Poly(ADP-ribose) polymerase inhibitor PJ-34 reduces mesenteric vascular injury induced by experimental cardiopulmonary bypass with cardiac arrest.
The aim of this study was to investigate effects of poly(ADP-ribose) polymerase (PARP) inhibition on mesenteric vascular function and metabolism in an experimental model of cardiopulmonary bypass (CPB) with cardiac arrest. Twelve anesthetized dogs underwent 90-min hypothermic CPB. After 60 min of cardiac arrest, reperfusion was started for 40 min following 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(-1).min(-1) infusion for 20 min, n = 6). PJ-34 led to better recovery of cardiac output (2.2 +/- 0.1 vs. 1.8 +/- 0.2 l/min in control) and mesenteric blood flow (175 +/- 38 vs. 83 +/- 4 ml/min, P < 0.05 vs. control) 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. control). Although plasma nitrate/nitrite concentrations were not significantly different between groups, mesenteric nitric oxide synthase activity was increased in the PJ-34 group (P < 0.05). Moreover, the treated group showed a marked attenuation of mesenteric venous plasma myeloperoxidase levels after CPB compared with the control group (75 +/- 1 vs. 135 +/- 9 ng/ml, P < 0.05). Pharmacological PARP inhibition protects against development of post-CPB mesenteric vascular dysfunction by improving hemodynamics, restoring nitric oxide production, and reducing neutrophil adhesion.
Andrási
Terézia B
TB
Dept. of Visceral, Thoracic and Vascular Surgery, Carl Gustav Carus Univ. Hospital, Fetscherstrasse 74, Haus 59, 01307 Dresden, Germany. tean74@hotmail.com
Blázovics
Anna
A
Szabó
Gábor
G
Vahl
Christian F
CF
Hagl
Siegfried
S
D000818:Animals; D002315:Cardiopulmonary Bypass / Q000379:methods*; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006323:Heart Arrest / Q000503:physiopathology* / Q000517:prevention & control*; D006439:Hemodynamics; D015425:Myocardial Reperfusion; D009195:Peroxidase / Q000097:blood; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013152:Splanchnic Circulation / Q000187:drug effects* / Q000502:physiology
D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009195:Peroxidase