Interactions among ACE, kinins and NO

Time for primary review 22 days. Angiotensin converting enzyme (ACE) is a transmembrane zinc metallopeptidase that cleaves carboxy-terminal dipeptides from several peptides and is expressed in great amounts in vascular endothelial cells 1, 2. A soluble form of the enzyme is found in plasma which is presumably derived from the membrane-bound form by proteolytic cleavage 3. ACE plays a major role in the regulation of the vascular tone by converting the biological inactive decapeptide angiotensin I (ANG I) into the vasoconstrictor and proliferative octapeptide angiotensin II (ANG II). In a similar manner, ACE inactivates the vasodilatory nonapeptide bradykinin (BK), which derives from a number of different sources 4. Endothelium-derived or exogenously added BK exerts its vasodilatory action through stimulation of endothelial B2 kinin receptors thereby causing the synthesis and release of vasodilator substances such as endothelium-derived hyperpolarizing factor (EDHF) 5, prostacyclin and nitric oxide (NO) 6. Many of the effects of NO on platelets 7, smooth muscle cells 8, and cardiac myocytes 9, 10 are mediated by activation of soluble guanylyl cyclase to synthesize cyclic GMP. The biological function of soluble guanylyl cyclase and NO/cyclic GMP in endothelial cells is not yet completely understood. One function of endothelial cyclic GMP may be a negative feed-back mechanism to turn off further NO synthesis 11, 12. Changes in the synthesis of ACE, BK and NO are associated with a number of cardiovascular conditions including hypertension, atherosclerosis or coronary heart disease. ACE inhibitors are able to treat these diseases by both, accumulation of endothelium-derived kinins and the inhibition of ANG II 13, 14. The separate effects of ACE, kinins as well as NO on the cardiovascular system have been thoroughly investigated and described. Since only a small amount of information is available concerning the physiological/pathophysiological significance of … * Corresponding author. Tel.: +49-69-305-6868, fax: +49-69-305-81252 wolfgang. linzathmrag. com