Different Actions of Cardioprotective Agents on Mitochondrial Ca^<2+> Regulation in a Ca^<2+> Paradox-Induced Ca^<2+> Overload

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Background Mitochondrial Ca^<2+> overload is a major cause of irreversible cell injury during various metabolic stresses. The protective effects of various agents that affect mitochondrial function against Ca^<2+> overload during Ca^<2+> paradox were investigated in rat ventricular myocytes. Methods and Results On Ca^<2+> repletion following Ca^<2+> depletion, [Ca^<2+>]_i increased rapidly, and 90 of 210 cells (43%) died. In viable cells, the increase in [Ca^<2+>]_i was lower than in dead cells. KB-R7943 prevented the increase in [Ca^<2+>]_i, and completely inhibited cell death. Ruthenium red (RuR), diazoxide (Dz) or cyclosporin A (CsA) prevented cell death (15%, 26% and 17%, respectively; p<0.05), and the protective effect of Dz was abolished by 5-hydroxydecanoate. These agents did not reduce the increase in [Ca^<2+>]_i in viable cells or the rate of initial increase in [Ca^<2+>]_i in all cells. RuR and Dz decreased [Ca^<2+>]_m in skinned myocytes, but CsA did not affect [Ca^<2+>]_m. Dz reduced NADH fluorescence, whereas RuR and CsA did not. Conclusions The protective effects of RuR and Dz could be ascribed to altered Ca^<2+> regulation by decreasing [Ca^<2+>]_m, and Dz could have an additional effect on oxidative phosphorylation. The protective effect of CsA could be directly associated with the mitochondrial permeability transition pore.
社団法人日本循環器学会の論文
2005-08-20