EFFECT OF REVERSIBLE ISCHEMIA ON THE ACTIVITY OF THE MITOCHONDRIAL ATPASE - RELATIONSHIP TO ISCHEMIC PRECONDITIONING

The mitochondrial ATPase enzyme accounts for roughly 35-50% of the ove rall energy demand that leads to ATP depletion under conditions of sev ere myocardial ischemia. In larger mammalian hearts, this energy squan dering action of the ATPase is modulated by an endogenous inhibitor pr otein. The present studies were undertaken to characterize the time co urse of inhibition of the mitochondrial ATPase in canine myocardium un der conditions of severe regional ischemia in vivo. In addition, we de termined if the energy sparing effects of ischemic preconditioning (PC ) can be explained by persistent inhibition of the mitochondrial ATPas e enzyme. The circumflex coronary artery was ligated for 1.5 min (n=4) , 5 min (n=6), or 15 min (n=5). In a separate group (n=7), hearts were preconditioned by four 5-min periods of ischemia each followed by 5 m in of reperfusion. Sub-mitochondrial particles were prepared from the sub-endocardial zone of the ischemic and nonischemic regions and were assayed for oligomycin-sensitive ATPase activity. ATPase activity was reduced to about 79% at 1.5 min and to approximately 55% at 5 and 15 m in of ischemia, relative to non-ischemic tissue from the same heart. T he rate of HEP utilization slowed concurrently with the development of ATPase inhibition. In preconditioned myocardium, ATPase activity was not significantly different from control myocardium from the same hear t. We conclude that the early inhibition of the mitochondrial ATPase a ctivity slows the utilization of high energy phosphate and thereby ser ves as an important endogenous cardioprotective mechanism. Nevertheles s, altered activity of the ATPase is not the explanation of the energy sparing effect of ischemic preconditioning. (C) 1996 Academic Press L imited