Neuro-endocrine regulation of blood pressure.

As our understanding of the underlying aetiology of hypertension is far from adequate, over 90% of patients with hypertension receive a diagnosis of essential hypertension. This non-specific diagnosis leads to suboptimal therapeutics and a major problem with non-compliance. Understanding the normal control of blood pressure (BP) is, hence, important for a better understanding of the disease.This review attempts to unravel the present understanding of BP control. The local mechanisms of BP control, the neural mechanisms, renal-endocrine mechanisms, and a variety of other hormones that have a bearing in normal BP control are discussed and the possible role in the pathophysiology is alluded to.

INTRODUCTION

Even with our present understanding of the pathophysiology of hypertension, in about 90% of cases the etiology is unclear and the patients are classified as having essential hypertension. This results in most patients being treated for hypertension nonspecifically resulting in a large number of minor side effects because of inappropriate choice of therapy and over 50% noncompliance rates. Moreover, essential or primary hypertension is a major public health issue, with approximately one fourth of the adult population being affected in industrialized countries. However, the cardiovascular disease epidemic has now moved to the developing countries, with the projected increase in the proportion of cardiovascular mortality expected to increase from around 25% in 1990 to more than 40% in 2020.[1]

With this background, it becomes important to understand the neuro-endocrine regulation of blood pressure (BP) control which is the subject of this review. The regulation of BP is a very complex physiologic function, dependent on a continuum of actions of cardiovascular, neural, renal, and endocrine systems. Investigating the pathophysiology of hypertension thus needs a good understanding of the factors responsible for normal BP control and looking for subclinical abnormalities that precede the increase of BP to abnormally high levels. Improvements in the understanding of the mechanisms that underlie hypertension and especially of those that regulate BP throughout its range should facilitate advances in the prevention and treatment of hypertension.

AN OVERVIEW

The control of BP is essentially the sum of the control of blood flow to a given tissue in proportion to its metabolic need. The local mechanisms that control blood flow include vasoconstriction and dilatation acutely, and chronically, change in the number and caliber of the blood vessels supplying a tissue. The endothelial autocrine secretions play an important role in vasoconstriction and vasodilation and will be briefly considered in the review.

In addition to the local control of blood flow, global control of blood flow including changes in cardiac output and control of arterial BP is mediated by the autonomic nervous system. Global neural control of arterial hypertension is essentially through the sympathetic nervous system (SNS). The parasympathetic nervous system contributes primarily to regulation of cardiac functions. The first part of the review looks at the role of SNS in the control of systemic hypertension.

The most powerful chronic mechanism that controls BP over weeks and months however is the integrated renal-endocrine systems that balance the body fluid and salt homeostasis with control of arterial hypertension. This is the second part of the review.

The overview of the mechanisms is given in Figure 1.

Figure 1

Outline of blood pressure regulation

NEURAL MECHANISMS

There is a wide spectrum of responses of the sympathetic nervous system (SNS) that range from mild to massive and from acute to chronic. The SNS is the only system of the body capable of both momentary and sustained regulation of BP.[23] Young adults with hypertension have associated tachycardia, increased cardiac output, and also a rise in plasma norepinephrine levels with an increased vasoconstrictor tone in the peripheral circulation. A rise in sympathetic activity is also noted in patients with hypertension associated with obstructive sleep apnea, obesity, chronic kidney disease, prediabetes, and heart failure.

REGULATION OF BLOOD PRESSURE AND SYMPATHETIC NERVOUS SYSTEM

While short-term changes in BP are regulated by SNS and renin–angiotensin-aldosterone system (RAAS), long-term BP control is controlled by the kidney.[4] High pressure baroreceptors in the carotid sinus and aortic arch respond to acute elevations in systemic BP by causing a reflex vagal bradycardia that is mediated through the parasympathetic systems and inhibition of sympathetic output from the CNS. Low pressure cardio pulmonary receptors in the atria and ventricles likewise respond to increases in atrial filling by causing tachycardia through inhibition of cardiac SNS, increasing atrial natriuretic peptide (ANP) release and inhibiting vasopressin release.[5-7]

Sympathetic regulation also plays a role in long-term BP regulation, as the most important stimulus to renin release in the juxtaglomerular apparatus is through renal sympathetic nerves.

Some of the strongest clinical evidence of sustained neurogenic hypertension comes from studies done in patients with obstructive sleep apnea. Activation of the carotid body chemoreceptors occurs during the apneic spells with arterial desaturation. This causes high BP episodes and a long-term resetting of the chemoreceptor reflex.

