertensive individuals, highlighting the complex nature of the relationship between inflammation and hypertension69.

Both innate and adaptive immune responses participate in the generation of reactive oxygen species and inflammatory changes in the kidneys, blood vessels and brain in hypertension68,70. Innate immune responses, especially those mediated by macrophages, have been linked to hypertension induced by angiotensin II, aldosterone and NO antagonism68,70. Reductions in macrophage infiltration of the kidney or the peri-adventitial space of the aorta and medium sized arteries lead to reductions in BP and salt-sensitivity68. Adaptive immune responses via T cells have also been linked to the genesis of hypertension and its target organ damage. T cells express AT1 receptors and mediate angiotensin II-dependent hypertension,70 and it has been shown that depletion of mature lymphocytes ameliorated hypertension and kidney injury resulting from a high-salt diet in the Dahl SS rat71. Thus, a balance between proinflammatory T cell reactivity and inflammatory suppression induced by T regulatory cells determines the development of hypertension, as demonstrated by the amelioration of hypertension with the adoptive transfer of T regulatory cells in several animal models of hypertension68-70. Abnormalities in both pro-inflammatory T cells and regulatory T cells are implicated in hypertension-induced target organ damage, as they regulate the inflammatory processes in the kidney and vasculature that underlie hypertension-induced kidney disease

DIAGNOSIS, SCREENING AND PREVENTION

Diagnosis and screening

Essential or primary hypertension is usually asymptomatic; thus, in clinical practice all adults should have their BP measured at regular office visits. Hypertension is most commonly diagnosed based on repeated BP measurements in a clinical office setting. Accurate measurement and recording of BP is essential to categorize the level of BP, ascertain BP-related CVD risk and guide management. Since 2010, methods to measure out-of-office BP have been increasingly introduced to guide diagnosis and treatment of hypertension72,73. Table 1 These include home BP monitoring (HBPM) and ambulatory BP monitoring (ABPM). HBPM refers to the measurement of BP at regular intervals by an individual at their home or elsewhere outside the clinic setting. ABPM consists of measuring and recording the BP at regular intervals (usually every 20-30 minutes), typically for the 24-hour period and while individuals go about their daily activities. The ability to measure out-of-office BP has enabled the identification of distinct BP phenotypes, including white coat or isolated clinic hypertension and masked or isolated ambulatory hypertension74,75. White coat hypertension is characterised by elevated office BP but normal ABPM or HBPM readings. By contrast, masked hypertension is characterised by normal office readings but elevated out -of-office readings ( ABPM and HBPM )74,75.

Diagnosis

The evaluation of a patient with hypertension requires more than the diagnosis of elevated BP. It should also include assessment of the CVD risk, target organ damage, and concomitant clinical conditions that may affect the BP or related target organ damage as well as recognition of features suggestive of secondary hypertension. Some of these investigations are routine tests necessary in all patients, but others only in specific patient groups identified by history, clinical examination, and routine tests. In rare inherited forms of hypertension, a single gene mutation explains the pathogenesis of hypertension7,8,9. ( Figure 4 ) A small proportion of patients have a potentially reversible cause of hypertension, and a correct diagnosis might lead to a cure or a substantial improvement in BP control with a reduction of CVD risk. It is therefore appropriate to implement a simple screening for secondary hypertension in all patients. The screening is based on clinical history, physical examination and routine laboratory investigations ( Box 2 and 3). Secondary hypertension should also be considered in cases of a sudden worsening of hypertension, poor BP response to drug treatment or severe target organ damage, which is out of proportion to the duration and severity of hypertension. In these cases, specific diagnostic tests are indicated ( Table 2 ).

Table 2 -

Possible causes

Clinical indications

Diagnostics

Clinical history

Physical examination

Laboratory investigations

First-line test(s)

Additional confirmatory test(s)

Common causes

Renal parenchymal disease

● History of urinary tract infection or obstruction, haematuria (blood in the urine), analgesic abuse
● family history of polycystic kidney disease

Abdominal masses (in case of polycystic kidney disease)

● Presence of protein, erythrocytes, or leucocytes in the urine
● decreased GFR

Renal ultrasound

Detailed work-up for kidney disease

Renal artery stenosis

● Fibromuscular dysplasia: early onset hypertension (especially in women).
● Atherosclerotic stenosis: hypertension of abrupt onset, worsening or increasingly difficult to treat; flash pulmonary oedema

Abdominal bruit (abnormal sound)

● Difference of >1.5 cm in length between the two kidneys (renal ultrasound),
● rapid deterioration in renal function (spontaneous or in response to RAA blockers)

Renal Duplex Doppler ultrasonography

● Magnetic resonance angiography,
● spiral computed tomography
● intra-arterial digital subtraction angiography

