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Eur J Cardiothorac Surg 2005;27:226-234
© 2005 Elsevier Science NL
a Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
b Department of Cardiovascular Surgery, Semmelweis University, Budapest, Hungary
c Institute of Pathology, University of Heidelberg, Heidelberg, Germany
d Department of Cardiology, University of Heidelberg, Heidelberg, Germany
e Inotek Pharmaceuticals Corporation, Beverly, MA, USA
f Department of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary
Received 31 July 2004; received in revised form 27 September 2004; accepted 13 October 2004.
* Corresponding author. Address: Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg 69120, Germany. Tel.: +49 6221 566 111; fax: +49 6221 565 585. (E-mail: dzsi{at}hotmail.com).
Objective: Poly (ADP-ribose) polymerase (PARP) activation plays a key role in free radical induced injury in ischemia/reperfusion. We investigated the effects of INO-1001 a novel PARP inhibitor on postischemic myocardial and endothelial function. Methods: In dogs, 12 orthotopic heart transplantations were performed after 4h ischemic preservation. At the beginning of reperfusion either saline vehicle (control, n=6), or INO-1001 (1mg/kg, n=6) was applied. Before explantation and after 120min of reperfusion we measured biventricular pressure–volume relationships by a combined conductance catheter and the adaptation potential of the right ventricle to acute afterload increase by pulmonary banding. Coronary blood flow (CBF), vasoreactivity, PARP-activation and ATP-content were also determined. Results: INO-1001 led to significantly better recovery of contractility (91±3 vs. 44±7%, P<0.05) and CBF (44±4 vs. 29±3ml/min, P<0.05) and higher increase in CBF after acetylcholine (61±10 vs. 27±8%, P<0.05). In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved after INO-1001. ATP content was significantly higher in the INO-1001 group (11.0±2.1 vs. 4.5±1.1µmol/g drw). Immunhistology revealed PARP activation in the control group which was abolished by INO-1001 treatment. Conclusions: PARP inhibition reduces myocardial and endothelial reperfusion injury after orthotopic heart transplantation.
Key Words: PARP • Heart transplantation • Reperfusion
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