Preclinical pharmacology of angiotensin II receptor antagonists: update and outstanding issues

The angiotensin II receptor antagonists (AIIRA) represent a new class of antihypertensive agents, with a mechanism of action that differs from that of other classes of antihypertensive agents that also affect the renin-angiotensin system (RAS), such as the angiotensin-converting enzyme (ACE) inhibitors. The AIIRA were developed to overcome several of the deficiencies of ACE inhibitors, which include the following: 1) competitive inhibition of the ACE enzyme results in a reactive increase in renin and angiotensin I (AI) levels, which may overcome the blockade; 2) ACE is a relatively nonspecific enzyme that has substrates in addition to AI, including bradykinin and other tachykinins; thus, inhibition of ACE may also result in accumulation of these substrates; 3) production of AII can occur through non-ACE pathways, in addition to being produced by the primary ACE pathway; these alternative pathways are unaffected by ACE inhibition; and 4) specific adverse effects are associated with inhibition of the ACE enzyme. This review summarizes the preclinical pharmacology of the AIIRA class of agents and describe the means by which the deficiencies associated with ACE inhibition are overcome. The specific characteristics of the new AIIRA irbesartan are described.