Primary aldosteronism

● Muscle weakness
● family history of early onset hypertension and cerebrovascular events at <40 years of age

Arrhythmias (in case of severe hypokalaemia)

● Hypokalaemia (spontaneous or diuretic-induced)
● incidental discovery of adrenal masses

Aldosterone-renin ratio under standardized conditions (corrected hypokalaemia and withdrawal of drugs affecting RAA system)

● Confirmatory tests (oral sodium loading, saline infusion, fludrocortisone suppression, or captopril test)
● adrenal CT scan
● adrenal vein sampling

Uncommon causes

Pheochromocytoma

● Paroxysmal hypertension or a crisis superimposed to sustained hypertension;
● headache, sweating, palpitations and pallor;
● positive family history of pheochromocytoma

Skin stigmata of neurofibromatosis (café-au-lait spots, neurofibromas)

Incidental discovery of adrenal (or in some cases, extra-adrenal) masses

Measurement of urinary fractionated metanephrines or plasma-free metanephrines

● CT or MRI of the abdomen and pelvis;
● ¹²³I-labelled meta-iodobenzyl-guanidine scanning;
● genetic screening for pathogenic mutations

Cushing syndrome

● Rapid weight gain,
● polyuria (excessive production of urine),
● polydipsia (excessive thirst),
● psychological disturbances

Typical body habitus (central obesity, moon-face, buffalo hump, red striae (stretch marks), hirsutism)

Hyperglycaemia

24-h urinary cortisol excretion

Dexamethasone-suppression test

Box 2 -

Box 3 -

The medical history has to address the time of the first diagnosis of hypertension, current and past BP measurements and antihypertensive medications. A history of pregnancy-related hypertension is an important factor in the assessment of women with hypertension. Hypertension results in an increased risk of CVD complications, and chronic kidney disease (CKD). Thus, a careful medical history should be taken in all patients to allow for assessment of global CVD risk, with special emphasis on current and past smoking habits and evidence of dyslipidaemia and diabetes mellitus. CVD risk should be estimated using an established calculator (e.g. http://ASCVD-Risk-Estimator/). Adults at high risk for CVD have a high probability to benefit from antihypertensive drug therapy in addition to lifestyle change76.

The physical examination aims to establish the diagnosis of hypertension and screen for target organ damage and secondary causes ( box 2). The patient should sit quietly for 5 minutes before a BP reading is taken and BP cuff should be at heart level. An average of 2 to 3 BP measurements obtained at 2 to 3 separate occasions provides an accurate basis for estimation of BP77,78. At least once, BP should be measured on both arms, and differences in SBP > 20 mmHg and/or in DBP >10mmHg should initiate investigations of vascular abnormalities77. Careful attention should be paid to choosing appropriately sized cuff, particularly for the increasing number of patients with obesity. Further, BP should be measured in both sitting and standing positions to rule out orthostatic hypotension (a sudden drop of the BP when a person stands up from a lying or sitting position). This is particularly important in elderly individuals.

All patients should undergo auscultation of the carotid arteries, heart and renal arteries. Detection of murmurs (sounds audible via the stethoscope) should lead to further investigations: carotid ultrasound, echocardiography and renal ultrasound, respectively. An irregular pulse frequently indicates atrial fibrillation, which should be confirmed by an electrocardiogram (EKG). Laboratory investigations are used to detect additional risk factors, to confirm or exclude secondary hypertension, to detect clinical or subclinical target organ damage and to estimate global CVD risk ( box 3).

Prevention

The association between BP and risk of CVD highlights the importance of treating hypertension, especially when severe. Further, it also underscores the importance of strategies to reduce BP-related CVD risk in those who have a higher than normal level of BP (average systolic BP 120-129 mmHg) but below the hypertension threshold. Reducing BP in adults with a high normal BP (referred to as elevated BP in the 2017 US guidelines) provides the potential to directly reduce CVD risk and to prevent or at least slow the age-related tendency for individuals to develop hypertension.

In most countries there is a strong tendency for BP, especially systolic BP, and the prevalence of hypertension to increase progressively from childhood until late in life79. However, studies in isolated societies that have limited contact with the outside world84,85 indicate that high BP is not an inevitable consequence of aging and that the rise in BP associated with local migration by members of isolated societies is related to changes in diet, decreased physical activity and consumption of alcohol. These reports underscore the logic of efforts to prevent high BP in settings where an age-related increase in BP is common.

