RT Journal Article SR Electronic T1 Effect of Poly(ADP-Ribose) Polymerase Inhibitors on the Ischemia-Reperfusion-Induced Oxidative Cell Damage and Mitochondrial Metabolism in Langendorff Heart Perfusion System JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1497 OP 1505 DO 10.1124/mol.59.6.1497 VO 59 IS 6 A1 Robert Halmosi A1 Zoltan Berente A1 Erzsebet Osz A1 Kalman Toth A1 Peter Literati-Nagy A1 Balazs Sumegi YR 2001 UL http://molpharm.aspetjournals.org/content/59/6/1497.abstract AB Ischemia-reperfusion induces reactive oxygen species (ROS) formation, and ROS lead to cardiac dysfunction, in part, via the activation of the nuclear poly(ADP-ribose) polymerase (PARP, called also PARS and ADP-RT). ROS and peroxynitrite induce single-strand DNA break formation and PARP activation, resulting in NAD+ and ATP depletion, which can lead to cell death. Although protection of cardiac muscle by PARP inhibitors can be explained by their attenuating effect on NAD+ and ATP depletion, there are data indicating that PARP inhibitors also protect mitochondria from oxidant-induced injury. Studying cardiac energy metabolism in Langendorff heart perfusion system by 31P NMR, we found that PARP inhibitors (3-aminobenzamide, nicotinamide, BGP-15, and 4-hydroxyquinazoline) improved the recovery of high-energy phosphates (ATP, creatine phosphate) and accelerated the reutilization of inorganic phosphate formed during the ischemic period, showing that PARP inhibitors facilitate the faster and more complete recovery of the energy production. Furthermore, PARP inhibitors significantly decrease the ischemia-reperfusion-induced increase of lipid peroxidation, protein oxidation, single-strand DNA breaks, and the inactivation of respiratory complexes, which indicate a decreased mitochondrial ROS production in the reperfusion period. Surprisingly, PARP inhibitors, but not the chemically similar 3-aminobenzoic acid, prevented the H2O2-induced inactivation of cytochrome oxidase in isolated heart mitochondria, suggesting the presence of an additional mitochondrial target for PARP inhibitors. Therefore, PARP inhibitors, in addition to their important primary effect of decreasing the activity of nuclear PARP and decreasing NAD+ and ATP consumption, reduce ischemia-reperfusion-induced endogenous ROS production and protect the respiratory complexes from ROS induced inactivation, providing an additional mechanism by which they can protect heart from oxidative damages.