Exogenous tetrahydrobiopterin causes endothelium-dependent
contractions in isolated canine basilar artery.
Kinoshita, H., and Z. S. Katusic.
Departments of Anesthesiology and Pharmacology, Mayo Clinic and
Mayo Foundation, 200 First Street SW, Rochester, MN 55905
APStracts 2:0561H, 1995.
Tetrahydrobiopterin is an essential cofactor in biosynthesis of nitric
oxide. In contrast, in the presence of oxygen autooxidation of
tetrahydrobiopterin leads to production of superoxide anions and
subsequent chemical inactivation of nitric oxide. Because of these
apparent opposing effects of tetrahydrobiopterin on nitric oxide
levels, 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 radioimmuno-assay technique
was used to measure production of cyclic GMP. Tetrahydrobiopterin
(10-7 to 10-4M), but not dihydrobiopterin or biopterin, caused
endothelium-dependent contractions. Superoxide dismutase (150 U/ml)
abolished tetrahydrobiopterin-induced contractions. A hydrogen
peroxide scavenger catalase (1200 U/ml), and hydroxyl radical
scavengers deferoxamine (10-4M) and DMSO (10-4 to 10-3M) did not
significantly affect contractions to tetrahydrobiopterin. A
cyclooxygenase inhibitor indomethacin (10-5M) significantly reduced
the contractile effect of tetrahydrobiopterin. In the presence of a
prostaglandin H2 / thromboxane A2 receptor antagonist SQ 29548 (10
-6M), contractions to tetrahydrobiopterin reversed to relaxations. In
rings with endothelium, tetrahydrobiopterin (10-4M) significantly
decreased the levels of cyclic GMP. These studies suggest that
autooxidation of exogenous tetrahydrobiopterin induces endothelium
-dependent contractions by 1) chemical inactivation of nitric oxide by
superoxide anions, 2) activation of arachidonic acid metabolism via
cyclooxygenase pathway with subsequent release of endoperoxide and/or
thromboxane A2 from endothelial cells.
Received 1 September 1995; accepted in final form 6 December
1995.
APS Manuscript Number H828-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 December 95