RATIONALE AND PHARMACOLOGY OF ANGIOTENSIN-II RECEPTOR ANTAGONISTS - CURRENT STATUS AND FUTURE-ISSUES

Background The renin-angiotensin system consists of a cascade of subst rate-enzyme interactions that culminates with the production of angiot ensin II, the active peptide responsible for all the known effects of the renin-angiotensin system, Blocking this enzymatic cascade has been the focus of considerable research to the extent that the renin-angio tensin system is implicated in the control of blood pressure, sodium a nd water homeostasis, and cardiovascular function and structure. Angio tensin converting enzyme inhibitors Angiotensin converting enzyme (ACE ) inhibitors provide one way of blocking the renin-angiotensin system, and to this end the compounds have proved efficacious in the treatmen t of hypertension and cardiovascular disease, However, these compounds are limited in the extent to which they block the renin-angiotensin s ystem, partly due to recently described alternate pathways for the gen esis of angiotensin I I and also because ACE is not a very specific en zyme and has multiple other potential substrates including bradykinin, tachykinins, neurotensin substance P, and others. Angiotensin II rece ptors The development of angiotensin II receptor antagonists represent s a new way to block the renin-angiotensin system at the receptor leve l, Irbesartan is a new angiotensin II receptor antagonist that provide s specific and insurmountable antagonism of the AT(1) receptor subtype , demonstrating a greater than 8500-fold specificity for the AT(1) rec eptor, the subtype which mediates all the known actions of angiotensin , compared to the AT(2) receptor. Comparative studies have demonstrate d that irbesartan is 10 times more potent than losartan and slightly m ore potent than E3174, losartan's active metabolite. Preclinical pharm acological studies in a variety of animal models have demonstrated tha t irbesartan provides a dose-dependent, insurmountable blockade of ang iotensin and reductions in blood pressure, urinary protein and glomeru lar sclerosis score.