Poly(ADP-ribose) polymerase inhibitor PJ-34 reduces mesenteric vascular injury induced by experimental cardiopulmonary bypass with cardiac arrest

Terézia B. Andrási, A. Blázovics, G. Szabó, Christian F. Vahl, Siegfried Hagl

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Abstract

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.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume288
Issue number6 57-6
DOIs
Publication statusPublished - Jun 2005

Fingerprint

Vascular System Injuries
Heart Arrest
Cardiopulmonary Bypass
Poly(ADP-ribose) Polymerases
Reperfusion
Blood Vessels
Control Groups
Superior Mesenteric Artery
Nitrites
Vasodilator Agents
Nitric Oxide Synthase
Cardiac Output
Nitrates
Peroxidase
Acetylcholine
Nitric Oxide
Neutrophils
Theoretical Models
Hemodynamics
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride

Keywords

  • Endothelial function
  • Hemodynamics
  • Neutrophil adhesion
  • Nitric oxide

ASJC Scopus subject areas

  • Physiology

Cite this

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title = "Poly(ADP-ribose) polymerase inhibitor PJ-34 reduces mesenteric vascular injury induced by experimental cardiopulmonary bypass with cardiac arrest",
abstract = "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.",
keywords = "Endothelial function, Hemodynamics, Neutrophil adhesion, Nitric oxide",
author = "Andr{\'a}si, {Ter{\'e}zia B.} and A. Bl{\'a}zovics and G. Szab{\'o} and Vahl, {Christian F.} and Siegfried Hagl",
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T1 - Poly(ADP-ribose) polymerase inhibitor PJ-34 reduces mesenteric vascular injury induced by experimental cardiopulmonary bypass with cardiac arrest

AU - Andrási, Terézia B.

AU - Blázovics, A.

AU - Szabó, G.

AU - Vahl, Christian F.

AU - Hagl, Siegfried

PY - 2005/6

Y1 - 2005/6

N2 - 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.

AB - 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.

KW - Endothelial function

KW - Hemodynamics

KW - Neutrophil adhesion

KW - Nitric oxide

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