Different Actions of Cardioprotective Agents on Mitochondrial Ca²⁺ Regulation in a Ca²⁺ Paradox-Induced Ca²⁺ Overload

Abstract

Background Mitochondrial Ca²⁺ overload is a major cause of irreversible cell injury during various metabolic stresses. The protective effects of various agents that affect mitochondrial function against Ca²⁺ overload during Ca²⁺ paradox were investigated in rat ventricular myocytes. Methods and Results On Ca²⁺ repletion following Ca²⁺ depletion, [Ca²⁺]_i increased rapidly, and 90 of 210 cells (43%) died. In viable cells, the increase in [Ca²⁺] _i was lower than in dead cells. KB-R7943 prevented the increase in [Ca²⁺]_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 [Ca²⁺]_i in viable cells or the rate of initial increase in [Ca²⁺] _i in all cells. RuR and Dz decreased [Ca²⁺] _m in skinned myocytes, but CsA did not affect [Ca²⁺] _m. Dz reduced NADH fluorescence, whereas RuR and CsA did not. Conclusions The protective effects of RuR and Dz could be ascribed to altered Ca²⁺ regulation by decreasing [Ca²⁺]_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. (Circ J 2005; 69: 1132 - 1140)