Cardioprotection in ischemic rat hearts with the SH-containing angiotensin-converting enzyme inhibitor zofenopril: possible involvement of the ATP-sensitive potassium channel.
The SH-containing angiotensin-converting enzyme (ACE) inhibitors zofenopril and captopril have been shown to protect the ischemic myocardium independently of ACE inhibition. Zofenopril (30-100 microM) enhanced reperfusion contractile function and reduced lactate dehydrogenase release. The cardioprotective activity of zofenopril was stereoselective in isolated globally ischemic rat hearts (S, S,R stereoisomer of zofenopril was inactive). The role of ATP-sensitive potassium channel (KATP) activation was investigated using two structurally different KATP blockers, 1 microM glyburide and 100 microM sodium 5-hydroxydecanoate. The cardioprotective activity of 100 microM zofenopril was abolished by both KATP blockers. Cardioprotection with the SH-containing compound n-acetyl cysteine (300 microM) was also reversed by glyburide, further demonstrating that ACE inhibition is not a prerequisite. Isobolographic analysis demonstrated that cotreatment with zofenopril and the KATP opener cromakalim resulted in a super-additive response in the ischemic myocardium. KB analysis demonstrated glyburide was a noncompetitive antagonist in the presence of zofenopril and a competitive antagonist in the presence of cromakalim. Zofenopril has been reported to cause relaxation in aortic smooth muscle rings via an endothelium-dependent component. This relaxation was shifted to the right by both glyburide and sodium 5-hydroxydecanoate. Isobolographic analysis of zofenopril and cromakalim in smooth muscle also demonstrated a super-additive response. These results demonstrate for the first time a link between the cardioprotective effects of the SH-containing compounds zofenopril and n-acetyl cysteine and the KATP. The activity appears to be a receptor-mediated event which occurs in a manner different from classical KATP openers such as cromakalim.
Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Pharmacology, Princeton, New Jersey.
C A
CA
Sargent
P G
PG
Sleph
S
S
Dzwonczyk
M A
MA
Smith
D
D
Normandin
M J
MJ
Antonaccio
G J
GJ
Grover
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000031:analogs & derivatives* / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000517:prevention & control*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000806:Angiotensin-Converting Enzyme Inhibitors; D015221:Potassium Channels; C044958:zofenopril; D000255:Adenosine Triphosphate; D002216:Captopril