Abstract
Amiodarone is a widely used and potent antiarrhythmic agent that is metabolized to desethylamiodarone. Both amiodarone and its metabolite possess antiarrhythmic effect, and both compounds can contribute to toxic side effects. Here, we compare the effect of amiodarone and desethylamiodarone on mitochondrial energy metabolism, membrane potential, and permeability transition and on mitochondria-related apoptotic events. Amiodarone but not desethylamiodarone protects the mitochondrial energy metabolism of the perfused heart during ischemia in perfused hearts. At low concentrations, amiodarone stimulated state 4 respiration due to an uncoupling effect, inhibited the Ca2+-induced mitochondrial swelling, whereas it dissipated the mitochondrial membrane potential (Δψ), and prevented the ischemia-reperfusion-induced release of apoptosis-inducing factor (AIF). At higher concentrations, amiodarone inhibited the mitochondrial respiration and simulated a cyclosporin A (CsA)-independent mitochondrial swelling. In contrast to these, desethylamiodarone did not stimulate state 4 respiration, did not inhibit the Ca2+-induced mitochondrial permeability transition, did not induce the collapse of Δψ in low concentrations, and did not prevent the nuclear translocation of AIF in perfused rat hearts, but it induced a CsA-independent mitochondrial swelling at higher concentration, like amiodarone. That is, desethylamiodarone lacks the protective effect of amiodarone seen at low concentrations, such as the inhibition of calcium-induced mitochondrial permeability transition and inhibition of the nuclear translocation of the proapoptotic AIF. On the other hand, both amiodarone and desethylamiodarone at higher concentration induced a CsA-independent mitochondrial swelling, resulting in apoptotic death that explains their extracardiac toxic effect.
Footnotes
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This work was supported by Hungarian Science Foundation T023076, Ministry of Health and Welfare ETT 35/2000, PTE-DD-KKK, and NKFP 1/026, and by Wellcome Trust 059917.
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DOI: 10.1124/jpet.103.053553.
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ABBREVIATIONS. Δψ, mitochondrial membrane potential; AIF, apoptosis-inducing factor; ROS, reactive oxygen species; CsA, cyclosporin A; Rh123, rhodamine 123; DRh123, dihydrorhodamine 123; Dea, desethylamiodarone; MTT+, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; ANOVA, analysis of variance; FCCP, carbonylcyanide p-trifluoro-methoxyphenylhydrazone.
- Received April 28, 2003.
- Accepted August 4, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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