Maintenance for the positive inotropic effect in ischemic myocardial mitochondria and the development of new cardiac drug.

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Cardiac mitochondria are recognized to play an essential role in the pumping action of the heart. Mitochondria (about 30% volume) and heart muscle cells form an intimate symbiotic relationship the basic myocardial functions of which are maintenance via energy production/utilization and ion transport mechanisms. Therefore, we used ^<31>P-NMR and fluorometry to measure energy currency-related substances of ALP, PCr etc and various ions of H^+ Ca^<2+>, Na^+ in mitochondria. In 1998, we found that the protective effects of Na-H exchange inhibitor against ischemia/reperfusion injury are due in part to the Ca^<2+>-paradox at the mitochondrial level. The elevation of mitochondrial pH by the perfusate containing Na^+ or K^+ indicate the existence of antiport mechanisms (Na-H, K-H) between protons an these monovalent cations in the mitochondrial membrane. Matrix Ca^<2+1> in mitochondria preloaded with abnormally high Ca^<2+> were elevated by reperfusion of either with physiological concentratio … More n of Ca^<2+> or acidified perfusate of pH 6.5. This finding will interpret the Ca^<2+>-paradox at mitochondria level. In 1999, we concluded that eNOS exits in mitochondria, and that NO may play an important protective role against reperfusion cardiac injury after ischemia, by inhibiting the Ca^<2+> influx into mitochondria which are otherwise damaged by O_2^-. The production of reactive oxygen species and NO in isolated mitochondria was detected by EPR.Pretreatment with SNAP or NOC5, which spontaneously generate NO, completely inhibited the mitochondrial Ca^<2+> (Cam) uptake. The agents that inhibit Cam influx improve contractility even in Langendorff preparations after ischemia. Therefore, NO exogenously supplied by NO donor (FK409) was responsible for the cardioprotective action, presumably by acting directly as an oxygen radical scavenger during reperfusion. Antioxidant effects of 5HT derivatives from safflower or 5HT_<2A>-blocker increasing the NO basal level might play an important role in ischemia-reperfusion injury hearts in close relation with NO. Less