Myocardial ischemia results in tetrahydrobiopterin (BH_4) oxidation with impaired endothelial function ameliorated by BH_4

摘要

Coronary vasodilation is impaired in the postischemic heart with a loss of endothelial nitric oxide synthase (eNOS) activity, but the mechanisms underlying ischemia-induced eNOS dysfunction are not understood. For nitric oxide (NO) synthesis, eNOS requires the redox-sensitive cofactor tetrahydrobiopterin (BH_4); however, the role of BH_4 in ischemia-induced endothelial dysfunction remains unknown. Therefore, isolated rat hearts were subjected to varying durations of ischemia, and the alterations in NOS-dependent vasodilation were measured and correlated with assays of eNOS activity and cardiac BH_4 concentrations. Ischemia time-dependently decreased cardiac BH_4 content with 85, 95, or 97% irreversible degradation after 30, 45, or 60 min of ischemia, respectively. Paralleling the decreases in BH_4, reductions of eNOS activity were seen of 58, 86, or 92%, and NOS-derived superoxide production was greatly increased. Addition of 10 μM BH_4 enhanced eNOS activity in nonischemic hearts and partially restored activity after ischemia. It also suppressed NOS-derived superoxide production. Impaired coronary flow during postischemic reperfusion was improved by BH_4 infusion. Thus, BH_4 depletion contributes to postischemic eNOS dysfunction, and BH_4 treatment is effective in partial restoration of endothelium-dependent coronary flow. Supplementation of BH_4 may therefore be an important therapeutic approach to reverse endothelial dysfunction in postischemic tissues.