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Concentration dependent mitochondrial effect of amiodarone.
Gabor Varbiro1, Ambrus Toth, Antal Tapodi
1Institute of Biochemistry and Medical Chemistry, Medical School, University of Pecs, 12 Szigeti st., H-7624 Pecs, Hungary.
Biochemical Pharmacology
|March 29, 2003
Summary
Amiodarone protects the heart from ischemia-reperfusion injury at low concentrations by preserving energy metabolism. However, it exhibits higher toxicity in liver and pancreatic cells, impacting mitochondrial function differently based on concentration.
Area of Science:
- Cardiovascular Pharmacology
- Mitochondrial Physiology
- Cellular Toxicology
Background:
- Amiodarone's antiarrhythmic effects are known, but its impact on post-ischemic hearts and extracardiac toxicity mechanisms remain unclear.
- Understanding amiodarone's dual action on cardiac and non-cardiac tissues is crucial for optimizing its therapeutic use.
Purpose of the Study:
- To investigate amiodarone's effects on energy metabolism in the post-ischemic heart using a Langendorff-perfused model.
- To analyze amiodarone's toxicity on cardiomyocytes and extracardiac cell lines.
- To elucidate the direct impact of amiodarone on mitochondrial functions, including permeability transition and respiratory chain activity.
Main Methods:
- Utilized 31P Nuclear Magnetic Resonance (NMR) spectroscopy to measure high-energy phosphate metabolites in Langendorff-perfused hearts during ischemia-reperfusion.
- Assessed amiodarone's toxicity in isolated cardiomyocytes, hepatocytes, and pancreatic cell lines.
- Examined amiodarone's direct effects on isolated mitochondria, measuring reactive oxygen species (ROS) production, calcium-induced permeability transition, and respiratory chain activity.
Main Results:
- Low concentrations of amiodarone, particularly when membrane-bound, protected cardiac and mitochondrial energy metabolism against ischemia-reperfusion damage.
- Amiodarone demonstrated significantly higher toxicity towards hepatocytes and pancreatic cells compared to cardiomyocytes.
- In isolated mitochondria, amiodarone inhibited Ca(2+)-induced mitochondrial permeability transition at concentrations below 10 microM (IC(50)=3.9+/-0.8 microM), but induced a cyclosporin A-independent transition at higher concentrations. It also uncoupled and inhibited the respiratory chain at specific concentrations.
Conclusions:
- Amiodarone exhibits a concentration-dependent effect on mitochondrial permeability transition, contributing to its protective cardiac effects at lower doses.
- Differential tissue sensitivity to amiodarone, coupled with its concentration-dependent mitochondrial effects, explains its beneficial cardiac actions and simultaneous extracardiac toxicity.
- Further research into amiodarone's specific molecular targets and tissue interactions is warranted to mitigate adverse effects.