MECHANISM OF MITOCHONDRIAL K_<ATP> CHANNEL-MEDIATED CARDIOPROTECTION

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MITOCHONDRIAL ATP-SENSITIVE POTASSIUM (MITO-K_<ATP>) CHANNELS ARE THOUGHT TO PLAY A KEY ROLE IN ISCHEMIC PRECONDITIONING. THIS STUDY WAS UNDERTAKEN TO KNOW THE MECHANISM OF MITO-K_<ATP> CHANNEL-MEDIATED CARDIOPROTECTION. THE RESULTS OF THIS INVESTIGATION ARE AS FOLLOWS.(1) OPENING OF MITO-K_<ATP> CHANNELS BY DIAZOXIDE DEPOLARIZED THE MITOCHONDRIAL MEMBRANE POTENTIAL AND THEREBY PRIVENTING THE MITOCHONDRIAL CALCIUM OVERLOAD. OTHER MITO-K_<ATP> CHANNEL OPENERS, NICORANDIL AND MINOXIDIL, SIMILARLY ATTENUATED THE MITOCHONDRIAL CALCIUM OVERLOAD.(2) THE KIR6.2-DEFICIENT MOUSE HEARTS IN VIVO LACK THE INFARCT SIZE-LIMITING EFFECT OF ISCHEMIC PRECONDITIONING. HOWEVER, ACTIVATION OF MITO-K_<ATP> CHANNELS BY DIAZOXIDE PROTECTED THE QUIESCENT CARDIOMYOCYTES FROM MITOCHONDRIAL CALCIUM OVERLOAD IN BOTH KIR6.2- AND KIR6.1-DEFICIENT MICE.(3) PRETREATMENT OF CARDIOMYOCYTES WITH DIAZOXIDE FOR 30 MINUTES PRIOR TO EXPOSURE TO H_2O_2 ELICITED THE TRANSIENT DEPOLARIZATION OF MITOCHONDRIAL MEMBRANE POTENTIAL, AND CONSEQUENTLY SUPPRESSED APOPTOSIS AFTER 2 HOURS EXPOSURE TO H_2O_2.THESE RESULTS, TAKEN TOGETHER, SUGGEST THAT OPENING OF MITO-KATP CHANNELS 1) PREVENTS A MITOCHONDRIAL CALCIUM OVERLOAD IN ASSOCIATION WITH DEPOLARIZATION OF MITOCHONDRIAL MEMBRANE POTENTIAL, 2) TRIGGERS CARDIOPROTECTION AGAINST APOPTOSIS INDUCED BY OXIDATIVE STRESS.