CARDIOPROTECTION IN ISCHEMIC RAT HEARTS WITH THE SH-CONTAINING ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR ZOFENOPRIL - POSSIBLE INVOLVEMENT OFTHE ATP-SENSITIVE POTASSIUM CHANNEL

The SH-containing angiotensin-converting enzyme (ACE) inhibitors zofen opril and captopril have been shown to protect the ischemic myocardium independently of ACE inhibition. Zofenopril (30-100 muM) enhanced rep erfusion contractile function and reduced lactate dehydrogenase releas e. The cardioprotective activity of zofenopril was stereoselective in isolated globally ischemic rat hearts (S, S,R stereoisomer of zofenopr il was inactive). The role of ATP-sensitive potassium channel (K(ATP)) activation was investigated using two structurally different K(ATP) b lockers, 1 muM glyburide and 100 muM sodium 5-hydroxydecanoate. The ca rdioprotective activity of 100 muM zofenopril was abolished by both K( ATP) blockers. Cardioprotection with the SH-containing compound n-acet yl cysteine (300 muM) was also reversed by glyburide, further demonstr ating that ACE inhibition is not a prerequisite. Isobolographic analys is demonstrated that cotreatment with zofenopril and the K(ATP) opener cromakalim resulted in a super-additive response in the ischemic myoc ardium. K(B) analysis demonstrated glyburide was a noncompetitive anta gonist in the presence of zofenopril and a competitive antagonist in t he presence of cromakalim. Zofenopril has been reported to cause relax ation in aortic smooth muscle rings via an endothelium-dependent compo nent. This relaxation was shifted to the right by both glyburide and s odium 5-hydroxydecanoate. Isobolographic analysis of zofenopril and cr omakalim in smooth muscle also demonstrated a super-additive response. These results demonstrate for the first time a link between the cardi oprotective effects of the SH-containing compounds zofenopril and n-ac etyl cysteine and the K(ATP). The activity appears to be a receptor-me diated event which occurs in a manner different from classical K(ATP) openers such as cromakalim.