Myocardial ischemia results in tetrahydrobiopterin (BH4) oxidation with impaired endothelial function ameliorated by BH4.
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 microM 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.
Dumitrescu
Cristian
C
Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, OH 43210, USA.
Biondi
Roberto
R
Xia
Yong
Y
Cardounel
Arturo J
AJ
Druhan
Lawrence J
LJ
Ambrosio
Giuseppe
G
Zweier
Jay L
JL
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation
D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C003402:sapropterin