Lifestyle changes

A variety of nonpharmacological interventions have been shown to be effective in lowering BP and preventing hypertension. The most effective interventions are weight loss88,89,90, reduced Na⁺ intake88,89,90,91, increased potassium intake92,93, increased physical activity94, reduced consumption of alcohol95,96 and diets like the Dietary Approaches to Stop Hypertension (DASH) diet97 that combine several elements which favorably affect BP98,99 ( table 3 ). The DASH diet is especially successful when combined with other effective BP lowering interventions such as a reduced intake of dietary sodium91. Lifestyle change is the best way for the individual to implement these interventions. Even small improvements in an individual's lifestyle can be valuable. Government agency and professional society websites provide helpful tips for lifestyle change and monitoring of BP. Careful monitoring of BP is essential because the beneficial effects of lifestyle change are predicated on maintenance of the intervention100.

Table 3.

Food group

Servings*

Examples of a serving

Whole grains

6-8 per day

1 slice whole grain bread

Vegetables

4-5 per day

1 cup of raw leafy vegetables

Fruits

4-5 per day

1 medium sized fruit

Dairy products (low-fat or fat-free)

2-3 per day

1 cup of milk or yogurt

Fats and oils

2-3 per day

1 teaspoon of margarine or vegetable oil or
1 tablespoon of mayonnaise or
2 tablespoons of salad dressing

Lean meat, poultry, fish

2-3 per day

2 ounces of cooked meats, chicken or fish

Nuts, seeds and legumes

4-5 per week

1/3 cup (1.5 ounces) of nuts or
2 tablespoons of peanut butter or
2 tablespoons (0.5 ounce) of seeds or
½ cup of cooked peas or beans

Candy and added sugars

5 or less per week

1 tablespoon of sugar, jelly or jam or
1 cup of lemonade

Two complementary strategies aimed at achieving a small population-wide reduction in BP or a larger reduction in those who are at higher risk to develop hypertension can be employed to implement hypertension prevention interventions98,99,101. Modeling studies suggest that a downward shift of as little as 2 mmHg in the population distribution of diastolic BP would result in a 17% reduction in the incidence of hypertension, a 14% reduction in the risk of stroke and transient ischemic attacks, and a 6% reduction in the risk of coronary heart disease102. Public health interventions focused on dietary improvements and increases in physical activity that are known to lower BP provide the basis for the population-wide strategy. Diet in the general population can be favorably influenced by means of public health education campaigns, food product labeling, and collaborations with food manufacturers to reduce the calorie and sodium content of their products, as well as with fast food companies and restaurants to reduce portion size and to promote healthier food preparation and promotion practices. Physical activity can be enhanced by making it easier for members of the community to engage in exercise on a routine basis.

Pharmacological interventions

Low-dose pharmacological therapy has also been shown to be effective in lowering BP and preventing hypertension in three randomized controlled trials conducted in adults with high normal BP103,104,105. The Brazilian multi-center PREVER-Prevention Trial compared treatment with the low-dose long-acting thiazide-like diuretic chlorthalidone in combination with the potassium sparing agent amiloride with treatment with placebo105. Treatment with the low-dose chlorthalidone and amiloride combination resulted in both a decrement in BP and prevention of hypertension and a reduction in left ventricular mass. A drug intervention is easier to implement and maintain than a lifestyle change intervention but there is a natural reluctance to recommend a lifetime of pharmaceutical therapy for prevention of hypertension. Consideration of low-dose pharmacotherapy should be restricted to those who are at high risk of developing hypertension despite energetic efforts to lower BP by means of one or more nonpharmacological interventions105.

MANAGEMENT

BP treatment thresholds and targets

Until 2015, most guidelines recommended a target BP < 140/90 mmHg for most patients and < 150/90 mmHg for elderly patients over 60 or 80 years of age ( Table 4 )77,106. However, after the publication of the Systolic blood PRessure Intervention Trial (SPRINT)107, target systolic BP values have been frequently debated. SPRINT was a randomized, open-label controlled trial that enrolled 9361 participants without diabetes mellitus but with increased CVD risk. Patients with a history of stroke were excluded. Participants were randomized to a standard systolic BP target < 140 mmHg or intensive systolic BP target < 120 mmHg. Intensive BP treatment in SPRINT resulted in a significantly greater (25%) reduction in the primary endpoint (first occurrence of myocardial infarction, acute coronary syndrome, stroke, heart failure or death from cardiovascular causes), compared with standard treatment. Office BP measurement in SPRINT was performed with an automated device timed to start measurement after 5 minutes of rest in an effort to standardize measurements in the various clinics and minimize the white coat effect. Because large differences had been observed between automated office BP measurement and conventional auscultatory measurements (with the automated technique showing lower values)108, some groups have questioned the applicability of the SPRINT intensive systolic BP target of < 120 mmHg to ordinary office practice109. Both the appropriate method(s) of measuring office BP (automated versus manual; unattended versus attended) and the appropriate BP targets for antihypertensive treatment are currently topics of vigorous debate. In summary, newer guidelines published after the SPRINT trial generally have more aggressive goals, at least for individuals < 65 years of age ( Table 4 ).