The normal control of the arterial BP by SNS is summarized in Figure 2.

Figure 2

CNS control of sympathetic outflow. Efferent SNS output is the result of integrated actions of several CNS centers, including many areas of the cortex as well as lower centers in hypothalamaus, basal ganglia(especially the locus ceruleus), and circumventricular regions, including the area postrema (AP) and the AV3V region. The critical integrator region is the nucleus tractussolitaries (NTS), which lies in the medulla oblongata. The NTS receives inhibitory afferent signals from the baroreflexes (volume and pressure signals) and stimulatory afferent signals from renal and muscular chemoreceptors (metabolic signals). SNS outflow is ultimately dependent on stimulation of the rostral ventrolateral (the RVLM or vasomotor control center), which is tonically inhibited by the adjacent NTS. Circumventricular regions such as the AP are of particular interest because they have no blood-brain barrier; stimulation of the AP by circulating angiotensin II (Ang II) blunts the inhibitory effects of the NTS. Ultimately, RVLM stimulation sends signals via the spinal cord and sympathetic ganglia to regulate heart rate, cardiac stroke volume(SV), and systemic vascular resistance(SVR), which together determine momentary and chronic blood pressure (BP) levels.[71]

RENAL ENDOCRINE-HORMONAL MECHANISMS

Renin-angiotensin-aldosterone system

Activation of the RAAS is a very important mechanism responsible for regulation of BP.[8]

Renin – Renin is an aspartyl protease that is first synthesized as an enzymatically inactive precursor, prorenin. The vast majority of renin in the circulation originates in the juxtaglomerular (JG) cells surrounding the renal afferent arterioles. Lab measurements for renin are most commonly expressed as the capacity of plasma to generate angiotensin I. Thus plasma renin activity (PRA) reflects not only the amount of renin in circulation but also the amount of substrate angiotensinogen and is therefore the best measure of RAS activity in vivo.

Angiotensinogen – Circulating angiotensinogen (a large protein with over 450 amino acids and 13% carbohydrate content) can be found in the alpha – 2 – globulin fraction of the plasma globulins. It is synthesized in the liver with 32 amino acid signal sequence that is removed in the endoplasmic reticulum. Renin acts enzymatically on angiotensinogen (renin substrate) to release a small 10-amino acid peptide, angiotensin I.

Angiotensin I – has mild vasoconstrictor properties but not enough to cause significant changes in circulatory function.

Angiotensin II – also called angiotonin previously, produces arteriolar constriction and a rise in systolic and diastolic BP.

Angiotensin Converting Enzyme – Angiotensin Converting Enzyme (ACE) is a dipeptidylcarboxypeptidase enzyme that is located in the endothelial cells. It splits off the histidyl – leucine complex from the physiologically inactive angiotensin I, to form the octapeptide angiotensin II. The same enzyme is responsible for inactivating bradykinin. Much of this conversion occurs as the blood carrying angiotensin I passes through the lungs, but this can also occur in many other parts of the body. In mammals, ACE occurs as two iso-forms that are produced from a single gene with alternate spacing.

A somatic form (sACE) which is a type I integral membrane glycoprotein and which is widely distributed in many endothelial cells in variety of tissues, including the heart[9] and kidney.

A testicular form (germinal ACE or gACE) that is smaller and found solely in post meiotic spermatogenic cells and spermatozoa.

Both ACEs have a single transmembrane domain and a short cytoplasmic tail. However, somatic ACE is a 170 kDa protein with two homologous extracellular domains, each containing an active site. Germinal ACE is a 90 kDa protein that has only one extracellular domain with an active site. Both enzymes are formed from a single gene.[1011]

The renin angiotensin system cascade is summarized in Figure 3.

Figure 3

Renin angiotensin system

The Angiotensin receptors: AT1 and AT2

The effects of angiotensin II, the principal effector hormone of the RAS, are mediated through its interaction with the above cell membrane receptors.[12-14] The development of highly selective angiotensin II receptor antagonists has allowed the characterization of at least two distinct angiotensin II receptor subtypes, AT1, and AT2.[15] Both receptors belong to the super family of seven transmembrane- spanning G protein coupled receptors.[1617] The expression of these receptors is not static and certain hormones, and pharmacologic agents, and pathologic conditions can enhance or suppress their expression.[1819]

The opposing post-receptor effects of the two subtypes are highlighted in Table 1 and Figures 4 and 5.

