1. Myocardial ischemia results in tetrahydrobiopterin (B[H.sub.4]) oxidation with impaired endothelial function ameliorated by B[H.sub.4]
- Author
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Dumitrescu, Cristian, Biondi, Roberto, Xia, Yong, Cardounel, Arturo J., Druhan, Lawrence J., Ambrosio, Giuseppe, and Zweier, Jay L.
- Subjects
Myocardial ischemia -- Physiological aspects ,Myocardial ischemia -- Complications and side effects ,Vascular endothelium -- Chemical properties ,Vascular endothelium -- Health aspects ,Nitric oxide -- Physiological aspects ,Blood circulation disorders -- Reports ,Science and technology - Abstract
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 (B[H.sub.4]); however, the role of B[H.sub.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 B[H.sub.4] concentrations. Ischemia time-dependently decreased cardiac B[H.sub.4] content with 85, 95, or 97% irreversible degradation after 30, 45, or 60 min of ischemia, respectively. Paralleling the decreases in B[H.sub.4], reductions of eNOS activity were seen of 58, 86, or 92%, and NOS-derived superoxide production was greatly increased. Addition of 10 [micro]M B[H.sub.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 B[H.sub.4] infusion. Thus, B[H.sub.4] depletion contributes to postischemic eNOS dysfunction, and B[H.sub.4] treatment is effective in partial restoration of endothelium-dependent coronary flow. Supplementation of B[H.sub.4] may therefore be an important therapeutic approach to reverse endothelial dysfunction in postischemic tissues. ischemia reperfusion injury | nitric oxide | nitric oxide synthase uncoupling | superoxide | vascular function
- Published
- 2007