(Circulation. 1996;94:1423-1429.)
© 1996 American Heart Association, Inc.
Articles |
Restoration of Endothelium-Dependent Vasodilation After Reperfusion Injury by Tetrahydrobiopterin
the Department of Medical Physiology and the Microcirculation Research Institute, Texas A&M University Health Science Center, College Station.
Correspondence to David V. DeFily, PhD, Center for Anesthesiology Research, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.
Background A deficit in the endothelial production of nitric oxide (NO) is associated with the sequelae of reperfusion injury. Because endothelial NO synthesis depends on the cofactor tetrahydrobiopterin (BH4), we hypothesized that depletion of this cofactor underlies the reduction of endothelium-dependent dilation in reperfusion injury.
Methods and Results After occlusion of the left anterior descending coronary artery of a pig for 60 minutes followed by 90 minutes of reperfusion (ischemia/reperfusion), hearts were removed and the arterioles were isolated, cannulated, pressurized, and placed on an inverted microscope stage. Dose responses to the endothelium-independent dilator sodium nitroprusside and the endothelium-dependent dilators serotonin, A23187, and substance P were obtained under control conditions, after incubation with sepiapterin (intracellularly converted to BH4) or synthetic BH4 6-methyltetrahydropterin (MH4), and again after their washout. After ischemia/reperfusion, sodium nitroprusside maximally dilated arterioles (99±3%), whereas relaxation to serotonin, A23187, and substance P was significantly reduced (19±9%, 44±9%, and 54±8%, respectively). During incubation with sepiapterin (1 µmol/L) or MH4 (10 µmol/L), endothelium-dependent dilation was significantly enhanced (P<.05), whereas the response to sodium nitroprusside was unaltered. After washout, the vasodilatory responses were not significantly different from the initial ischemia/reperfusion responses. Sepiapterin and MH4 did not affect vasodilatory responses in vessels obtained from nonischemic control hearts. As after ischemia/reperfusion, incubation of control vessels with 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP cyclohydrolase I, decreased endothelium-dependent vasodilation, which was restored in the presence of sepiapterin or MH4.
Conclusions These data indicate that exogenous administration of sepiapterin or MH4 restores the response to endothelium-dependent vasodilators in pig coronary arterioles after ischemia/reperfusion. We therefore conclude that ischemia/reperfusion alters the availability or production of BH4, which contributes to blunted endothelial nitroxidergic vasodilation.
Key Words: endothelium-derived factors • arteries • ischemia
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