Physiological Mechanisms Involved in Development of Essential Hypertension

Physiological mechanisms involved in development of essential hypertension
Cardiac output
Peripheral resistance
Renin-angiotensin-aldosterone system
Autonomic nervous system

Other factors:
Bradykinin
Endothelin
EDRF (endothelial derived relaxing factor) or nitric oxide
ANP (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.


The heart, arteries, and arterioles in hypertension
Plasma renin in black and white hypertensive patients. Adapted from Freis ED, Materson BJ, Flamenbaum V. Comparison of propranolol or hydrochlorothiazide alone for treatment of hypertension. III. Evaluation of the renin-angiotensin system. Am J Med 1983;74:1029-41

Local versus systemic renin-angiotensin systems

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.
 
Renin-angiotensin system and effects on blood pressure and aldosterone release
•    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.

The autonomic nervous system and its control of blood pressure. Reproduced with permission from Swales JD, Sever PS, Plart WS. Clinical atlas of hypertension. London: Gower Medical, 1991

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.    

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.

 
The control of peripheral arteriolar resistance.
 
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.
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.

 
Virchow's triad and the prothrombotic state in hypertension

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.