Increasing dihydrobiopterin causes dysfunction of endothelial nitric oxide synthase in rats in vivo
| Autor: | Kazuhiro Sugahara, Naobumi Hamadate, Toshihiro Matsuzaki, Shogo Ishiuchi, Haruaki Kubota, Mayuko Sakanashi, Katsuhiko Noguchi, Taro Uchida, Matao Sakanashi, Masato Tsutsui, Junko Nakasone, Kumiko Arakaki, Hiroaki Masuzaki, Yusuke Ohya |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Nitroprusside medicine.medical_specialty Sepiapterin Nitric Oxide Synthase Type III Physiology Vasodilator Agents Blood Pressure Nitric Oxide medicine.disease_cause chemistry.chemical_compound Superoxides In vivo Dihydrobiopterin Physiology (medical) Internal medicine medicine Animals Nitric Oxide Donors Phosphorylation Rats Wistar Analysis of Variance Dose-Response Relationship Drug Endothelial nitric oxide synthase Superoxide Dismutase Superoxide Tetrahydrobiopterin Biopterin Acetylcholine Pterins Rats Up-Regulation Vasodilation Tetrahydrofolate Dehydrogenase Methotrexate Endocrinology chemistry Folic Acid Antagonists Endothelium Vascular Protein Multimerization Cardiology and Cardiovascular Medicine Oxidation-Reduction Oxidative stress medicine.drug |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 301:H721-H729 |
| ISSN: | 1522-1539 0363-6135 |
| DOI: | 10.1152/ajpheart.01089.2010 |
| Popis: | An elevation of oxidized forms of tetrahydrobiopterin (BH4), especially dihydrobiopterin (BH2), 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 BH2in the regulation of eNOS activity in vivo remains to be evaluated. This study was designed to clarify whether increasing BH2concentration causes endothelial dysfunction in rats. To increase vascular BH2levels, the BH2precursor sepiapterin (SEP) was intravenously given after the administration of the specific dihydrofolate reductase inhibitor methotrexate (MTX) to block intracellular conversion of BH2to BH4. MTX/SEP treatment did not significantly affect aortic BH4levels compared with control treatment. However, MTX/SEP treatment markedly augmented aortic BH2levels (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 BH4levels but decreased the BH4-to-BH2ratio. 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 BH2causes eNOS dysfunction in vivo even in the absence of BH4deficiency, demonstrating a novel insight into the regulation of endothelial function. |
| Databáze: | OpenAIRE |
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