Table 4.

Guideline

Population

Goal BP (mmHg)

Adults 65 years and older

<150/90 (<140/90 if tolerated)

Adults with diabetes, CHD or renal disease

<130/80

Adults > 80 years

< 150/90

Adults with diabetes

< 140/85

Adults with CKD without proteinuria

< 140/90

Adults with CKD with overt proteinuria

< 130/90

Adults with CHD

< 140/90

Young adults

< 130/80

Elderly > 80 years

< 150/90

Adults ≥ 60 years

< 150/90

Adults with diabetes

< 140/90

Adults with CKD

< 140/90

Adults > 80 years

SBP 140-150

Late phase elderly patients

<150/90 (<140/90 if tolerated)

Adults with diabetes or CKD

< 130/80

Adults with CHD or CVD

< 140/90

Adults ≥ 80 years

< 150

High-risk adults ≥ 50 years

≤ 120*

Adults with diabetes in whom prevention of stroke is priority

< 120

Adults with diabetes and high risk for CVD

< 130/80

Adults without additional markers of increased CVD risk

< 130/80

Older adults ≥ 65 years of age,
noninstitutionalized, ambulatory

< 130/80

Older adults ≥ 65 years of age, with comorbidities and limited life expectancy

Individualized goal based on clinical judgement and patient preference

Patient's global CVD risk and comorbidities should be considered in determining the need for pharmacologic antihypertensive treatment. The 2017 US ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults110 recommend the use of antihypertensive medication in patients with pre-existing CVD and those without a CVD event but an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 10% or higher at BP levels ≥ 130/80 mmHg. In individuals without CVD and with 10-year ASCVD risk < 10%, antihypertensive medication should be initiated at BP ≥ 140/90 mmHg. ( Figure 5 ).

Non-Pharmacological Management

Lifestyle advice is recommended for all patients with hypertension. The most effective interventions are the same as for prevention of hypertension. Targeted dietary approaches can reduce the systolic BP in individuals with hypertension. For example, reducing sodium intake (ideally to <2.3 g per day, or <1.5 g per day in those most susceptible to the effects of sodium on BP, but reduction by at least 1.0 g per day is desirable) can lower the systolic BP by 2-4 mmHg (Ref). A similar reduction can be expected with increases in potassium intake to 3.5- 5.0 g per day92.

Reduced salt intake

For metabolic balance, the amount of salt consumed must be equal to that lost. Thus, under normal living conditions and physical activity levels, an intake of 5 g salt/day is considered sufficient, in line with the WHO recommendation (< 5 g per day)113. By contrast, the currently estimated dietary intake of salt is about 9-12 g per day in most countries. The current recommendations of the American Heart Association114 and American Society of Hypertension115 are stricter than the European guidelines, recommending lowering salt intake to 3.8 g per day, whereas the 2013 ESH/ESC guidelines recommend 5-6 g of salt per day77.

There is strong evidence to support population-wide recommendations to lower salt intake119,120. As more than 75% of dietary salt comes from processed foods (in western countries), any population strategy to reduce salt intake must involve food manufacturers and restaurants, in order to progressively reduce salt added to foods. So far, only three countries (Japan, Finland and the United Kingdom) have successfully reduced population salt intake121.

Moderate alcohol consumption

Keeping alcohol intake ≤2 standard drinks (~3.5 alcohol units) per day for men and ≤1 standard drink (~1.75 alcohol units) per day for women can also contribute to a 2-4 mmHg BP reduction. 95,96

Physical activity

Regular physical activity reduces BP in individuals with hypertension. Endurance training reduces BP more in persons with hypertension than in individuals with normal BP. A narrative review of 27 randomized clinical trials in individuals with hypertension showed that regular medium-intensity to high-intensity aerobic activity reduced BP by a mean of 11/5 mmHg125. Sessions lasting 40-60 minutes performed at least three times a week had the greatest effect on BP. Three randomized controlled trials of isometric exercise (strength training) showed a BP reduction of similar magnitude to that induced by aerobic exercise in individuals with hypertension125. A meta-analysis of 64 controlled studies of the efficacy of dynamic resistance training as stand-alone antihypertensive therapy showed BP reductions comparable with or greater than those with aerobic exercise training126. Greater BP reductions occurred in individuals with higher resting BP (approx. 6/5 mmHg for individuals with hypertension and 3/3 mmHg for individuals with pre-hypertension) and in non-white individuals126.

