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 ϭ 6) or a potent PARP inhibitor, PJ-34 (10 mg/kg iv bolus and 0.5 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 infusion for 20 min, n ϭ 6). PJ-34 led to better recovery of cardiac output (2.2 Ϯ 0.1 vs. 1.8 Ϯ 0.2 l/min in control) and mesenteric blood flow (175 Ϯ 38 vs. 83 Ϯ 4 ml/min, P Ͻ 0.05 vs. control) after reperfusion. The impaired vasodilator response of the superior mesenteric artery to acetylcholine, assessed in the control group after CPB (Ϫ32.8 Ϯ 3.3 vs. Ϫ57.6 Ϯ 6.6% at baseline, P Ͻ 0.05), was improved by PJ-34 (Ϫ50.3 Ϯ 3.6 vs. Ϫ54.3 Ϯ 4.1% at baseline, P Ͻ 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 Ͻ 0.05). Moreover, the treated group showed a marked attenuation of mesenteric venous plasma myeloperoxidase levels after CPB compared with the control group (75 Ϯ 1 vs. 135 Ϯ 9 ng/ml, P Ͻ 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. endothelial function; nitric oxide; neutrophil adhesion; hemodynamics THERE IS A LARGE BODY OF EVIDENCE suggesting that the mesenteric vasculature has to be considered a primary target in the development of gastrointestinal complications after surgical procedures involving cardiopulmonary bypass (CPB) and cardiac arrest (1,8,31,32). Indeed, CPB is known to induce a systemic inflammatory reaction with free radical release leading to endothelial dysfunction in the mesenteric micro-and macrocirculation (1, 31). Factors that are related to this damage include reduced expression and activity of the endothelial nitric oxide synthase (eNOS) and reduced L-arginine availability that results in reduced bioavailability of NO (2, 15). Moreover, increased production of superoxide leads to increased degradation of NO and the formation of oxidant peroxynitrite, a potent trigger of various forms of oxidative cell injury (4, 20).Current evidence suggests that an important candidate pathway of free radical-induced endothelial vascular injury involves the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 inhibitors have been shown to diminish brain damage after cerebral ischemia (30), prevent myocardial injury in heart ischemia (28), and reduce renal ischemiareperfusion injury (18). In addition, several recent reports indicate that PARP inhibition counteracts the mesenteric dysfunction in ischemia-reperfusion (17), colon inflammation (35), and hemorrhagic (16) and endotoxemic shock (25).Because most ...

NAD+/NADH and NADP+/NADPH in Cellular Functions and Cell Death: Regulation and Biological Consequences

“…Mounting evidence has suggested that NAD and NADP metabolism also plays significant roles in vascular damage under various pathological conditions. For example, a PARP inhibitor was found to decrease cardiopulmonary bypass-induced mesenteric vascular dysfunction by improving hemodynamics, decreasing neutrophil adhesion, and restoring nitric oxide production (12); and the C242T CYBA polymorphism of NADPH oxidase was found to be associated with essential hypertension (205).…”

Mechanisms and Inhibitors of Apoptosis in Cardiovascular Diseases

“…They concluded that cardiac preservation (global deep hypothermic ischemia) followed by reperfusion leads to a significant activation of PARP, which was blocked by the novel PARP inhibitor PJ34 [108]. In a dog model, pharmacological PARP inhibition with PJ34 during reperfusion represents a viable modality to achieve not only better heart function [108,109] but also intestinal protection against the cardiopulmonary bypass associated malperfusion damage [110]. PJ34 significantly attenuated the CHF-induced suppression of systolic +dP/dt and diastolic dP/dt and an increase in left ventricular end diastolic pressure (LVEDP); it also improved decreased mean blood pressure in CHF and also tended to increase left ventricular systolic pressure (LVSP) [111].…”

Strategies for Pharmacological Organoprotection during Extracorporeal Circulation Targeting Ischemia-Reperfusion Injury

“…It is classified as a phenanthridinone and besides its PARP-inhibiting activity it exhibits also antiviral and anti-tumorous functions (Lin et al, 2014 ; Liang et al, 2015 ). Additionally, Szabo et al ( 2004a , b ) and Andrasi et al ( 2005 ), demonstrated in a canine model of CPB that administration of PJ34 was able to significantly reduce endothelial dysfunction of mesenteric vessels (frequently seen after CPB). Moreover, it improved myocardial contraction and even pulmonary function.…”