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

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

doi:10.1086/677361

“…32 Francis et al reported that BH 4 , given in a dose of 100 mg/kg, which corresponds to a fivefold higher dose than was administered here, increased cGMP levels, reversed pulmonary hypertension, and reduced right ventricular hypertrophy.…”

Section: Discussionmentioning

confidence: 64%

Combined oral administration of L-arginine and tetrahydrobiopterin in a rat model of pulmonary arterial hypertension

Schreiber

¹

,

Eilenberg

²

,

Panzenboeck

³

et al. 2017

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Alterations in the nitric oxide (NO) pathway play a major role in pulmonary arterial hypertension (PAH). L-arginine (LA) and tetrahydrobiopterin (BH 4 ) are main substrates in the production of NO, which mediates pulmonary vasodilation. Administration of either LA or BH 4 decrease pulmonary artery pressure (PAP). A combined administration of both may have synergistic effects in the therapy of PAH. In a telemetrically monitored model of unilateral pneumonectomy and monocrotaline-induced PAH, male SpragueDawley rats received either LA (300 mg/kg; n ¼ 15), BH 4 (20 mg/kg; n ¼ 15), the combination of LA and BH 4 (300 mg/kg, 20 mg/kg; n ¼ 15), or vehicle (control group; n ¼ 10) from day 28 after monocrotaline induction. Therapy was orally administered once daily over consecutive 14 days. LA, BH 4 , or both equally lowered PAP, increased pulmonary vascular elasticity, restored spontaneous locomotoric activity, prevented body weight loss and palliated small vessel disease of severely pulmonary hypertensive rats. BH 4 substitution lowered asymmetric dimethylarginine levels sustainably at 60 min after administration and downregulated endothelial NO synthase mRNA expression. No significant survival, macro-and histomorphologic or hemodynamic differences were found between therapy groups at the end of the study period. Administration of LA and BH 4 both mediated a decrease of mean PAP, attenuated right ventricular hypertrophy and small vessel disease in monocrotaline-induced pulmonary hypertensive rats, though a combined administration of both substances did not reveal any synergistic therapy effects in our animal model. Pulmonary arterial hypertension (PAH) is a fatal disease leading to a significant shortening of life. Constriction and occlusion of the pulmonary arterial bed pose an increased afterload on the right ventricle, thereby leading to right heart failure and death.Besides prostacyclines and endothelin receptor blockers, nitric oxide (NO) is a potent modulator of pulmonary hemodynamics. Intermittently administered, inhaled NO effectively lowers pulmonary artery pressures (PAP).1 In addition, pulmonary vasoreactivity response to NO predicts long-term survival.2 Further downstream, the NO pathway is modified by phosphodiesterase-5 inhibitors or by the novel substance riociguat that interacts with the soluble guanylate cyclase.3 These and several other publications suggest a pivotal role of NO alteration in the pathogenesis of PAH. Upregulation and maintenance of the endogenous NO production in the pulmonary vasculature have therefore been a target of extensive experimental research.

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“…Similarly, antioxidant treatment with melatonin, or supplementation with tetrahydrobiopterin, reduces mean pulmonary arterial blood pressure and increases pulmonary NO bioavailability in newborn sheep and adult rats, respectively (Francis et al . ; Torres et al . ).…”

Section: Discussionmentioning

confidence: 99%

The role of nitric oxide in the cardiopulmonary response to hypoxia in highland and lowland newborn llamas

