Protective effect of amiodarone but not N-desethylamiodarone on postischemic hearts through the inhibition of mitochondrial permeability transition.
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 (Deltapsi), 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 Deltapsi 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.
Varbiro
Gabor
G
Institute of Biochemistry and Medical Chemistry, Medical School, University of Pecs, 12 Szigeti St., H-7624 Pecs, Hungary.
Toth
Ambrus
A
Tapodi
Antal
A
Bognar
Zita
Z
Veres
Balazs
B
Sumegi
Balazs
B
Gallyas
Ferenc
F
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D051033:Apoptosis Inducing Factor; D001692:Biological Transport; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005420:Flavoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D017202:Myocardial Ischemia / Q000150:complications; D010101:Oxygen Consumption / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D020011:Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*
C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; D020011:Protective Agents; D017382:Reactive Oxygen Species; C036116:desethylamiodarone; D000638:Amiodarone