Different actions of cardioprotective agents on mitochondrial Ca2+ regulation in a Ca2+ paradox-induced Ca2+ overload

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 [Ca2+]i in viable cells or the rate of initial increase in [Ca(2+)]i in all cells. RuR and Dz decreased [Ca2+]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.