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

Background: We hypothesized that cardiopulmonary bypass induces a selective alteration of the coronary arterial endothelial cell signal transductionwhichcould be explainedbya state of depletionand/or decreasedactivity 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.