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 mu M) end chelerythrine (2 mu M) on myocardial ischemia-reperfusion injury in in situ and isolated perfused rabbit hearts. In non-ischemic isolated hearts, bisindolylmaleimide (1 mu M) and chelerythrine (2 mu M) blocked sn-1,2-dioctanoylglycerol (DOG)-induced coronary vasoconstriction by approximately 80%, Intact hearts were subjected to 45 min coronary artery occlusion and 2h 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, PI(C inhibitors can be cardioprotective during prolonged ischemia. (C) 1997 Academic Press Limited.