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Eur J Cardiothorac Surg 2004;25:825-832
© 2004 Elsevier Science NL

Role of poly(ADP-ribose) polymerase activation in the pathogenesis of cardiopulmonary dysfunction in a canine model of cardiopulmonary bypass

^a Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
^b Department of Cardiovascular Surgery, Semmelweis University Medical School, Budapest, Hungary
^c Department of Cardiology, Angiology and Pulmonology, University of Heidelberg, Heidelberg, Germany
^d Inotek Pharmaceuticals Corporation, Beverly, MA, USA
^e Institute of Pathology, University of Heidelberg, Heidelberg, Germany
^f Institute of Human Physiology and Clinical Experimental Research, Semmelweis University Medical School, Budapest, Hungary

Received 21 August 2003; received in revised form 11 December 2003; accepted 9 January 2004.

^* Corresponding author. Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Tel.: +49-6221-566111; fax: +49-6221-565585
e-mail: dzsi{at}hotmail.com

Objective: To investigate the effects of PARP inhibition on cardiac and pulmonary function during reperfusion in a clinically relevant experimental model of cardiopulmonary bypass. Methods: 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 the potent PARP-inhibitor PJ34 (5 mg/kg; n=6). Biventricular hemodynamic variables were measured by combined pressure–volume–conductance catheters. Coronary and pulmonary blood flow, vasodilator responses to acetylcholine and sodium-nitroprusside and pulmonary function were also determined. The cardiac and pulmonary activation of PARP was detected by poly(ADP-ribose) immunohistochemistry. Results: Administration of PJ34 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 PJ34 treated group (P<0.05). PJ34 treatment preserved the acetylcholine-induced increases in coronary and pulmonary blood (P<0.05). Pulmonary function in terms of alveolar arterial oxygen difference was better maintained in the PJ34 treated animals (P<0.05). Immunohistochemical staining revealed PARP activation after cardiopulmonary bypass in both the heart and lung, which was prevented by PJ34. Conclusions: PARP inhibition improves the recovery of myocardial and endothelial function after hypothermic cardiac arrest and protects against the development of remote pulmonary injury during cardiopulmonary bypass.

Key Words: Cardiopulmonary bypass • Reperfusion injury • PARP inhibition • Endothelial function

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