Role of poly(ADP-ribose) polymerase activation in the pathogenesis of cardiopulmonary dysfunction in a canine model of cardiopulmonary bypass.
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.
Szabó
Gábor
G
Department of Cardiac Surgery, University of Heidelberg, Germany. dzsi@hotmail.com
Soós
Pál
P
Bährle
Susanne
S
Zsengellér
Zsuzsanna
Z
Flechtenmacher
Christa
C
Hagl
Siegfried
S
Szabó
Csaba
C
D000818:Animals; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D003331:Coronary Vessels / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D004730:Endothelium, Vascular / Q000503:physiopathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006324:Heart Arrest, Induced / Q000009:adverse effects; D006439:Hemodynamics / Q000187:drug effects; D008168:Lung / Q000201:enzymology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D014664:Vasodilation
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases