Cardioprotection with ACE inhibitors: non-angiotensin II-related mechanisms

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in variou s tissues and organs, most notably within the endothelium. This localized A CE, known as tissue ACE, is now recognized as a key factor in cardiovascula r and renal disease. ACE activation, in response to a number of risk factor s or injury, such as hypertension, diabetes mellitus, hypercholesterolaemia , cigarette smoking, acute ischaemia and heart failure, has deleterious eff ects on the heart, vasculature and the kidneys. Furthermore, local ACE acti vation contributes to endothelial dysfunction, a condition in which the bal ance between vasodilation and vasoconstriction, vascular smooth muscle cell growth, and the inflammatory and oxidative state of the vessel wall is dis rupted. These effects are mediated through increased local formation of ang iotensin II and decreased bradykinin (BK) formation. Thus, the selective in hibition of tissue ACE favourably modifies the underlying pathophysiology o f cardiovascular disease. The enhanced BK availability consequent on ACE in hibition seems to be particularly relevant for the improvement in endotheli al dysfunction which, in turn, is pivotal for the anti-ischaemic profile of ACE inhibition. BK exerts several effects on the endothelium, including ph ysiological stimulation of endothelial constitutive nitric oxide (NO) synth etase (ecNOS), the key enzyme for NO production. In addition, it exerts pot ent anti-growth action as well as a pre-conditioning effect on the heart. Recent evidence suggests that ACE inhibitors may be differentiated from one another according to their binding affinity for tissue ACE and their capac ity for improving BK formation. This distinction is important: whereas all ACE inhibitors effectively reduce high blood pressure, the greatest biologi cal and structural cardio- and renoprotective effects of ACE inhibition may be attributed to those agents with the highest affinity for tissue ACE and for reversing BK breakdown.