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(Hypertension. 2003;41:136.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Specific Potentiation of Endothelium-Dependent Contractions in SHR by Tetrahydrobiopterin

Di Yang; Nigel Levens; Ji Nan Zhang; Paul M. Vanhoutte; Michel Félétou

From Jiangsu Province Hospital, First Affiliated Hospital of Nanjing Medical University (D.Y., J.N.Z.), Nanjing, Peoples Republic of China; Pharmacologie et Physico-Chimie, Université Louis Pateur de Strasbourg (D.Y.), Illkirch, France; Institut de Recherches Servier (N.L., M.F.), Suresnes, France; and Institut de Recherches Internationales Servier (P.M.V.), Courbevoie Cedex, France.

Correspondence to Michel Félétou, Département Diabète et Maladies Métaboliques, Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes, France. E-mail michel.feletou{at}fr.netgrs.com

This study was designed to determine the effect of pteridines, R- and S-tetrahydrobiopterin, sepiapterin, and dihydrobiopterin on endothelium-dependent contractions to acetylcholine in isolated aortas from spontaneously hypertensive rat and normotensive Wistar-Kyoto rat. The noncumulative addition of redox-active pteridines R- and S-tetrahydrobiopterin (but not the oxidized analogues sepiapterin and dihydrobiopterin) produced a concentration-dependent transient contraction in isolated aortic rings from both normotensive and hypertensive rats. R- and S-tetrahydrobiopterin (but not sepiapterin or dihydrobiopterin) potentiated the endothelium-dependent contractions to acetylcholine but only in aortas from hypertensive rats and in the presence of N^G-nitro-L-arginine. In these aortas, the generation of oxygen-derived free radicals by the combination of xanthine plus xanthine oxidase also potentiated the endothelium-dependent contractions to acetylcholine. The presence of R-tetrahydrobiopterin did not alter the characteristics of the endothelium-dependent contractions because they were inhibited by valeryl salicylate, an inhibitor of cyclooxygenase-1, by S18886, a TP-receptor antagonist or by Tiron, a cell permeable superoxide anion scavenger. However, the contractions to acetylcholine, which are unaffected by the combination of superoxide dismutase and catalase, become significantly inhibited by these two scavengers in the presence of R-tetrahydrobiopterin. In the presence of N^G-nitro-L-arginine, R-tetrahydrobiopterin did not affect the contractions to phenylephrine, U 46619, or to oxygen-derived free radicals generated by xanthine plus xanthine oxidase. These results indicate that the production of superoxide by the autoxidation of tetrahydrobiopterin selectively enhances endothelium-dependent contractions in the spontaneously hypertensive rat when nitric oxide synthase is inhibited.

Key Words: tetrahydrobiopterin • nitric oxide • endothelium-dependent contractions • rats, spontaneously hypertensive

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