The pathophysiology of hypertension

British Medical Journal, April 14, 2001 by Gareth Beevers, Gregory Y H Lip, Eoin O'Brien

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.

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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 yasodilatation.

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.

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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.