Converting enzyme inhibition: search for additional mechanisms of action

Although the therapeutic usefulness of angiotensin converting enzyme (ACE) inhibitors in patients with hypertension and congestive heart failure has been clearly demonstrated, important unanswered questions remain about these drugs, including patient selection criteria, side effects, long-term effects, and especially their precise mechanism of action. The principal explanation of the effect of ACE inhibitors remains the inhibition of the renin-angiotensin system (RAS). However, in chronic treatment with ACE-inhibitory drugs, this relationship may not held true. Additional mechanisms of action postulated to explain the effect of ACE-inhibitors include inhibition of angiotensin II formation in the central RAS, neutralization of renin activity in the vascular wall, blockade of vasoconstrictor response to sympathetic nerve stimulation, and possible involvement of prostaglandins linked, for instance, to bradykinin accumulation. The search for additional mechanisms of action should lead to clinically important findings, provide a better understanding of the pathophysiology of cardiovascular disease, and improve patient treatment with ACE inhibitory drugs.