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Effects of tetrahydrobiopterin oral treatment in hypoxia-induced pulmonary hypertension in rat.

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Title: Effects of tetrahydrobiopterin oral treatment in hypoxia-induced pulmonary hypertension in rat.
Authors: Francis, BN
Hale, A
Channon, KM
Wilkins, MR
Zhao, L
Item Type: Journal Article
Publication Date: 2015-07-29T06:00:13Z
Abstract: Endothelial nitric oxide synthase (eNOS) plays a major role in maintaining pulmonary vascular homeostasis. Tetrahydrobiopterin (BH4), an essential cofactor that stabilizes the dimerization of eNOS and balances nitric oxide (NO) and superoxide production, may have therapeutic potential in pulmonary hypertension. In the isolated perfused lung, we demonstrated a direct effect of exogenous administration of BH4 on pulmonary NO production, leading to acute vasorelaxation during the plateau phase of hypoxia-induced pulmonary vasoconstriction. In the chronic hypoxia-induced pulmonary hypertension rat model, chronic BH4 oral administration attenuated the pressor response to hypoxia (mean pulmonary artery pressure ± standard error of the mean, 31.8 ± 0.5 mmHg at 100 mg/kg/day; placebo group, 36.3 ± 0.6 mmHg; P < 0.05). During telemetric monitoring, right ventricular systolic pressure was reduced by approximately 50% after 1 week of BH4 treatment at 100 mg/kg/day. BH4 at 100 mg/kg/day reduced right ventricular hypertrophy (from 0.55 ± 0.01 to 0.50 ± 0.01; P < 0.05) and pulmonary vascular muscularization (from 79.2% ± 2% to 65.2% ± 3%; P < 0.01). BH4 treatment enhanced lung eNOS activity and reduced superoxide production, with a net increase in cyclic guanosine monophosphate levels. BH4 is effective in attenuating pulmonary hypertension in the hypoxic rat model when given as a rescue therapy.
Issue Date: 30-Sep-2014
URI: http://hdl.handle.net/10044/1/21728
DOI: http://dx.doi.org/10.1086/677361
ISSN: 2045-8932
Start Page: 462
End Page: 470
Journal / Book Title: Pulm Circ
Volume: 4
Issue: 3
Copyright Statement: © 2014 by the Pulmonary Vascular Research Institute. All rights reserved.
Conference Place: United States
Appears in Collections:Department of Medicine



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