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Cardiovascular Research 1999 44(3):556-567; doi:10.1016/S0008-6363(99)00233-3
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

On the mechanism of the failure of mitochondrial function in isolated guinea-pig myocytes subjected to a Ca2+ overload

Kazunobu Ban*, Shunnosuke Handa and Reg A Chapman{dagger}

Division of Cardiology, Department of Medicine, School of Medicine, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan

* Corresponding author. Tel.: +81-463-931-121; fax: +81-463-936-679 ban{at}is.icc.u-tokai.ac.jp

Objective: The influence of agents that inhibit the movement of Ca2+ across the mitochondrial membrane or Ca2+ dependent changes to this membrane upon the response of isolated ventricular myocytes to a Ca2+ overload has been investigated. Methods: The changes of intracellular Ca2+ and Mg2+ ([Ca2+]i, [Mg2+]i) (as reflected by cellular ATP), mitochondrial membrane potential ({Psi}m) and NADH was measured upon the response of isolated ventricular myocytes to a Ca2+ overload. Results: A slow depolarization of {Psi}m during Ca2+ depletion and its prompt recovery on Ca2+ repletion were unaffected by ruthenium red, clonazepam, CGP-37157 which is a high potent inhibitor of the mitochondrial Na+/Ca2+ antiport or cyclosporin A but a large delayed sustained depolarization was inhibited. The slow small fall in [Mg2+]i on Ca2+ depletion and a rapid recovery on Ca2+ repletion were unaffected by ruthenium red, clonazepam, CGP-37157 or cyclosporin A. A delayed sustained larger rise in [Mg2+]i was inhibited. The marked sustained fall in NADH autofluorescence that occurs on Ca2+ overload was attenuated and transient in the presence of ruthenium red, CGP-37157 and cyclosporin A. Conclusion: These results are consistent with an increase in Ca2+ cycling across the mitochondrial membrane provoked by the combined Na+ and Ca2+ overload of cardiac myocytes, causing a depolarization sufficient to uncouple respiration and lead to the depletion of cellular ATP.

KEYWORDS Calcium (cellular); Mitochondria; Myocytes

{dagger} Deceased.


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