Effect of Decreased Levels of Intrinsic Tetrahydrobiopterin on Endothelial Function in Anesthetized Rats

• Published in: Journal of Pharmacological Sciences Vol. 107; no. 1; pp. 49 - 56
• Main Authors: Hamadate, Naobumi, Noguchi, Katsuhiko, Sakanashi, Mayuko, Matsuzaki, Toshihiro, Nakasone, Junko, Sakanashi, Matao
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 2008; The Japanese Pharmacological Society; Elsevier
• Subjects: 2,4-diamino-6-hydroxypyrimidine; acetylcholine; Acetylcholine - pharmacology; Anesthesia, General; Animals; Aorta, Thoracic - metabolism; Biopterins - analogs & derivatives; Biopterins - blood; Biopterins - metabolism; Dose-Response Relationship, Drug; Down-Regulation; endothelial function; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Endothelium, Vascular - metabolism; Enzyme Inhibitors - pharmacology; GTP Cyclohydrolase - antagonists & inhibitors; GTP Cyclohydrolase - metabolism; Hypoxanthines - pharmacology; Male; Nitrates - metabolism; Nitric Oxide Synthase Type II - metabolism; Nitric Oxide Synthase Type III; Nitrites - metabolism; Nitroprusside - pharmacology; Rats; Rats, Wistar; sodium nitroprusside; tetrahydrobiopterin; Vasodilation - drug effects; Vasodilator Agents - pharmacology; endothelial function; 2,4-diamino-6-hydroxypyrimidine; tetrahydrobiopterin; acetylcholine; sodium nitroprusside
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.FP0071967

Tetrahydrobiopterin (BH4) deficiency has been suggested to be an important factor in vascular endothelial dysfunction. In this study, we investigated the influence of decreased BH4 level produced by administration of 2,4-diamino-6-hydroxypyrimidine (DAHP), a specific inhibitor of the rate-limiting enzyme of BH4 synthesis, on vascular endothelial function in anesthetized rats. Wistar rats were given DAHP (0.1 – 1.0 g/kg, i.p.) or the vehicle 5 h before the experiment. Depressor responses to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside were tested. After the experiment, blood and thoracic aorta were taken for estimating their BH4 levels and plasma concentrations of nitrite plus nitrate. DAHP produced marked decreases in BH4 levels in plasma and aorta in a dose-related manner. Baseline values for hemodynamics were not affected by DAHP. Depressor responses to acetylcholine were attenuated with the highest dose of DAHP (1.0 g/kg) but not with DAHP (0.3 g/kg), although similar decreases in BH4 levels were seen with these two doses of DAHP. Treatment with DAHP at each dose did not decrease plasma concentrations of nitrite plus nitrate. These findings suggest that a decrease in BH4 levels by acute inhibition of de novo BH4 synthesis does not necessarily cause endothelial dysfunction.