Recent studies have indicated that repeated brief episodes of
ischemia and reperfusion render the myocardium more tolerant to subsequent lethal ischemic injury. In view of the previous observations that
ischemia-reperfusion potentiates
phospholipase D signaling and that such signaling is beneficial for the heart, we investigated whether a similar
phospholipase D signaling is responsible for the beneficial effects associated with repeated
ischemia and reperfusion. Using an isolated perfused working rat heart model, we demonstrated that four brief episodes of 5 min of
ischemia and 10 min of reperfusion reduced the incidence of ventricular arrhythmias, enhanced the postischemic ventricular performance, and decreased the release of
creatine kinase from the reperfused heart, with simultaneous activation of
phospholipase D generating the second messengers
diacylglycerol and
phosphatidic acid and leading to the translocation and activation of
protein kinase C. The specific antiphospholipase D antibody blocked the activation of
phospholipase D and attenuated the generation of
diacylglycerol and
phosphatidic acid and activation of
protein kinase C. In concert,
phospholipase D inhibition increased the incidence of ventricular arrhythmias, blocked the beneficial effects of preconditioning on the ventricular performance, and increased the amount of
creatine kinase release from the coronary effluent. The results of this study indicate that repeated brief episodes of
ischemia and reperfusion exert beneficial effects on the intact rat heart by triggering the activation of a
phospholipase D signaling mechanism.