Beneficial effect of tetrahydrobiopterin on ischemia-reperfusion injury in isolated perfused rat hearts

Abstract

Objective: It has recently been proposed that nitric oxide synthase, in the presence of suboptimal levels of tetrahydrobiopterin, an essential cofactor of this enzyme, might favor increased production of oxygen radicals. The aim of this study was to clarify whether supplement with tetrahydrobiopterin would exert a cardioprotective effect against ischemia-reperfusion injury. Methods: Isolated perfused rat hearts were subjected to 30 minutes of global ischemia and 30 minutes of reperfusion at 37°C. Hearts were treated with tetrahydrobiopterin or vehicle for 5 minutes just before ischemia and during the first 5 minutes of the reperfusion period. Effects of tetrahydrobiopterin on left ventricular function, myocardial contents of lipid peroxidation and high-energy phosphates, and levels of lactate dehydrogenase and nitrite plus nitrate in perfusate during ischemia and after reperfusion were estimated and further compared with those of superoxide dismutase plus catalase or L-ascorbic acid. Results: Tetrahydrobiopterin and superoxide dismutase plus catalase both improved contractile and metabolic abnormalities in reperfused hearts. On the other hand, L-ascorbic acid at a dose having an equipotent radical scavenging activity with tetrahydrobiopterin did not significantly affect the postischemic changes. Although tetrahydrobiopterin and superoxide dismutase plus catalase significantly alleviated ischemic contracture during ischemia, diminished perfusate levels of nitrite plus nitrate after reperfusion were restored only with tetrahydrobiopterin. Conclusion: Results demonstrated that tetrahydrobiopterin lessens ischemia-reperfusion injury in isolated perfused rat hearts, probably independent of its intrinsic radical scavenging action. The cardioprotective effect of tetrahydrobiopterin implies that tetrahydrobiopterin could be a novel and effective therapeutic option in the treatment of ischemia-reperfusion injury.