Weight Loss

Excess adiposity generally raises BP in susceptible individuals, and patients with hypertension who also have obesity require more antihypertensive medications to control their BP and are more likely to be treatment resistant127. In a recent meta-analysis, any reduction in body weight lowered systolic BP by on average 2.69 mmHg and in diastolic BP by on average 1.34 mmHg (Ref128). However, the response varies substantially between individuals. Lifestyle interventions, including hypocaloric diets and physical exercise, are commonly recommended for patients with obesity and hypertension, yet average weight loss is modest and most patients regain weight129 ( box 4).

Box 4

Weight loss is recommended for individuals with obesity, and may be particularly important if these patients also have hypertension. Medications have been developed for the treatment of obesity, but their approval status differs between the United States and Europe: some drugs are only approved in the United States (for example, lorcaserin and topiramate/phentermine), whereas others are approved in Europe only. BP reductions in patients with hypertension have been reported for some weight loss medications201, but their specific pharmacological actions may attenuate the positive influences of weight loss on BP and CVD outcomes133. Bariatric surgery is very effective in reducing body weight, and the risk for arterial hypertension is substantially reduced up to five years following bariatric surgery202. However, large and sustained body weight reductions are needed to substantially reduce BP following bariatric surgery203 and there are no large clinical trials specifically testing the effects of weight loss medications or bariatric surgery on hypertension control.

Antihypertensive Pharmacotherapy

Antihypertensive pharmacotherapy has evolved over several decades driven by development of various antihypertensive medication classes and large-scale outcomes trials proving their benefits on CVD morbidity and mortality130. Clinicians are now faced with a plethora of antihypertensive medications of different drug classes and a variety of fixed dose combinations. Typically, antihypertensive pharmacotherapy begins with first-line antihypertensive medications either in monotherapy or in combination131. Combination therapy may be preferable in patients with higher levels of pretreatment BP. First-line antihypertensive medications include ACE inhibitors, angiotensin II receptor blockers (also known as sartans), dihydropyridine calcium channel blockers, and thiazide diuretics106. Beta-blockers are also indicated in patients with heart failure and reduced left ventricular ejection fraction or post myocardial infarction, and some guidelines recommend beta-blockers as first line antihypertensive medications 77,132. The choice should be based on individual efficacy and tolerability. Ethnicity affects the response to antihypertensive medications, and it has been suggested that calcium channel blockers and diuretics may be the first choice in blacks. Further, in specific clinical situations, for example hypertension in pregnant women, other medications such as alpha-methyldopa (an agonist of alpha adrenoreceptors in the central nervous system that inhibits the sympathetic nervous system) or labetalol (a beta adrenoreceptor blocker) are preferable, whereas some first line antihypertensives, for example ACE inhibitors and angiotensin II receptor blockers, are contraindicated because of increased risk for renal teratogenicity. Divided dosing of antihypertensive drugs tends to decrease adherence and should be avoided when possible135.

BP cannot be controlled with monotherapy in many patients, particularly those with severe hypertension. When combining antihypertensive medications, it is important to consider whether the drugs have additive effects on BP or adverse effects, and whether the patient has comorbidities that mandate particular drug choices77. ACE inhibitors or angiotensin II receptor blockers, thiazide diuretics and dihydropyridine calcium channel blockers are additive in lowering BP and can be combined as double or triple combination therapies. By contrast, combining ACE inhibitors and angiotensin II receptor blockers adds little BP lowering while increasing the risk for renal dysfunction and hyperkalemia (high blood potassium levels, which can lead to cardiac arrhythmias). Similarly, combining RAAS inhibitors with beta-adrenoreceptor blockers adds little BP reduction, but this combination is indicated in patients following acute myocardial infarction or heart failure with reduced left ventricular ejection fraction for reasons beyond BP reduction.

Dihydropyridine calcium channel blockers.

Dihydropyridine calcium channel blockers elicit vasodilation by blocking vascular smooth muscle L-type calcium channels. They are effective antihypertensive drugs with extensive experience in large clinical trials136. A practical advantage of this drug class is that it can be combined with all other first-line antihypertensives. Peripheral edema, which is explained by peripheral arterial vasodilation rather than worsening heart failure or kidney dysfunction, is a common side effect, particularly in individuals with obesity. Non-dihydropyridine calcium channel blockers, especially verapamil, also inhibit cardiac calcium channels, which can reduce heart rate and cardiac contractility141. Calcium channel blockers can induce or worsen constipation, especially in institutionalized older persons142. All calcium channel blockers modestly inhibit the drug metabolizing enzyme cytochrome P450 3A4, and, therefore, could elicit important drug-interactions143.

Thiazide-type and thiazide-like diuretics.

