Concentration dependent mitochondrial effect of amiodarone

Gabor Varbiro, Ambrus Toth, Antal Tapodi, Balazs Veres, Balazs Sumegi, Ferenc Gallyas

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Abstract

Although, the antiarrhythmic effect of amiodarone is well characterized, its effect on post-ischemic heart and cardiomyocytes, as well as the mechanism of its toxicity on extracardiac tissues is still poorly understood. In this study, we analyzed energy metabolism in situ during ischemia-reperfusion in Langendorff-perfused heart model by measuring the high-energy phosphate metabolites using 31P NMR spectroscopy. The toxicity of amiodarone on cardiomyocytes and cell lines of extracardiac origin, as well as direct effect of the drug on mitochondrial functions in isolated mitochondria was also analyzed. Amiodarone, when was present at low concentrations and predominantly in membrane bound form, protected heart and mitochondrial energy metabolism from ischemia-reperfusion-induced damages in Langendorff-perfused heart model. Toxicity of the drug was significantly higher on hepatocytes and pancreatic cells than on cardiomyocytes. In isolated mitochondria, amiodarone did not induce reactive oxygen species formation, while it affected mitochondrial permeability transition in a concentration dependent way. Up to the concentration of 10 μM, the drug considerably inhibited Ca2+-induced permeability transition, while at higher concentrations it induced a cyclosporin A independent permeability transition of its own. At concentrations where it inhibited the Ca2+-induced permeability transition (IC50 = 3.9 ± 0.8 μM), it did not affect, between 6 and 30 μM it uncoupled, while, at higher concentrations it inhibited the respiratory chain. Thus, the concentration dependent nature of amiodarone's effect on permeability transition together with the different sensitivities of the tissues toward amiodarone can be involved in the beneficial cardiac and the simultaneous toxic extracardiac effects of the drug.

Original languageEnglish
Pages (from-to)1115-1128
Number of pages14
JournalBiochemical Pharmacology
Volume65
Issue number7
DOIs
Publication statusPublished - Apr 1 2003

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Keywords

  • Amiodarone
  • High-energy phosphates
  • Langendorff-perfused heart
  • Mitochondria
  • P NMR
  • Permeability transition

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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