VASCULAR RENIN-ANGIOTENSIN SYSTEM, ENDOTHELIAL FUNCTION AND ATHEROSCLEROSIS

Clinical observations demonstrate an enhanced risk for myocardial infa rction in patients with substained activation of the local and/or syst emic renin-angiotensin system, such as a high renin-sodium profile or a heritably enhanced expression of angiotensin converting enzyme. Chro nic renin-angiotensin system blockade by angiotensin converting enzyme inhibition in patients with moderate heart failure reduces the rate o f myocardial infarction and reinfarction. Preliminary experimental evi dence suggests that these clinical observations may be partially expla ined by a proatherogenic effect of an activated renin-angiotensin syst em, which can downregulate the endothelial releasability of nitric oxi de. Nitric oxide exerts many potentially antiatherogenic effects on en dothelium, platelets and low density lipoproteins and indirectly on mo nocytes and leukocytes. Hypertension-induced chronic distension of ela stic arteries upregulates the local renin-angiotensin system in these arteries and thereby downregulates nitric oxide releasability. Enhance d local synthesis of the trophic factor angiotensin-II and reduced rel easability of the antitrophic factor nitric oxide appear to cooperate in the trophic adaptation of the distended vessel wall to the enhanced load, but with the disadvantage of enhanced susceptibility for athero ma development due to reduced releasability of nitric oxide. Chronic b lockade of the renin angiotensin system by angiotensin converting enzy me inhibitors or by angiotensin receptor type-1 antagonists normalizes a reduced endothelial releasability of nitric oxide in several models , partially by a bradykinin-dependent mechanism. This endothelial prot ection proved to attenuate the progression of atheroslerosis in experi mental models. The antiatherogenic potential of renin angiotensin syst em blockade in humans is presently under study.