Effects of protein kinase C inhibitors in in situ and isolated ischemic rabbit myocardium.
We tested the effects of the protein kinase C (PKC) inhibitors bisindolylmaleimide (1 microM) and chelerythrine (2 microM) on myocardial ischemia-reperfusion injury in in situ and isolated perfused rabbit hearts. In non-ischemic isolated hearts, bisindolylmaleimide (1 microM) and chelerythrine (2 microM) blocked sn-1,2-dioctanoylglycerol (DOG)-induced coronary vasoconstriction by approximately 80%. Intact hearts were subjected to 45 min coronary artery occlusion and 2 h reperfusion. Infarct size, determined by triphenyltetrazolium chloride (TTC)-staining and expressed as percentage of risk area, was reduced approximately 50% by both bisindolylmaleimide (0.05 mg/kg, i.v.) and chelerythrine (0.1 mg/kg, i.v.) compared to vehicle treated controls. In contrast, a higher dose of chelerythrine (3.8 mg/kg, i.v.) did not significantly reduce infarct size. Isolated hearts were subjected to 45 min of global normothermic (37 degrees C) ischemia and 60 min reperfusion. Control hearts exhibited 45+/-2% recovery of pre-ischemic left ventricular developed pressure (LVDP) compared to bisindolylmaleimide- (73+/-7%) and chelerythrine-treated hearts (70+/-11%). Bisindolylmaleimide and cherythrine reduced infarct size from a control value of 24+/-4 to 8+/-2 and 9+/-3%, respectively. Preconditioning isolated hearts with 5 min ischemia and 10 min reperfusion prior to prolonged ischemia reduced infarct size to 10.4+/-2.3%, an effect which was blocked by chelerythrine (22.5+/-4.2% infarct size). These results suggest that although PKC may play a role in ischemic preconditioning, PKC inhibitors can be cardioprotective during prolonged ischemia.
Lasley
R D
RD
Department of Surgery, University of Wisconsin School of Medicine, Madison, WI, USA.
Noble
M A
MA
Mentzer
R M
RM
D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009203:Myocardial Infarction / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011687:Purines / Q000378:metabolism; D011817:Rabbits
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D010617:Phenanthridines; D011687:Purines; C016299:chelerythrine; D011493:Protein Kinase C; C088060:bisindolylmaleimide