MECHANISMS OF ISCHEMIC PRECONDITIONING IN RAT MYOCARDIUM - ROLES OF ADENOSINE, CELLULAR-ENERGY STATE, AND MITOCHONDRIAL F1F0-ATPASE

Background Adenosine has been proposed as one mediator for the precond itioning effect in the myocardium of some animals, but recent investig ations have shown that this may not be the mechanism in the rat heart, although the effect itself is clearly demonstrable. The cellular ener gy state has been shown to be better in preconditioned hearts, and the role of ATP consumption has been discussed. The role of inhibition of mitochondrial F1Fo-ATPase as a mechanism for the preservation of ATP in preconditioned hearts remains controversial. Methods and Results Th ree-minute global ischemia followed by 9 minutes of reperfusion was us ed to precondition Langendorff-perfused rat hearts, and control hearts were perfused under normoxic conditions for the same time. The durati on of sustained ischemia in both groups of hearts was 21 minutes, afte r which the hearts were reperfused for 15 minutes to evaluate their me chanical and metabolic recovery. Separate experiments were performed f or tissue metabolite determinations, mitochondrial ATPase activity mea surements, and P-31 nuclear magnetic resonance studies. The recovery o f the rate-pressure product was better in the preconditioned group. Th ree-minute preconditioning ischemia caused inhibition of the mitochond rial ATPase that persisted throughout the 9-minute intervening reperfu sion so that at the early stages of sustained ischemia the enzyme acti vity was still more inhibited in preconditioned hearts. ATP was better preserved in preconditioned hearts than in control hearts during sust ained ischemia. The accumulation of adenosine and its degradation prod ucts during sustained ischemia was greater in the control group. More lactate and H+ ions accumulated in this group, indicating higher anaer obic glycolysis. Also, inhibition of mitochondrial ATPase by oligomyci n slowed ATP depletion during ischemia. Conclusions The results indica te that preconditioning causes inhibition of rat heart mitochondrial A TPase that persists during reperfusion so that the enzyme is inhibited from the very beginning of the sustained ischemia. This inhibition le ads to sparing of high-energy phosphates and improves the time-average d energy state during ischemia. Although a causal relationship is diff icult to prove, this reversible inhibition may contribute to postische mic recovery of the heart.