An ACE up the researcher's sleeve?

The recent discovery of renin-like substances, ACE, immunoreactive angiotensins and angiotensin II receptors in many tissues, including blood vessels, has indicated that local renin-angiotensin systems may exist. Some of the renin activity in blood vessel walls results from uptake of plasma renin, but renin and angiotensin are also synthesised locally, independent of plasma levels. The local effects of this renin-angiotensin activity are mixed. Vasoconstriction can arise from direct stimulation of vascular smooth muscle receptors and increased catecholamine release, and vasodilatation can occur by increased endothelial prostacyclin synthesis. In animal models, angiotensin causes contraction in some vessels and relaxation in others, depending on the relative contribution of the different local effects.

ACE inhibitors can lower BP independently of renin status. This was thought to be because of increased bradykinin and prostaglandin synthesis, resulting in vasodilatation. However, renin inhibitors and angiotensin antagonists, neither of which affect bradykinin or prostaglandin synthesis, also decrease BP irrespective of the renin status of the patient or study animal. In such animal models with hypertension and normal plasma renin activity, increased vascular renin-angiotensin activity has been demonstrated. Thus, it appears that elevated vascular angiotensin II may significantly contribute to hypertension. In a number of studies, the duration and extent of th~ antihypertensive effects of ACE inhibitors have correlated more closely with local, rather than plasma ACE activity. It has been suggested that the main antihypertensive effects are mediated through ACE inhibition in blood vessels, and possibly in the heart and kidney, and the effect on plasma renin activity is responsible only for short term BP reduction. Thus, the efficacy of an ACE inhibitor is dependent on its tissue levels, and serum half-life has a minimal impact on duration of action. The physicochemical properties of the drug are therefore important, influencing distribution in different tissues. For example, captopril and enalapril concentrations differ in some tissues, with enalapril inhibiting ACE longer in the heart and kidney. The sulfhydryl group of captopril appears to influence its .Iocal tissue activity, as captopril, but not enalapril, stimulates prostaglandin synthesis. Thus, by correlating chemical structure of the ACE inhibitors with their physiological activity, it is conceivable that a range of drugs with unique and specific physiological actions can be synthesised. Dzau VJ. American Journal of Medicine 84 (Suppl. 4A): 4·8. Apr 1988 ,.,.

0156-2703/ 88/ 0709-0003/ 0$01 .00/ 0 © ADIS Press INPHARMA® 9 July 1988 3