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

PVRI Member Authors: Martin Wilkins, Lan Zhao


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.

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Animal Models
Endothelin and Endothelium & Epithelium and Epithelial Transport
Hypoxia/ Intermittent Hypoxia/ Hypoxia-Ischemia and Ischemia-Reperfusion Injury
Nitric Oxide and Nitric Oxide Synthase
Oxidative stress and Oxidants/Antioxidants and Free Radicals
Pulmonary Hypertension
Vasoreactivity: Vasoconstriction and Vasodilatation


Bahaa N. Francis, Ashley Hale, Keith M. Channon, Martin R. Wilkins, Lan Zhao

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Pulmonary Circulation Vol 4: No 3 cover image

August 2014

Pulmonary Circulation Vol 4: No 3

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