Verapamil but not calpain or creatine alters arsenate-induced cardiac cell death.
The objective of this study was to examine the potential of arsenate to induce cardiomyocyte cell death and to explore the cellular mechanisms of arsenate toxicity. Isolated cardiomyocytes in culture from embryonic chick hearts were treated with a pentavalent arsenic species (H3AsO4) or arsenate. Arsenate produced a significant (P < 0.01) concentration-dependent increase in cell death with an EC50 about 1 mM. Cardiomyocytes manifested a loss of actin structure, reduced size, and damaged nuclei. Creatine 0.1-100 uM did not significantly modify arsenate-induced cell death. In contrast, verapamil, 0.01-1 uM, produced a significant concentration-dependent accentuation of arsenate-induced cell death. The effect of verapamil was evident at low concentrations of arsenate, which produced only a small increase in cell death, and at high concentrations of arsenate, which induced a large amount of cell death. Verapamil alone did not alter cardiomyocyte cell death. By comparison, calpain inhibitor II did not modify arsenate-induced cardiomyocyte cell death. These data suggest that cardiomyocytes are vulnerable to the effects of verapamil to increase the cellular toxicity of arsenate. Two potential cellular mechanisms of arsenate toxicity, however, are likely not involved in arsenate toxicity namely calpain activation and reduction of creatine phosphate production.
Luong
M W
MW
Department of Medicine (Cardiology), University of British Columbia, Vancouver, British Columbia, Canada.
Rabkin
S W
SW
D000818:Animals; D001149:Arsenates / Q000494:pharmacology*; D002154:Calpain / Q000494:pharmacology*; D016923:Cell Death; D002642:Chick Embryo; D003401:Creatine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*
D001149:Arsenates; D009842:Oligopeptides; C069861:calpain inhibitor 2; D014700:Verapamil; D002154:Calpain; D003401:Creatine; C025657:arsenic acid