title: Restoration of endothelium-dependent vasodilation after reperfusion injury by tetrahydrobiopterin.
abstract: 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 tetra-hydrobiopterin (BH4), we hypothesized that depletion of this cofactor underlies the reduction of endothelium-dependent dilation in reperfusion injury.
  
  
  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 mumol/L) or MH4 (10 mumol/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.
authors.affiliation: Department of Medical Physiology, Texas A&M University Health Science Center, College Station, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Tiefenbacher
authors.forename: W M
authors.initials: WM
authors.lastname: Chilian
authors.forename: M
authors.initials: M
authors.lastname: Mitchell
authors.forename: D V
authors.initials: DV
authors.lastname: DeFily
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics; D007042:Hypoxanthines / Q000494:pharmacology; D066298:In Vitro Techniques; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D011621:Pteridines / Q000494:pharmacology; D011622:Pterins / Q000494:pharmacology; D012016:Reference Values; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D011621:Pteridines; D011622:Pterins; D001708:Biopterins; C017523:6-methyltetrahydropterin; C016727:sepiapterin; C017202:2,4-diaminohypoxanthine; C003402:sapropterin