Submitted on October 12, 2004
Accepted on January 17, 2005
Poly(ADP-ribose) polymerase inhibitor PJ-34 reduces the mesenteric vascular injury induced by experimental cardiopulmonary bypass with cardiac arrest
Terezia B Andrasi1*, Anna Blazovics2, Gabor Szabo3, Christian F Vahl3, and Siegfried Hagl3
1 Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany; Department of Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany
2 Department of Internal Medicine, Semmelweis University, Budapest, Hungary
3 Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
* To whom correspondence should be addressed. E-mail: tean74{at}hotmail.com.
The aim of the study was to investigate the effects of Poly (ADP-ribose) polymerase (PARP) inhibition on mesenteric vascular function and metabolism in an experimental model of cardiopulmonary bypass with cardiac arrest.
Twelve anesthetized dogs underwent 90 min hypothermic cardiopulmonary bypass (CPB). After 60 min cardiac arrest, reperfusion was started for 40 min after application of either saline vehicle (control, n=6) or a potent PARP inhibitor, PJ-34 (10 mg/kg iv. bolus and 0.5 mg/kg/min infusion for 20 min, n=6).
PJ-34 led to a better recovery of the cardiac output (2.2±0.1 vs. 1.8±0.2 L/min in controls) and mesenteric blood flow (175±38 vs. 83±4 ml/min, p<0.05 vs. control group) after reperfusion. The impaired vasodilator response of the superior mesenteric artery to acetylcholine assessed in the control group after CPB (-32.8±3.3 % vs. -57.6±6.6 % at baseline, p<0.05) was improved by PJ-34 (-50.3±3.6 % vs. -54.3±4.1 % at baseline, p<0.05 vs. controls). Although plasma nitrate/ nitrite concentrations were not significantly different between groups, mesenteric nitric oxide synthase activity was increased in the PJ-34 treated animals (p<0.05). Moreover, treated group showed a marked attenuation of mesenteric venous plasma myeloperoxidase levels after CPB compared to controls (75±1 vs. 135±9 ng/ml, p<0.05).
Pharmacological PARP inhibition protects against the development of post-CPB mesenteric vascular dysfunction by improving hemodynamics, restoring nitric oxide production and reducing neutrophil adhesion.
