title: INO-1001 a novel poly(ADP-ribose) polymerase (PARP) inhibitor improves cardiac and pulmonary function after crystalloid cardioplegia and extracorporal circulation.
abstract: Poly(ADP-ribose) polymerase (PARP) activation plays a key role in free radical-induced injury in the context of systemic inflammation and ischemia/reperfusion. In the present preclinical study, we investigated the effects of INO-1001, a novel PARP inhibitor, on cardiac and pulmonary function during reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 min of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or INO-1001 (1 mg/kg), a potent PARP inhibitor (n = 6). Biventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and pulmonary blood flow and vasodilative responses to acetylcholine and sodium nitroprusside as well as pulmonary gas exchange were also determined. The administration of INO-1001 led to a significantly better recovery of left and right ventricular systolic function (P < 0.05) after 60 min of reperfusion. Coronary blood flow was also significantly higher in the INO-1001 group (P < 0.05). Although the vasodilative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary and pulmonary blood flow in the INO-1001 group (P < 0.05). Pulmonary function in terms of alveolar arterial oxygen difference was better preserved in the INO-1001-treated group (P < 0.05). Thus, PARP inhibition improves the recovery of myocardial and endothelial function after hypothermic cardiac arrest and reduces pulmonary injury associated with extracorporal circulation.
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany, D-69120. dzsi@hotmail.com
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
authors.forename: Pál
authors.initials: P
authors.lastname: Soós
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandera
authors.forename: Ulrike
authors.initials: U
authors.lastname: Heger
authors.forename: Christa
authors.initials: C
authors.lastname: Flechtenmacher
authors.forename: Susanne
authors.initials: S
authors.lastname: Bährle
authors.forename: Leila
authors.initials: L
authors.lastname: Seres
authors.forename: Attila
authors.initials: A
authors.lastname: Cziráki
authors.forename: Andre
authors.initials: A
authors.lastname: Gries
authors.forename: Zsuszanna
authors.initials: Z
authors.lastname: Zsengellér
authors.forename: Christian F
authors.initials: CF
authors.lastname: Vahl
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hagl
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000246:Adenosine Diphosphate Ribose; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals; D006321:Heart / Q000502:physiology; D006323:Heart Arrest / Q000188:drug therapy; D006324:Heart Arrest, Induced; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation; D008168:Lung / Q000473:pathology; D009119:Muscle Contraction; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009206:Myocardium / Q000473:pathology; D009599:Nitroprusside / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012039:Regional Blood Flow; D015427:Reperfusion Injury / Q000188:drug therapy; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D005609:Free Radicals; C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009599:Nitroprusside; D000246:Adenosine Diphosphate Ribose; D011064:Poly Adenosine Diphosphate Ribose; D000109:Acetylcholine; D010100:Oxygen