Thiazide-type diuretics (for example, hydrochlorothiazide) have a benzothiadiazine ring, whereas thiazide-like diuretics (for example, chlorthalidone, metolazone and indapamide) lack the benzothiadiazine structure. Both subclasses of thiazide diuretics inhibit Na⁺ and CI⁻ co-transporters in renal tubules, thereby promoting natriuresis, and have been an important component of pharmacological hypertension management ever since the first trials showing morbidity benefits of antihypertensive therapy144. Over the years, diuretic doses have been substantially reduced to attain better risk-benefit profiles. Thiazide-type and thiazide-like diuretics can worsen glucose metabolism increasing the risk for new onset diabetes mellitus, but whether or not this metabolic action translates into long-term increases in CVD risk has been called into question145. Hydrochlorothiazide, the most commonly prescribed thiazide-type diuretic worldwide, may be less effective in mitigating CVD risk compared to chlorthalidone or indapamide146,147. Drug-related electrolyte disturbances, including hypokalemia and hyponatremia (low blood potassium and sodium levels, respectively), are particularly important adverse effects; hypokalemia can lead to cardiac arrhythmias and muscle weakness, and hyponatremia can cause confusion, seizures and coma. The risk for hypokalemia is reduced when thiazide-type and thiazide-like diuretics are combined with potassium supplements or potassium-sparing agents, such as ACE inhibitors, angiotensin receptor blockers, or potassium-sparing diuretics. Hyponatremia is a potentially life threatening adverse effect, particularly in elderly persons.

Beta-adrenoreceptor blockers.

Beta-adrenoreceptor blockers lower BP reducing cardiac output, heart rate, renin release and adrenergic control nervous system effects148. They improve outcomes following acute myocardial infarction and in patients with heart failure with reduced left ventricular ejection fraction, but, in the absence of these comorbidities, beta-adrenoreceptor blockers are inferior to other first line antihypertensives in reducing CVD morbidity and mortality149. This effect has been attributed to lesser reductions in aortic BP150 and adverse effects on body weight151 and glucose metabolism with beta-adrenoreceptor blockade. Some of these disadvantages might be mitigated with newer vasodilator beta-adrenoreceptor blockers, such as nebivolol and carvedilol152. However, there are no large-scale antihypertensive trials demonstrating that this difference translates into better clinical outcomes. Beta-adrenoreceptor blockers may promote bronchial obstruction is patients with asthma and should not be combined with non-dihydropyridine calcium channel blockers such as verapamil that lower sinus node rate or atrioventricular conduction.

Treatment Resistant Hypertension

Treatment resistant hypertension is commonly diagnosed when office BP is >140/90 mmHg despite treatment with three or more properly dosed antihypertensive drugs including a diuretic and secondary hypertension has been ruled out159. Poor treatment adherence is a common cause of apparent treatment resistant hypertension. The true prevalence of treatment resistant hypertension is unknown, but an estimated 12.8% of all individuals with hypertension in the United States and 15.3 % of those treated with antihypertensives fulfill the criteria for treatment resistant hypertension160. Adding a fourth or fifth drug could lead to satisfactory BP control in these patients. The PATHWAY trial rotated patients with treatment resistant hypertension through different add on drugs or placebo in a randomized fashion161. All patients received a standardized antihypertensive regimen comprising three drugs, including a diuretic. Compared with alpha-adrenoreceptor or beta-adrenoreceptor blockade, the mineralocorticoid receptor antagonist spironolactone was the most effective fourth antihypertensive drug. In another study in patients whose BP was uncontrolled despite receiving three drugs, sequential addition of a mineralocorticoid receptor antagonist followed by a loop diuretic (which acts at the ascending limb of the loop of Henle in the kidney) was more effective than adding an ACE inhibitor followed by a beta-adrenoreceptor blocker162. Overall, mineralocorticoid receptor antagonism is a reasonable choice in patients with difficult to control hypertension. Given the risk of inducing hyperkalemia163, serum potassium concentrations should be monitored.

Device-based Treatments

Device-based treatments have been primarily developed for patients with severe resistant hypertension whose BP cannot be controlled with antihypertensive drugs156. Catheter-based renal nerve ablation164,165, electrical carotid sinus stimulation166,167, modulation of baroreflex transduction with a dedicated carotid stent168, carotid body denervation169, and deep brain stimulation170 are thought to lower BP through SNS inhibition. Creation of a defined arteriovenous stent with a coupler device lowers BP by reducing peripheral vascular resistance171. These treatments are in various stages of clinical development, with the most extensive data available on renal nerve ablation and electrical carotid sinus stimulation. None has yet been proven efficacious in lowering BP in randomized sham-controlled clinical trials164,161,167, because either the primary endpoint was not achieved or no trials have been conducted. Finally, trials with hard clinical endpoints do not exist.

