Abstract
[Background] Much attention has been devoted to the role of apoptosis in the pathogenesis of drug-induced cardiac toxicity. However, the pro-apoptotic effects of antiarrhythmic drugs are poorly understood. Therefore, we examined the effects of several antiarrhythmic drugs, i.e., pilsicainide, propranolol, nifekalant, verapamil, and amiodarone, on apoptotic parameters in H9c2 cardiac cells. [Methods] The cultured H9c2 cells were incubated for 24 hours with 1, 2, 4, and 8 times the highest clinically attainable concentration of each drug. To determine apoptosis in H9c2 cells, mitochondrial transmembrane potential (Δψm) and the percentage of the cells with hypodiploid DNA were measured quantitatively by flow cytometric assay with DiOC6(3) and propidium iodide, respectively. The activity of caspase-3 was determined by colorimetric protease assay. [Results] Amiodarone at 4 and 8 times but not at 2 times or less the highest clinically attainable concentration induced loss of Δψm, the occurrence of hypodiploid cells, and activation of caspase-3. Other drugs did not produce these pro-apoptoic effects even at 8 times the concentration. [Conclusion] All the antiarrhythmic drugs tested except amiodarone did not induce apoptosis in the H9c2 cells up to the level of 8 times the greatest therapeutic range. Na+, K+ and Ca2+ channels blockers, or β adrenergic receptor antagonist did not induce apoptosis, suggesting that the pro-apoptotic effect of amiodarone is independent of its multichannel blocking actions. [Jpn J Physiol 55 Suppl:S95 (2005)]