Table 1

Actions at receptors[19]

Figure 4

AT1 receptor actions

Figure 5

AT2 receptor actions

Aldosterone

Aldosterone is a steroid hormone produced mainly though not exclusively in the adrenal cortex Aldosterone's mineralocorticoid activity is 3000 times greater than that of cortisol, but the plasma concentration of cortisol is 2000 times that of aldosterone. Aldosterone increases absorption of sodium and increases secretion of K+ by the renal tubular epithelial cells mainly in the collecting tubules, but also in the distal tubules and collecting ducts, though to a lesser degree. Aldosterone thus causes conservation of extra cellular Na+ and increases urinary excretion of K+.

Cellular mechanisms of aldosterone action

Aldosterone is lipid soluble and diffuses into the tubular epithelial cells

It combines with a receptor protein and diffuses into the nucleus to form different types of messenger RNA

The mRNA diffuses out of the nucleus and forms enzymes and membrane transport proteins like sodium – potassium adenosine triphosphatase which are required for Na/K+ transport across the cells.

LOCAL ENDOTHELIUM-DERIVED FACTORS

Nitric oxide

Nitric oxide (NO) also called endothelium-derived relaxing factor (EDRF) is a free radical gas with a very short half-life. It is released from endothelial cells in response to blood flow-induced shear stress and by activation of a number of receptors.[20-22] NO is synthesized from arginine by NO synthase (NOS).[23] In addition to vasodilatation NO also has anti-proliferative, anti-thrombotic, leukocyte adhesion inhibition effects, and influences myocardial contractility.[24-27] The primary hemodynamic effect of pharmacologic NO inhibition includes an increase in systemic and pulmonary arterial BP, and a parallel decrease in cardiac output. The vasoconstrictor effect of Ang II is enhanced in the absence of NO.[28]

Endothelin

Endothelial cells produce endothelin 1 (ET-1), which is one of the most potent vasoconstrictor ever isolated. The evidence suggesting the existence of ET was shown by studies by Hickey et al.[29] It was named endothelin by Yanagisawa et al.,[30] due to its origin from vascular endothelium. ET-1, ET-2, and ET-3 are members of a family of similar polypeptides but each is encoded by different genes. There are two different types of ET receptors which have been cloned, ETA and ETB. ETB receptor activation leads to decreased arterial pressure and natriuresis through effects on adrenal gland, heart (negative inotropy), decreasing sympathetic activity and systemic vasodilatation. ETA receptor activation leads to increased arterial pressure and sodium retention via increased sympathetic activity, positive inotropy of the heart, increased catecholamine release and, systemic vasoconstriction.[31] Stimulators of ET-1 secretion include angiotensin II, catecholamines, growth factors, hypoxia, insulin, oxidized LDL, HDL, sheer stress and thrombin. Inhibitors of ET-1 secretion include NO, ANP, PGE-2, and prostacyclin. Several reports show that ET levels maybe high in hypertensive patients,[3233] while there are other studies which have reported no difference in ET levels in patients with or without hypertension.[3435] ET receptor antagonists have been investigated for their use as anti-hypertensive agents.[3637] ET antagonists are available now for the treatment of pulmonary hypertension.

OTHER HORMONES INVOLVED IN BP CONTROL

Natriuretic peptides

These are a group of hormones which include ANP, brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). ANP was the first NP to be discovered.[38] It is synthesized mainly in the atrial myocardium. BNP is synthesized mainly in the ventricles, while CNP is secreted by the vascular endothelium. NPs exert their functions by binding to the guanylyl cyclase-linked NP receptors: type A (NPR-A) and type B (NPR-B).[39] The biological effects of ANP and BNP are mediated through NPR-A and those of CNP are mediated through NPR-B. NPs inhibit the RAAS and regulate water and electrolyte balance. They inhibit the sympathetic nervous system causing bradycardia and a decrease in BP. In this context of sympathetic outflow control ANP plays a major role.[40] NPs play an active role in cardiac remodeling and have been used as markers of left and right ventricular hypertrophy.[4142] ANP has been accepted to behave as a friendly mechanism toward hypertrophic cardiac responses,[43] and an inadequate response of this system favors cardiac hypertrophy and long-term development of cardiac failure. ANP also induces endothelium-independent vasodilatation in both small and large arteries. NPs have anti-inflammatory and anti-fibrotic effects and also affect cardiac fibroblasts by reducing collagen synthesis. High levels of NPs have been associated with acute cardiac failure especially with BNP. BNP levels have been studied to reflect severity of LV dysfunction in heart failure and help to provide prognostic information about future outcomes in patients with congestive cardiac failure.[44]

