Rationale and pharmacology of angiotensin II receptor antagonists: current status and future issues

The renin-angiotensin system consists of a cascade of substrate-enzyme interactions that culminates with the production of angiotensin 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-angiotensin system is implicated in the control of blood pressure, sodium and water homeostasis, and cardiovascular function and structure.

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 treatment of hypertension and cardiovascular disease. However, these compounds are limited in the extent to which they block the renin-angiotensin system, partly due to recently described alternate pathways for the genesis of angiotensin II and also because ACE is not a very specific enzyme and has multiple other potential substrates including bradykinin, tachykinins, neurotensin substance P, and others.

The development of angiotensin II receptor antagonists represents a new way to block the renin-angiotensin system at the receptor level. Irbesartan is a new angiotensin II receptor antagonist that provides specific and insurmountable antagonism of the AT1 receptor subtype, demonstrating a greater than 8500-fold specificity for the AT1 receptor, the subtype which mediates all the known actions of angiotensin, compared to the AT2 receptor. Comparative studies have demonstrated that irbesartan is 10 times more potent than losartan and slightly more potent than E3174, losartan's active metabolite. Preclinical pharmacological studies in a variety of animal models have demonstrated that irbesartan provides a dose-dependent, insurmountable blockade of angiotensin and reductions in blood pressure, urinary protein and glomerular sclerosis score.