Poly-ADP-ribose polymerase inhibition protects against myocardial and endothelial reperfusion injury after hypothermic cardiac arrest.
OBJECTIVE
Free radical production and related cytotoxicity during ischemia and reperfusion might lead to DNA strand breakage, which activates the nuclear enzyme poly-ADP-ribose synthetase and initiates an energy-consuming and inefficient cellular metabolic cycle with transfer of the adenosine diphosphate-ribosyl moiety of nicotinamide adenine dinucleotide (NAD(+)) to protein acceptors. We investigated the effects of poly-ADP-ribose synthetase inhibition on myocardial and endothelial function during reperfusion in an experimental model of cardiopulmonary bypass.


METHODS
Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6) or PJ34 (10 mg/kg), a potent poly-ADP-ribose synthetase inhibitor (n = 6). Biventricular hemodynamic variables were measured by means of a combined pressure-volume conductance catheter, and the slope of the end-systolic pressure-volume relationships was calculated at baseline and after 60 minutes of reperfusion. Left anterior descending coronary blood flow, endothelium-dependent vasodilatation to acetylcholine, and endothelium-independent vasodilatation to sodium nitroprusside were also determined.


RESULTS
The administration of PJ34 led to a significantly better recovery of left and right ventricular systolic function (P <.05) after 60 minutes of reperfusion. In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved in the PJ34 group. Coronary blood flow was also significantly higher in the PJ34 group (P <.05). Although the vasodilatory response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly higher increase in coronary blood flow in the PJ34 group (P <.05).


CONCLUSIONS
Poly-ADP-ribose synthetase inhibition improves the recovery of myocardial and endothelial function after cardiopulmonary bypass with hypothermic cardiac arrest.
D000818:Animals; D003326:Coronary Circulation; D004285:Dogs; D004730:Endothelium, Vascular; D006324:Heart Arrest, Induced / Q000009:adverse effects*; D006439:Hemodynamics; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014652:Vascular Diseases / Q000209:etiology / Q000517:prevention & control; D016276:Ventricular Function
D000067856:Poly(ADP-ribose) Polymerase Inhibitors