Poly-ADP-Ribose Polymerase Inhibition Reduces Mesenteric Injury after Cardiopulmonary Bypass[*]

Abstract

Background: We investigated the effects of PARS inhibition on intestinal injury in a canine model of cardiopulmonary bypass (CPB). Methods: Twelve dogs underwent 90 minutes of hypothermic CPB. 6 dogs received 5 mg/kg PJ34, a selective PARP inhibitor during CPB, 6 vehicle-treated animals served as controls. Mesenteric blood flow (MBF) and mesenteric vascular resistance (MVR) were measured before and 60 minutes after weaning from CPB. Endothelium-dependent vasorelaxation to acetylcholine (ACH) and endothelium-independent vasorelaxation to sodium-nitroprussid (SNP) were expressed as percent change of MVR. In addition, mesenteric creatinkinase (CK) and lactate release were determined. Results: Baseline hemodynamics, MBF, response to ACH (- 41 ± 3 vs. - 55 ± 6 %) and SNP (- 60 ± 2 vs. - 56 ± 4 %) did not differ significantly between the groups. The response to ACH decreased significantly in the control group while it remained unchanged in the PJ34 group (- 29 ± 5 vs. - 46 ± 9 %, p < 0.05). The response to SNP did not change. Mesenteric CK release (325 ± 99 vs. 16 ± 10 U/l, p < 0.05) and lactate production (0.96 ± 0.17 vs. 0.4 ± 0.2 mmol/l, p < 0.05) were significantly lower in the PJ34 group. Conclusion: PARP inhibition prevents CPB-induced mesenteric endothelial dysfunction and tissue damage.

Key words

Poly (ADP-ribose) polymerase - cardiopulmonary bypass - mesenteric injury

1 This study was presented at the 4th Joint Meeting of the German, Austrian, and Swiss Society for Thoracic and Cardiovascular Surgery, Hamburg, February 15 - 18, 2004

References

• 1 Wallace A, Lam H W, Nose P S. et al . Changes in systolic and diastolic ventricular function with cold cardioplegic arrest in man. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group.  J Card Surg. 1994;  9 497-502
• 2 Wan S, LeClerc J L, Vincent J L. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies.  Chest. 1997;  112 676-692
• 3 Andrási T B, Buhmann V, Soós P. et al . Mesenteric complications after hypothermic cardiopulmonary bypass with cardiac arrest: underlying mechanisms.  Artificial Organs. 2002;  26 943-946
• 4 Byhahn C, Strouhal U, Martens S. et al . Incidence of gastrointestinal complications in cardiopulmonary bypass patients.  World J Surg. 2001;  25 1140-1144
• 5 Klempnauer J, Grothues F, Bektas H. et al . Acute mesenteric ischemia following cardiac surgery.  J Cardiovasc Surg. 1997;  38 639-643
• 6 Andrási T B, Soós P, Bakos G. et al . L-arginine protects the mesenteric vascular circulation against cardiopulmonary bypass-induced vascular dysfunction.  Surgery. 2003;  134 72-79
• 7 Virág L, Szabó C. The therapeutic potential of poly (ADP-ribose) polymerase inhibitors.  Pharmacol Rev. 2002;  54 375-429
• 8 Szabó G, Liaudet L, Hagl S. et al . Poly (ADP-ribose) polymerase activation in the reperfused myocardium.  Cardiovasc Res. 2004;  61 471-480
• 9 Szabó C, Zingarelli B, O'Connor M. et al . DNA strand breakage, activation of poly-ADP ribosyl synthase, and cellular energy depletion are involved in the cytotoxicity in macrophages and smooth muscle cells exposed to peroxynitrite.  Proc Natl Acad Sci USA. 1996;  93 1753-1758
• 10 Szabó C, Cuzzocrea S, Zingarelli B. et al . Endothelial dysfunction in a rat model of endotoxin shock. Importance of the activation of poly (ADP-ribose) synthetase by peroxynitrite.  J Clin Invest. 1997;  100 723-735
• 11 Szabó G, Buhmann V, Andrási T B. et al . Poly-ADP-Ribose polymerase (PARP)-inhibition protects against myocardial and endothelial reperfusion injury after hypothermic cardiac arrest.  J Thorac Cardiovasc Surg. 2003;  126 651-658
• 12 Szabó G, Soós P, Bährle S. et al . Role of poly (ADP-ribose) polymerase activation in the pathogenesis of cardiopulmonary dysfunction in a canine model of cardiopulmonary bypass.  Eur J Cardiothorac Surg. 2004;  25 825-832
• 13 Szabó G, Bährle S, Stumpf N. et al . Poly (ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation.  Circ Res. 2002;  90 100-106
• 14 Sack F U, Dollner R, Reidenbach B. et al . Extracorporeal circulation induced microvascular perfusion injury of the small bowel.  Eur Surg Res. 2002;  34 418-424
• 15 Sack F U, Reidenbach B, Schledt A. et al . Dopexamine attenuates microvascular perfusion injury of the small bowel in pigs induced by extracorporeal circulation.  Br J Anaesth. 2002;  88 841-847
• 16 Tofukuji M, Stahl G L, Metais C, Tomita M. et al . Mesenteric dysfunction after cardiopulmonary bypass: role of complement C5a.  Ann Thorac Surg. 2000;  69 799-807
• 17 Akata T, Yoshitake J, Nakashima M. et al . Effects of protamine on vascular smooth muscle of rabbit mesenteric artery.  Anesthesiology. 1991;  75 833-846
• 18 Ohri S K, Bowles C W, Mathie R T. et al . Effects of cardiopulmonary bypass protocols on gut tissue oxygenation and blood flow.  Ann Thorac Surg. 1997;  64 163-170
• 19 Cuzzocrea S, Zingarelli B, Constantino G. et al . Beneficial effects of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase in a rat model of splanchnic artery occlusion and reperfusion.  Br J Pharmacol. 1997;  121 1065-1074
• 20 Mazzon E, Dugo L, De Sarro A. et al . Beneficial effects of GPI 6150, an inhibitor of poly (ADP-ribose) polymerase in a rat model of splanchnic artery occlusion and reperfusion.  Shock. 2002;  17 222-227

1 This study was presented at the 4th Joint Meeting of the German, Austrian, and Swiss Society for Thoracic and Cardiovascular Surgery, Hamburg, February 15 - 18, 2004

2 Gábor Szabó and Leila Seres contributed equally to this work