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.
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.
Authors: J Santo-Domingo; L Vay; E Hernández-Sanmiguel; C D Lobatón; A Moreno; M Montero; J Alvarez Journal: Br J Pharmacol Date: 2007-04-30 Impact factor: 8.739
Authors: Alessandro Rimessi; Chiara Pozzato; Lorenzo Carparelli; Alice Rossi; Serena Ranucci; Ida De Fino; Cristina Cigana; Anna Talarico; Mariusz R Wieckowski; Carla M P Ribeiro; Claudio Trapella; Giacomo Rossi; Giulio Cabrini; Alessandra Bragonzi; Paolo Pinton Journal: Sci Adv Date: 2020-05-06 Impact factor: 14.136