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Francis BN, Hale A, Channon KM, et al. Effects of tetrahydrobiopterin oral treatment in hypoxia-induced pulmonary hypertension in rat. Pulm Circ. 2014;4(3):462-70doi: 10.1086/677361.
Francis, B. N., Hale, A., Channon, K. M., Wilkins, M. R., & Zhao, L. (2014). Effects of tetrahydrobiopterin oral treatment in hypoxia-induced pulmonary hypertension in rat. Pulmonary circulation, 4(3), 462-70. https://doi.org/10.1086/677361
Francis, Bahaa N, et al. "Effects of tetrahydrobiopterin oral treatment in hypoxia-induced pulmonary hypertension in rat." Pulmonary circulation vol. 4,3 (2014): 462-70. doi: https://doi.org/10.1086/677361
Francis BN, Hale A, Channon KM, Wilkins MR, Zhao L. Effects of tetrahydrobiopterin oral treatment in hypoxia-induced pulmonary hypertension in rat. Pulm Circ. 2014 Sep;4(3):462-70. doi: 10.1086/677361. PMID: 25621160; PMCID: PMC4278606.
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Pulm Circ. 2014 Sep;4(3):462-70. doi: 10.1086/677361.

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

Pulmonary circulation

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

Affiliations

  1. Centre for Pharmacology and Therapeutics, Experimental Medicine and Toxicology, Imperial College London, Hammersmith Hospital, London, United Kingdom.
  2. Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

PMID: 25621160 PMCID: PMC4278606 DOI: 10.1086/677361

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.

Keywords: endothelium; nitric oxide; pulmonary hypertension; superoxide; tetrahydrobiopterin

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