Tetrahydrobiopterin and the regulation of hypoxic pulmonary vasoconstriction

Francis, Bahaa; Wilkins, Martin R.; Zhao, Lan

doi:10.1183/09031936.00188809

Cited by 21 publications

(26 citation statements)

References 36 publications

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“…In addition, it is possible that exogenous BH 4 acted as an antioxidant and scavenged reactive oxygen species such as superoxide. 15 The effect of BH 4 was dose dependent. BH 4 , administered at 100 mg/kg/day, effectively reduced pulmonary pressure, RVH, and pulmonary muscularization, whereas BH 4 at 10 mg/kg/day did not have any significant effect.…”

Section: Discussionmentioning

confidence: 96%

“…Acute pharmacologic effects of BH 4 : the isolated perfused rat lung The pulmonary vascular response to 6R-BH 4 (sapropterin dihydochloride or BH 4 ) was studied using the isolated rat lung preparation as previously described 15 ( Fig. S1; Figs.…”

Section: Animalsmentioning

confidence: 99%

“…Hypoxic pulmonary vasoconstriction (HPV) was induced by ventilating the lung with 2% O 2 , 5% CO 2 , and 93% N 2 . BH 4 (final concentration, 0.3 μg/mL and 1 μg/mL, freshly prepared as previously described 15 ) or vehicle was added to the perfusate when consistent HPV had been achieved (usually after 3 hypoxic challenges). Perfusate samples were collected after passage through the lungs 1 minute before and 3 minutes after BH 4 administration for determination of nitrate/nitrite (NOx) concentration.…”

Section: Animalsmentioning

confidence: 99%

“…15 BH 4 or placebo pellets were given after 2 weeks of hypoxia exposure and continued for an additional 2 weeks under hypoxia. Rats were divided into 5 groups: (1) normoxia control; (2) 2 weeks hypoxia; (3) 4 weeks hypoxia placebo control; (4) 4 weeks hypoxia with 2 weeks BH 4 low dose (10 mg/kg/day) treatment; and (5) 4 weeks hypoxia with 2 weeks BH 4 high-dose (100 mg/kg/day) treatment.…”

Section: Animalsmentioning

confidence: 99%

“…15 This led to the hypothesis that pharmacological treatment with BH 4 may improve pulmonary endothelial function and has therapeutic potential in pulmonary hypertension. Employing a hypoxia-induced pulmonary hypertension rat model, we investigated the chronic pharmacological effects of BH 4 on hemodynamics, right ventricular hypertrophy, and pulmonary vascular remodeling.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Tetrahydrobiopterin Oral Treatment in Hypoxia‐Induced Pulmonary Hypertension in Rat

et al. 2014

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Endothelial nitric oxide synthase (eNOS) plays a major role in maintaining pulmonary vascular homeostasis. Tetrahydrobiopterin (BH 4 ), 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 BH 4 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 BH 4 oral administration attenuated the pressor response to hypoxia (mean pulmonary artery pressure AE standard error of the mean, 31.8 AE 0.5 mmHg at 100 mg/kg/day; placebo group, 36.3 AE 0.6 mmHg; P < 0.05). During telemetric monitoring, right ventricular systolic pressure was reduced by approximately 50% after 1 week of BH 4 treatment at 100 mg/kg/day. BH 4 at 100 mg/kg/day reduced right ventricular hypertrophy (from 0.55 AE 0.01 to 0.50 AE 0.01; P < 0.05) and pulmonary vascular muscularization (from 79.2% AE 2% to 65.2% AE 3%; P < 0.01). BH 4 treatment enhanced lung eNOS activity and reduced superoxide production, with a net increase in cyclic guanosine monophosphate levels. BH 4 is effective in attenuating pulmonary hypertension in the hypoxic rat model when given as a rescue therapy.

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Section: Discussionmentioning

confidence: 96%

Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Tetrahydrobiopterin Oral Treatment in Hypoxia‐Induced Pulmonary Hypertension in Rat

et al. 2014

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Pulmonary Arterial Hypertension and Oxidative Stress

Chrobak

Haeger

Maracle

et al. 2014

Oxidative Stress in Applied Basic Research and Clinical Practice

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Molecular Basis of Nitrative Stress in the Pathogenesis of Pulmonary Hypertension

Evans¹,

Zhao²

2017

Advances in Experimental Medicine and Biology

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Pulmonary hypertension (PH) is a lung vascular disease with marked increases in pulmonary vascular resistance and pulmonary artery pressure (>25 mmHg at rest). In PH patients, increases in pulmonary vascular resistance lead to impaired cardiac output and reduced exercise tolerance. If untreated, PH progresses to right heart failure and premature lethality. The mechanisms that control the pathogenesis of PH are incompletely understood, but evidence from human and animal studies implicate nitrative stress in the development of PH. Increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) result in nitrative stress, which in turn induces posttranslational modification of key proteins important for maintaining pulmonary vascular homeostasis. This affects their functions and thereby contributes to the pathogenesis of PH. In this chapter, molecular mechanisms underlying nitrative stress-induced PH are reviewed, molecular sources of ROS and RNS are delineated, and evidence of nitrative stress in PH patients is described. A better understanding of such mechanisms could lead to the development of novel treatments for PH.

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Tetrahydrobiopterin and the regulation of hypoxic pulmonary vasoconstriction

Cited by 21 publications

References 36 publications

Effects of Tetrahydrobiopterin Oral Treatment in Hypoxia‐Induced Pulmonary Hypertension in Rat

Effects of Tetrahydrobiopterin Oral Treatment in Hypoxia‐Induced Pulmonary Hypertension in Rat

Pulmonary Arterial Hypertension and Oxidative Stress

Molecular Basis of Nitrative Stress in the Pathogenesis of Pulmonary Hypertension

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