Angiotensin-Converting Enzyme and Converting Enzyme Inhibitors

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Abstract
Angiotensin I (AngI), an inactive decapeptide generated by action of the enzyme renin on a glycoprotein substrate angiotensinogen, is converted to the active pressor octapeptide angiotensin II (AngII). The exopeptidase responsible for this conversion was first identified and isolated in plasma by Skeggs et al., 1 who accordingly named it angiotensin-converting enzyme (ACE). This enzyme was later found to be the same enzyme as kininase II, and is able to hydrolyze bradykinin and various other peptides. 2 , 3 The conversion of AngI to AngII was assumed to take place in the circulation until Ng and Vane 4 determined that the enzyme activity present in the plasma was insufficient to account for the rapidity of the in vivo conversion and demonstrated that most of the conversion of circulating AngI to AngII occurred during passage through the lungs. The importance of the lung as a site of ACE activity was confirmed by Stanley and Biron, 5 who demonstrated that conversion of AngI to AngII in dogs on cardiopulmonary bypass was markedly lowered. However, the amount of conversion was still higher than that in blood alone, suggesting that ACE was present in vascular beds other than the lungs. Indeed, this dipeptidyl carboxypeptidase has been found to be widely distributed throughout the body as a membrane-bound ectoenzyme on the surface of vascular endothelial cells and epithelial cells of many organs. Since AngII is a potent vasoconstrictor shown to be involved in normal blood pressure regulation as well as in the pathogenesis of hypertension, it is believed that ACE plays a role in blood pressure regulation. In fact, over the past 10 years, inhibitors of ACE have become highly effective agents in the treatment of hypertension and heart failure. 10 – 13 In spite of the effectiveness of converting enzyme inhibitors in lowering blood pressure, the antihypertensive mechanisms of these agents are not fully understood.

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