Reyes

¹

,

Díaz

²

,

Ebensperger

³

et al. 2018

The Journal of Physiology

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Llamas are born in the Alto Andino with protection against pulmonary hypertension. The physiology underlying protection against pulmonary vasoconstrictor responses to acute hypoxia in highland species is unknown. We determined the role of nitric oxide (NO) in the cardiopulmonary responses to acute hypoxia in high- and lowland newborn llamas. The cardiopulmonary function of newborn llamas born at low (580 m) or high altitude (3600 m) was studied under acute hypoxia, with and without NO blockade. In pulmonary arteries, we measured the reactivity to potassium and sodium nitroprusside (SNP), and in lung we determined the content of cGMP and the expression of the NO-related proteins: BKCa, PDE5, PSer92-PDE5, PKG-1, ROCK1 and 2, MYPT1, PSer695-MYPT1, PThr696-MYPT1, MLC20 and PSer19-MLC20. Pulmonary vascular remodelling was evaluated by morphometry and based on α-actin expression. High- compared to lowland newborn llamas showed lower in vivo pulmonary arterial pressor responses to acute hypoxia. This protection involved enhanced NO function, as NO blockade reverted the effect and the pulmonary arterial dilatator response to SNP was significantly enhanced in highland neonates. The pulmonary expression of ROCK2 and the phosphorylation of MLC20 were lower in high-altitude llamas. Conversely, MYPT1 was up-regulated whilst PSer695-MYPT1 and PThr695-MYPT1 did not change. Enhanced NO-dependent mechanisms were insufficient to prevent pulmonary arterial remodelling. Combined, the data strongly support that in the highland newborn llama reduced ROCK, increased MYPT1 expression and Ca desensitization in pulmonary tissue allow an enhanced NO biology to limit hypoxic pulmonary constrictor responses. Blunting of hypoxic pulmonary hypertensive responses may be an adaptive mechanism to life at high altitude.

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“…32 Francis et al. reported that BH 4 , given in a dose of 100 mg/kg, which corresponds to a fivefold higher dose than was administered here, increased cGMP levels, reversed pulmonary hypertension, and reduced right ventricular hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Combined oral administration of L‐arginine and tetrahydrobiopterin in a rat model of pulmonary arterial hypertension

Schreiber

¹

,

Eilenberg

²

,

Panzenboeck

³

et al. 2017

View full text Add to dashboard Cite

Alterations in the nitric oxide (NO) pathway play a major role in pulmonary arterial hypertension (PAH). L-arginine (LA) and tetrahydrobiopterin (BH4) are main substrates in the production of NO, which mediates pulmonary vasodilation. Administration of either LA or BH4 decrease pulmonary artery pressure (PAP). A combined administration of both may have synergistic effects in the therapy of PAH. In a telemetrically monitored model of unilateral pneumonectomy and monocrotaline-induced PAH, male Sprague-Dawley rats received either LA (300 mg/kg; n = 15), BH4 (20 mg/kg; n = 15), the combination of LA and BH4 (300 mg/kg, 20 mg/kg; n = 15), or vehicle (control group; n = 10) from day 28 after monocrotaline induction. Therapy was orally administered once daily over consecutive 14 days. LA, BH4, or both equally lowered PAP, increased pulmonary vascular elasticity, restored spontaneous locomotoric activity, prevented body weight loss and palliated small vessel disease of severely pulmonary hypertensive rats. BH4 substitution lowered asymmetric dimethylarginine levels sustainably at 60 min after administration and downregulated endothelial NO synthase mRNA expression. No significant survival, macro- and histomorphologic or hemodynamic differences were found between therapy groups at the end of the study period. Administration of LA and BH4 both mediated a decrease of mean PAP, attenuated right ventricular hypertrophy and small vessel disease in monocrotaline-induced pulmonary hypertensive rats, though a combined administration of both substances did not reveal any synergistic therapy effects in our animal model.

show abstract

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

Cited by 19 publications

References 44 publications

Combined oral administration of L-arginine and tetrahydrobiopterin in a rat model of pulmonary arterial hypertension

Combined oral administration of L-arginine and tetrahydrobiopterin in a rat model of pulmonary arterial hypertension

The role of nitric oxide in the cardiopulmonary response to hypoxia in highland and lowland newborn llamas

Combined oral administration of L‐arginine and tetrahydrobiopterin in a rat model of pulmonary arterial hypertension

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