Mechanism of preconditioning against myocardial infarction

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Previous studies, including ours, demonstrated that activation of A1 receptor triggers the cardioprotective effect of ischemic preconditioning (PC). However, mechanism subsequent to the A1 receptor activation remains unclear. The present study aimed to test the roles of Na-H exchanger, ATP sensitive potassium channel (KATP), and protein kinase C in preconditioning. Under pentobarbital anesthesia, myocardial infarction was induced in the rabbit by occluding coronary artery for 30 min and reperfusion. Preconditioning with 5 min ischemia/5 min reperfusion limited infarct size to approximately 40% of thecontrol values. An inhibitor of Na-H exchanger, amiloride (1.3 mg/kg and 3.0 mg/kg) given 60 min before PC failed to block preconditioning, though this agent significantly reduces arterial pH and HCO3^-, suggesting inhibition of Na-H exchanger in the kidneys. A specific blocker of KATP,glibenclamide (0.3 mg/kg) attenuated PC in the rabbit anesthetized with pentobarbital/xylazine, but such inhibitory effect was not observed in those given pentobarbital alone. Two different PKC inhibitors, staurosporine (50 mug/kg) and polymyxin B (2.5 mg/kg) completely abolished infarct size-limiting effect of an A1 receptor agonist, R-phenylisopropyladenosine, which mimics preconditioning. Those doses of staurosporine and polymyxin B were shown to block inotropic response to 4beta-12-myristate 13-acetate in the rabbits, suggesting that the dose of the PKC inhibitors were sufficient to block PKC in vivo. These results suggest that activation of PKC subsequent to A1 receptor activation mediates infarct size limitation by preconditioning in the rabbit. KATP may also contribute to preconditioning, but its role may be modified by anesthetics. Relationship between PKC and KATP warrants further investigation.