Effect of calmodulin and protein kinase C inhibitors on globally ischemic rat hearts.
Several calmodulin inhibitors have been reported to be cardioprotective, but the ability of these compounds to inhibit protein kinase C (PKC) suggests that calmodulin inhibition may not be the sole mechanism responsible. To distinguish between the effects, we determined the cardioprotective activity of several calmodulin inhibitors with differing PKC inhibitory potencies in isolated globally ischemic rat hearts. Twenty-five minutes of global ischemia caused significant myocardial dysfunction, contracture formation, and lactate dehydrogenase (LDH) release on reperfusion in vehicle-treated hearts. The calmodulin inhibitors trifluoperazine, W-7, calmidazolium, W-13, and CGS 9343B improved postischemic contractile function and/or reduced LDH release. They also reduced preischemic cardiac function, although cardioprotection did not appear to be correlated with cardiodepression. Calmodulin inhibitors increased preischemic coronary flow (CF) and decreased heart rate (HR), but controlling these parameters did not affect the cardioprotection. Pretreatment of ischemic hearts with trifluoperazine was associated with preservation of myocardial ATP. Pretreatment of ischemic rat hearts with the PKC inhibitors staurosporine, calphostin C, polymyxin B, and H-7 did not result in cardioprotection. Thus, calmodulin inhibition causes cardioprotection that appears to be independent of PKC inhibition.
Sargent
C A
CA
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543.
Sleph
P G
PG
Dzwonczyk
S
S
Smith
M A
MA
Grover
G J
GJ
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D003327:Coronary Disease / Q000188:drug therapy* / Q000503:physiopathology; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009281:Naphthalenes; D010879:Piperazines / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D019311:Staurosporine; D013449:Sulfonamides / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology
D000470:Alkaloids; D001562:Benzimidazoles; D002147:Calmodulin; D007546:Isoquinolines; D009281:Naphthalenes; D010879:Piperazines; D011083:Polycyclic Compounds; D013449:Sulfonamides; C052087:CGS 9343B; D014268:Trifluoperazine; C017967:W 7; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C; D019311:Staurosporine; C058819:calphostin C; D011112:Polymyxin B