QUALITY OF LIFE

Health-related quality of life (HRQoL) is a multi-dimensional concept that includes domains related to physical, mental, emotional, and social functioning; studies demonstrate that each additional disease, as well as the severity of these diseases, is associated with declines in HRQOL 172. Population-based studies have consistently shown that being diagnosed with hypertension is associated with worsening of HRQoL even after adjusting for other comorbidities173,174. Altered HRQoL in persons with hypertension has been attributed to a variety of factors, including the diagnosis, treatment, and effects of alterations (both elevations and reductions) in BP173.

Antihypertensive medication use is associated with a variety of symptoms that could lower HRQoL177. Observational studies showed an association between the number of antihypertensive medications prescribed and worsening of the HRQoL178. Some classes of antihypertensive medications, (for example, ACE inhibitors) are better tolerated than others (for example, beta blockers and centrally acting agents, such as alpha-methyldopa) and result in significantly better scores on measures of general well-being179. Further, small differences in HRQoL have even been reported among medications of the same class, e.g., enalapril vs. captopril180. However, clinical trials with newer antihypertensive agents have generally indicated that they are extremely well-tolerated and can enhance the effects of non-pharmacological treatment on HRQoL177,181. In the Treatment of Mild Hypertension Study (TOMHS), combining lifestyle modifications with any of five different antihypertensive medication classes resulted in greater improvements in HRQoL than lifestyle modifications plus placebo181.

Treatment-related reductions in BP could have a negative effect on HRQoL, particularly in older and more frail patients at high risk of hypotension. Clinical trials performed in the 1990s that evaluated patients with very high baseline BP, for example, the Systolic Hypertension in the Elderly Program Trial (SHEP) and the Systolic Hypertension in Europe Trial (Syst-Eur), generally found minimal effects of BP reductions on HRQoL182,183. Two more recent clinical trials have targeted lower BPs (intensive systolic BP target < 120 mmHg versus standard systolic BP target < 140 mmHg ), it had been postulated that this lower BP might be expected to cause cerebral hypoperfusion, resulting in falls, dizziness, and cognitive impairment184,185,107. In a substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, HRQoL was evaluated in 1,028 participants randomized to either intensive or standard therapy. No differences in mental function were noted between treatment groups, but intensive therapy was associated with a small, not clinically significant, decrease in physical function185. In the Systolic Blood Pressure Intervention Trial (SPRINT), targeting systolic BP <120 mmHg required 1 additional antihypertensive medication compared to standard treatment to target systolic BP < 140 mmHg and was generally safe and well tolerated107,186. Compared to standard treatment, intensive treatment did not affect the perceived HRQOL of SPRINT participants, measured by patient reported outcomes of physical and mental health, self-reported satisfaction with care and medication adherence, even when stratifying on age and comorbidities186. Almost 90% of participants in both treatment groups reported satisfaction with their BP care, and more than 1/3 described improvement in satisfaction over baseline levels.

Quality of life concerns remain an important aspect of hypertension management. SPRINT has demonstrated that with careful clinical management, lower BP can be targeted without concern of worsening physical and mental function. Clinicians must seek the optimal balance of reducing CVD morbidity and mortality while maximizing well-being for each individual patient.

OUTLOOK

Overall, prevention will probably contribute least to any improvement in BP-associated disease burden. This is because 80% of the world is in the process of developing, which hitherto has inevitably been associated with increased exposure to the main environmental determinants of raised BP such as excess intake of calories, alcohol and salt. Food and drink industries, governments and education systems would be required to cooperate in order to reverse this pattern

Implementation of preventive strategies has largely been limited to high income countries. Despite reasonably compelling evidence to the contrary111, recommendations that the general population should restrict salt intake have been questioned on the basis of largely suboptimal observational data189. Such confusion worsens an already very difficult public health challenge. Data show that only approximately half of people with hypertension are aware of their condition190, and the Lancet Commission on hypertension identified improving awareness of hypertension is a critical action needed to improve the current disease burden191,192. The global BP awareness campaign promoted by the International Society of Hypertension whereby World Hypertension Day was extended to become May Measurement Month (MMM) in 2017 could contribute substantially to improving rates of routine BP screening around the world83. Over 1.20 million adults (≥18 years) from >100 countries were screened as part of MMM and the ensuing data allied to health-economic analyses will be used to persuade policy makers in each country that enhanced local BP screening and treatment facilities are wise financial investments.

Meanwhile, single-pill formulations of the drug combinations most commonly recommended in current guidelines (calcium channel blocker plus a diuretic, calcium channel blocker plus a RAAS-blocker or diuretic plus a RAAS-blocker) are readily available and have low production costs. In addition, a 3-drug combination of a calcium channel blocker, a diuretic and a RAAS-blocker132 should also be produced for more severe hypertension, with low dose spironolactone available as a fourth-line agent161. Hence, 1 or 2 tablets will be able to control BPs of all but a small proportion of patients with hypertension.