The vasopressin system

Vasopressin, also known as anti-diuretic hormone (ADH) is synthesized in the hypothalamus. The human hormone is called arginine vasopressin (AVP) as it contains arginine. There are three kinds of vasopressin receptors: V1A,V1B, and V2 all of which are G-protein coupled. ADH increases the permeability of the collecting ducts of the kidney so as to concentrate the urine leading to its primary physiological effect of retention of water and decreasing the effective osmotic pressure of the body fluids. Vasopressin secretion is stimulated by increased effective osmotic plasma pressure, decreased ECF volume, pain, emotion, nausea, vomiting and inhibited by decreased effective osmotic plasma pressure, increased ECF volume and alcohol ingestion. Vasopressin receptor antagonists decrease vascular smooth muscle contraction (V1 antagonists) and have diuretic effects (V2 antagonists). Both drugs are under clinical evaluation.[45-48]

Vasodilator peptides: Adrenomedulin, Substance P, and calcitonin gene related peptide

Adrenomedulin (ADM) is a 52 amino acid peptide whose name comes from its abundance in normal adrenal medulla as well as pheochromocytoma tissue arising from adrenal medulla.[49] Plasma ADM levels are increased in hypertensive patients and the rise in ADM is proportionate to the severity of hypertension and the target organ damage.[5051] This suggests that ADM is released to compensate for the elevated BP.[52]

Substance P is an 11 amino acid peptide that is found in the intestine, peripheral nerves and many parts of the CNS. It is probably the mediator at the first synapse in the pathways for pain transmission in the dorsal horn of the spinal cord. It is also found in high concentration in the nigrostriatal system and in the hypothalamus where it may play a role in neuro-endocrine regulation. It is also a potent vasodilator with little effect on heart rate and cardiac contractility.[53]

Calcitonin gene related peptide (CGRP) is a 37 amino acid neuro-peptide which is widely distributed in the nervous and cardiovascular systems.[5455] It is a very potent vasodilator and has positive chronotropic and inotropic effects.[5657]

The levels of circulating immunoreactive CGRP in hypertensive patients reported in different studies have been inconsistent,[5558] and its role in human hypertension is unclear.

The tissue Kallikrein-Kinin system

The KKS comprises kallikreins (kinin forming enzymes), kininogens (substrates), kinins (vasoactive peptides), kinin-degrading enzymes and kinin receptors. The KKS plays a major role in controlling systemic and local hemodynamics. The actions of kinins include contraction of visceral smooth muscles and relaxation of vascular smooth muscle via NO, lowering BP. Angiotensin converting enzyme inhibitors partially exert their beneficial cardiovascular effects by potentiating endogenous kinins.[59]

Phosducin

PDC is a 33-kDa cytosolic regulator of G-protein mediated signaling and is found in the retina, CNS, pineal gland, and sympathetic ganglia. Recent research has revealed the potential role of the PDC gene in modulating the adrenergic and BP response to stress and hence its significance as a mediator in stress-dependent hypertension.[60]

Adipose tissue and adipokines

Adipose tissue is not just a passive reservoir for energy storage but is an endocrine organ which secretes bioactive peptides like adipokines.[61] Adipokines include hormones, inflammatory cytokines, and other proteins like angiotensinogen which act at both local (autocrine/ paracrine) and systemic (endocrine) levels. Adipokines influence vascular tone under normal conditions but this regulation of vascular tones is compromised with patients with obesity. leptin and tumor necrosing factor alpha (TNF-α) have vasorelaxing and vasoconstricting physiologic effects.[6263] Adiponectin is released by both brown and white adipocytes and has cardio-protective properties.[64] It is a vasorelaxing adipokine which increases NO and inhibits TNF-α production. A decrease in adiponectin levels, which are found in obesity related disorders, leads to endothelial dysfunction and are an independent predictor of premature atherosclerosis.[65] Other adipokines which have vasorelaxing properties omentin, visfatin and adipocyte-derived relaxing factor.

Leptin

Leptin is a 16 kDa 167 amino acid polypeptide hormone and plays an important link between obesity and the development of cardiovascular disease.[66] Increased leptin levels are associated with lower arterial distensibility and leptin levels have been positively co related with systolic and diastolic BP in both obese,[6768] and non-obese individuals.[6970]

CONCLUSIONS

A combination of local endothelial derived factors, sympathetic nervous system, changes in renal hemodynamics and endocrine secretions are responsible for the control of BP in normal human beings. Understanding the systems help us in understanding the pathophysiology behind the elevations in BP seen in primary and secondary hypertension.