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Eur J Cardiothorac Surg 2006;30:464-471
© 2006 Elsevier Science NL

Effect of tetrahydrobiopterin on selective endothelial dysfunction of epicardial porcine coronary arteries induced by cardiopulmonary bypass

^a Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Que. H1T 1C8, Canada
^b Department of Surgery, Montreal Heart Institute, 5000 Belanger Street, Montreal, Que. H1T 1C8, Canada
^c Department of Pharmacology, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, Que. H3C 3J7, Canada

Received 17 January 2006; received in revised form 18 May 2006; accepted 2 June 2006.

^_* Corresponding author. Address: Department of Surgery, Montreal Heart Institute, 5000 Belanger Street, Montreal, Que. H1T 1C8, Canada. Tel.: +1 514 376 3330; fax: +1 514 376 1355. (Email: louis.perrault{at}icm-mhi.org).

Background: We hypothesized that cardiopulmonary bypass induces a selective alteration of the coronary arterial endothelial cell signal transduction which could be explained by a state of depletion and/or decreased activity of endogenous tetrahydrobiopterin (BH₄). The aim of this study was to assess the effects of cardiopulmonary bypass and BH₄ on the endothelial function of epicardial coronary arteries in a swine model of cardiopulmonary bypass. Methods: Swine underwent 90 min of cardiopulmonary bypass alone (N = 19) or in association with a brief cardioplegic arrest with (N = 6) or without (N = 5) in vivo BH₄ administration, followed by a 60-min period following weaning from cardiopulmonary bypass and were compared to a control group (N = 7). Endothelium-dependent relaxations of epicardial coronary artery rings were studied using standard organ chamber experiments in the presence or absence of in vitro BH₄ or superoxide dismutase (SOD) and catalase. Results: Cardiopulmonary bypass caused a statistically significant reduction of endothelium-dependent relaxations to serotonin (p < 0.0001), bradykinin (p < 0.001), UK14304 (p < 0.0001) and calcium ionophore (p < 0.01) in epicardial porcine coronary arteries. In vitro and in vivo BH₄ supplementation improved endothelium-dependent relaxations to serotonin and bradykinin, which were left unchanged by SOD-catalase administration. Cardiopulmonary bypass was associated with a decrease in nitric oxide availability (p = 0.002) and increased oxidative stress (p < 0.001), which were both restored by in vivo BH₄ administration (p < 0.001). Conclusion: Treatment with BH₄ improves the endothelial dysfunction of porcine epicardial coronary arteries, restores nitric oxide availability and reduces the oxidative stress associated with cardiopulmonary bypass.

Key Words: Antioxidant • Cardiopulmonary bypass • Coronary artery • Endothelial dysfunction • Nitric oxide • Superoxide dismutase • Tetrahydrobiopterin