These formulations should be made available and affordable in all countries of the world.191 Additional local obstacles to the distribution and delivery of these agents to patients with hypertension within each country will also have to be overcome - among which the lack of effective screening programmes is crucial191.

Antihypertensive medications are prescribed by different health professionals in different countries. However, even in high income countries, much of the "routine" uncomplicated hypertension management could, and probably should be carried out by nurse practitioners or other non-physician health workers. In more remote parts of the world, the use of e-healthcare techniques196 should be increasingly used to facilitate task-shifting or task sharing by non-physician health-workers where doctors are unavailable197.

In summary, although there are many interesting unanswered scientific research questions in the field of hypertension ( Box 5), perhaps the most pressing need to reduce the diseas burden is to evaluate the best way(s), at a local level, to screen routinely for raised BP and then to deliver the best, most affordable, evidence-based combination of antihypertensive agents. Meanwhile, efforts to drive public health policy towards encouraging more healthy diets and lifestyles from a BP and CVD viewpoint should be encouraged and basic scientific research that might allow precision medicine to be applied to patients with hypertension must also continue.

Box 5

Measurement Issues

Is hypertension management improved by basing treatment strategies on serial unattended office BP measurements, out of office (home or ambulatory) BP measurements or central BP measurements?

How should BP be measured in patients with atrial fibrillation?

Treatment Issues

Should salt restriction at the population level continue to be recommended at current targets?

To what extent should age, estimated CVD risk and concomitant conditions influence treatment thresholds?

Should white-coat hypertension be treated?

If management strategy is to be influenced by central or out of office BP levels, what treatment thresholds and targets should be used?

Should reducing 24-hour and longer-term BP variability be a consideration in the selection of drug treatment for optimal CVD protection?

What combinations of antihypertensive agents give optimal CVD protection, stratified by age and ethnicity?

What is the optimal BP treatment target stratified by age, CVD risk and concomitant disease status?

What is the optimal management of treatment resistant hypertension that is resistant to 4 agents including spironolactone?

If treatment thresholds are to be driven by estimated CVD risk, at what level should antihypertensive drug treatment be initiated and what other CVD protective agents should be considered?

Is initiating drug therapy with 2 hypertensive agents more effective than initiating with monotherapy for optimal CVD prevention?

Acknowledgments

P.K.W. was supported by P20GM109036 (Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases) from the National Institute of General Medical Sciences.

Footnotes

Competing interests

G.B. served as Consultant for Janssen, Bayer, AbbVie, Vascular Dynamics, Relypsa and Merck; served/serves as Principal Investigator for FIDELIO trial (Bayer), Steering Committee member (CREDENCE)-Janssen, SONAR-AbbVie, and CALM-2-Vascular Dynamics. J.J. served as consultant for Novartis, Novo-Nordisc, Boehringer-Ingelheim, Sanofi, Orexigen, Riemser, Theravance, Vivus; and is cofounder of Eternygen GmbH. S.O. (in the previous 24 months) has received research grant support or reimbursement for travel to meetings or other, non-financial support from Actelion Clinical Research/George Clinical; AstraZeneca AB; Bayer; Lundbeck; Novartis; Novo Nordisk; Rox Medical; has consulted for Actelion/George Clinical, Lundbeck, Novo Nordisk and ROX Medical; served as Director/Principal Investigator, SPRINT University of Alabama at Birmingham (UAB) Clinical Center Network (CCN); and sub-investigator UAB CCN clinical site; for which Takeda and Arbor Pharmaceuticals donated 5% of medication used. N.R.P. served as advisory board member (ad hoc) for Pfizer, Takeda, MSD, Servier, and Medtronic (companies producing blood pressure lowering agents/devices); received speaker honoraria from Servier, AstraZeneca, Napi Labs, and Menarini; received research funding from Servier, Pfizer and Menarini; and is the President of the International Society of Hypertension. George Health Enterprises, the social enterprise arm of The George Institute for Global Health, has applied for a patent in the area of low-dose combinations on which A.R. is listed as an inventor; and has received investment to develop fixed-dose combinations containing aspirin, statin and BP lowering drugs. AR is an investigator on grants for several trials of blood pressure lowering interventions. G.G. has received lectures fees from Merck and Astra Zeneca. M.C.A., R.C., A.F.D., D.R.B. and P.K.W. declare no competing interests.

How to cite this Primer

Publisher's note

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Systemic arterial hypertension is the most important modifiable risk factor for all-cause morbidity and mortality worldwide and is associated with increased risk of cardiovascular disease (CVD). Fewer than half of those with hypertension are aware of ...