GLYBURIDE-REVERSIBLE CARDIOPROTECTIVE EFFECTS OF CALCIUM-INDEPENDENT PHOSPHOLIPASE A(2) INHIBITION IN ISCHEMIC RAT HEARTS

Objectives: A myocardial calcium-independent PLA(2) has been described that is activated during myocardial ischemia and this enzyme may modu late ATP-sensitive potassium channels (K-ATP). The aim of this study w as to determine the effect of an inhibitor of this enzyme, a bromoenol lactone, in isolated globally ischemic rat hearts. Methods: Isolated rat hearts were treated for 10 min with 0.3-6 mu M bromoenol lactone a nd then subjected to 25 min ischemia and 30 min reperfusion. Results: The bromoenol lactone significantly increased coronary flow in nonisch emic myocardium, and slightly reduced cardiac function at 6 mu M Durin g global ischemia, time to contracture was significantly increased fro m vehicle group values in the presence of the bromoenol lactone (EC(50 ) = 1.2 mu M). During reperfusion, a concentration-dependent increase in function and a reduction in LDH release were observed for the PLA(2 ) inhibitor. The concentrations of the PLA(2) inhibitor which were sig nificantly cardioprotective, inhibited this enzyme in membrane fractio ns of rat myocardium (IC50 = 0.87 mu M). The K-ATP blocker sodium 5-hy droxydecanoate (5-HD) inhibited the increase in time to contracture ob served for the bromoenol lactone. During reperfusion, 5-HD abolished t he protective effects of the bromoenol lactone on cardiac function and LDH release. Glyburide had similar effects on the cardioprotective ac tivity of the bromoenol lactone, although it only partially abolished the LDH reducing effect of this agent. Conclusions: The bromoenol lact one protects ischemic myocardium at concentrations which also inhibit calcium-independent PLA(2). This cardioprotection can be attenuated by blockers of K-ATP, suggesting a potential mechanism for modulation of myocardial K-ATP.