Exogenous tetrahydrobiopterin causes endothelium-dependent contractions in isolated canine basilar artery.
Tetrahydrobiopterin is an essential cofactor in the biosynthesis of nitric oxide, but in the presence of O2, autooxidation of tetrahydrobiopterin leads to the production of superoxide anions and the subsequent chemical inactivation of nitric oxide. As a result, the present experiments were designed to determine the effect of exogenous tetrahydrobiopterin on isolated canine basilar arteries. Rings with and without endothelium were suspended for isometric force recording in modified Krebs-Ringer bicarbonate solution bubbled with 94% O2-6% CO2 (37 degrees C; pH 7.4). A radioimmunoassay technique was used to measure guanosine 3',5' cyclic monophosphate production (cGMP). Tetrahydrobiopterin (10(-7) to 10(-4) M), but not dihydrobiopterin or biopterin, caused endothelium-dependent contractions. Superoxide dismutase (150 U/ml) abolished tetrahydrobiopterin-induced contractions, but a H2O2 scavenger, catalase (1,200 U/ml), and hydroxyl radical scavengers deferoxamine (10(-4) M) and dimethylsulfoxide (10(-4) to 10(-3) M) did not significantly affect the contractions. A cyclooxygenase inhibitor, indomethacin (10(-5) M), significantly reduced the contractile effect of tetrahydrobiopterin. With the prostaglandin H2/ thromboxane A2 receptor antagonist, SQ-29548 (10(-6) M) present, contractions reversed to relaxations. In rings with endothelium, tetrahydrobiopterin (10(-4) M) significantly decreased the levels of cGMP. These studies suggest that autooxidation of exogenous tetrahydrobiopterin induces endothelium-dependent contractions by 1) chemical inactivation of nitric oxide by superoxide anions and 2) activation of arachidonic acid metabolism via the cyclooxygenase pathway with subsequent release of endoperoxide and/or thromboxane A2 from endothelial cells.
Kinoshita
H
H
Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Katusic
Z S
ZS
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001488:Basilar Artery / Q000187:drug effects* / Q000502:physiology*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D014661:Vasoconstriction / Q000502:physiology*
D000975:Antioxidants; D001708:Biopterins; C003402:sapropterin