In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 301, No. 3 ( 2011-09), p. H721-H729
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.01089.2010
Language:
English
Publisher:
American Physiological Society
Publication Date:
2011
detail.hit.zdb_id:
1477308-9
SSG:
12
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