Diadenosine tetraphosphate (AP4A) mimics cardioprotective effect of ischemic preconditioning in the rat heart: contribution of K-ATP channel and PKC

Diadenosine tetraphosphate (AP4A) administration is reported to mimic the e ffect of ischemic preconditioning (PC) via purine 2y receptors (P2yR) and a denosine receptors. This study was designed to test the contributions of th e ATP-sensitive potassium channel (K-ATP channel) and protein kinase C (PKC ), two of the main regulator in PC, to the effect of AP4A. Isolated buffer- perfused rat hearts were subjected to 20 min of global ischemia (37 degrees C) and 20 min of reperfusion. Three cycles of 1-min ischemia and 3-min rep erfusion induced PC. Chemicals were administrated for 2 min before 20 min o f ischemia. AP4A (10 mu M) administration was as effective as PC in improvi ng the recovery of post-ischemic contractile function and reducing creatine kinase leakage after reperfusion, whereas adenosine (10 and 100 mu M) have not effect. AP4A had not effect on reperfusion-induced arrhythmia, whereas PC significantly prevented it. These effects of AP4A and PC were reversed by co-administration of glibenclimade (K-ATP channel blocker, 100 mu M) and GF109203X (PKC inhibitor, 10 mu M); the effects of AP4A but not PC were re versed by co-administration of reactive blue (P2yR antagonist, 13 nM). AP4A appears to activate the K-ATP channel and PKC via P2yR mimic the effects o f PC in part. The role of P2yR indicated that trigger mechanism of the effe ct of PC and AP4A administration might differ in rat hearts.