Under several pathological conditions, reactive oxygen species-induced damages play important roles in pathogenesis (1-3). High levels of reactive oxygen species are generated from a variety of sources such as the xanthine oxidase system (1), the leakage of electrons from the mitochondrial respiratory chain (2, 4), the cyclooxygenase pathway of arachidonic acid metabolism (3,5), and the respiratory burst of phagocyte cells (6, 7), and they can cause DNA damage-generating singlestranded DNA breaks (8). Poly(ADP-ribose)polymerase (PARP-1, 2 EC 2.4.2.30) is a multifunctional nuclear enzyme (9) that is activated by DNA strand breaks and catalyzes the covalent coupling of branched chains of ADP-ribose units to various nuclear proteins such as histone proteins and PARP-1 itself. PARP-1 is involved in chromatin remodeling, DNA repair, replication, transcription, and the maintenance of genomic stability by, in part, poly(ADP-ribosyl)ation (9). With moderate amounts of DNA damage, PARP-1 is thought to participate in the DNA repair process (10, 11). However, oxidative stress, which induces a large amount of DNA damage, can cause excessive activation of PARP-1, leading to depletion of its substrate NAD ϩ ; and in an effort to resynthesize NAD ϩ , ATP is also depleted, resulting in cell death as a consequence of energy loss (12-15). PARP inhibitors show pronounced protection against myocardial ischemia (16), neuronal ischemia (17, 18), acute lung inflammation (19), acute septic shock (20), zymogen-induced multiple organ failure (21), and diabetic pancreatic damage (22-24), providing evidence for the role of excessive PARP-1 activation in cell death. It is believed that by preventing excessive NAD ϩ and ATP utilization, PARP inhibitors protect cells against oxidative damage, but some recent data suggest a more complex mechanism for the cytoprotection (25, 26). There is evidence that PARP activation can contribute to exaggeration of mitochondrial damage (27) and mitochondrial reactive oxygen species production (28), indicating that PARP activation can modulate processes outside of the nucleus. Recent works reported the existence of mitochondrial PARP that can be blocked with PARP-1 inhibitors (29); therefore, it would be important to clarify whether the mitochondrial protection by PARP inhibitors is a direct consequence of the inhibition of mitochondrial ADP-ribosylation or the inhibition of nuclear PARP modulation by yet unidentified processes that are responsible for the mitochondrial protection. Our previous works demonstrated that PARP inhibitors induced the phosphorylation and activation of Akt in the liver, lung, and spleen of lipopolysaccharide-treated mice, raising the possibility that the protective effect of PARP inhibition can be mediated through the PI3-kinase/Akt pathway (30). These observations indicate that the protective effect of PARP inhibitors should be far more In the present study, we analyzed the effect of PARP inhibition by pharmacologic agents, by the transdominant expression of the PARP N-terminal DNA...

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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 Ca 2ϩ -induced mitochondrial swelling, whereas it dissipated the mitochondrial membrane potential (⌬⌿), 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 Ca 2ϩ -induced mitochondrial permeability transition, did not induce the collapse of ⌬⌿ 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.Amiodarone (2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl-ketone hydrochloride) is one of the most effective antiarrhythmic drugs and is frequently used in the clinical practice for treating ventricular and supraventricular arrhythmias. It is a class III antiarrhythmic agent, prolonging action potential duration whose effect may involve blocking of ␤-adrenergic receptors, sodium channels, and L-type calcium channels (Singh and Vaughan Williams, 1970;Nokin et al., 1983;Nattel et al., 1987;Varro et al., 1996). It may also have a role in preventing mortality after myocardial infarction (Julian et al., 1997). Despite its effective antiarrhythmical properties, the use of amiodarone is often limited by its toxic side effects, including thyroid dysfunction, liver, and pancreas fibrosis (Amico et al., 1984;Martin and Howard, 1985). However, the most severe adverse effect of the drug is pulmonary fibrosis, occurring in up to 13% of the patients receiving the amiodarone in doses higher than 400 mg day Ϫ1 (Martin and Rosenow, 1988). The etiology of the amiodarone-induced pulmonary toxicity is unknown.Desethylamiodarone, the major metabolite of amiodarone, also has antiarrhyth...

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