Increasing dihydrobiopterin causes dysfunction of endothelial nitric oxide synthase in rats in vivo

An elevation of oxidized forms of tetrahydrobiopterin (BH(4)), especially dihydrobiopterin (BH(2)), has been reported in the setting of oxidative stress, such as arteriosclerotic/atherosclerotic disorders, where endothelial nitric oxide synthase (eNOS) is dysfunctional, but the role of BH(2) in the...

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Published in:American journal of physiology. Heart and circulatory physiology 2011-09, Vol.301 (3), p.H721-H729
Main Authors: Noguchi, Katsuhiko, Hamadate, Naobumi, Matsuzaki, Toshihiro, Sakanashi, Mayuko, Nakasone, Junko, Uchida, Taro, Arakaki, Kumiko, Kubota, Haruaki, Ishiuchi, Shogo, Masuzaki, Hiroaki, Sugahara, Kazuhiro, Ohya, Yusuke, Sakanashi, Matao, Tsutsui, Masato
Format: Article
Language:English
Subjects:
Acetylcholine - pharmacology
Analysis of Variance
Animals
Biopterins - analogs & derivatives
Biopterins - metabolism
Blood Pressure - drug effects
Cardiovascular system
Cells
Dose-Response Relationship, Drug
Endothelium, Vascular - drug effects
Endothelium, Vascular - enzymology
Endothelium, Vascular - physiopathology
Folic Acid Antagonists - pharmacology
Hypertension
Male
Methotrexate - administration & dosage
Nitric oxide
Nitric Oxide - metabolism
Nitric Oxide Donors - pharmacology
Nitric Oxide Synthase Type III - metabolism
Nitroprusside - pharmacology
Oxidation-Reduction
Phosphorylation
Physiology
Protein Multimerization
Pterins - administration & dosage
Pterins - metabolism
Rats
Rats, Wistar
Rodents
Superoxide Dismutase - metabolism
Superoxides - metabolism
Tetrahydrofolate Dehydrogenase - metabolism
Up-Regulation
Vasodilation - drug effects
Vasodilator Agents - pharmacology
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Summary:An elevation of oxidized forms of tetrahydrobiopterin (BH(4)), especially dihydrobiopterin (BH(2)), has been reported in the setting of oxidative stress, such as arteriosclerotic/atherosclerotic disorders, where endothelial nitric oxide synthase (eNOS) is dysfunctional, but the role of BH(2) in the regulation of eNOS activity in vivo remains to be evaluated. This study was designed to clarify whether increasing BH(2) concentration causes endothelial dysfunction in rats. To increase vascular BH(2) levels, the BH(2) precursor sepiapterin (SEP) was intravenously given after the administration of the specific dihydrofolate reductase inhibitor methotrexate (MTX) to block intracellular conversion of BH(2) to BH(4). MTX/SEP treatment did not significantly affect aortic BH(4) levels compared with control treatment. However, MTX/SEP treatment markedly augmented aortic BH(2) levels (291.1 ± 29.2 vs. 33.4 ± 6.4 pmol/g, P < 0.01) in association with moderate hypertension. Treatment with MTX alone did not significantly alter blood pressure or BH(4) levels but decreased the BH(4)-to-BH(2) ratio. Treatment with MTX/SEP, but not with MTX alone, impaired ACh-induced vasodilator and depressor responses compared with the control treatment (both P < 0.05) and also aggravated ACh-induced endothelium-dependent relaxations (P < 0.05) of isolated aortas without affecting sodium nitroprusside-induced endothelium-independent relaxations. Importantly, MTX/SEP treatment significantly enhanced aortic superoxide production, which was diminished by NOS inhibitor treatment, and the impaired ACh-induced relaxations were reversed with SOD (P < 0.05), suggesting the involvement of eNOS uncoupling. These results indicate, for the first time, that increasing BH(2) causes eNOS dysfunction in vivo even in the absence of BH(4) deficiency, demonstrating a novel insight into the regulation of endothelial function.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.01089.2010