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

Schreiber, C; Eilenberg, Magdalena; Panzenboeck, Adelheid; Winter, Max‐Paul; Bergmeister, Helga; Mascherbauer, Julia; Lang, Irene M.; Bonderman, Diana

doi:10.1086/689289

Cited by 12 publications

(10 citation statements)

References 37 publications

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“…BH 4 levels are decreased in many models of cardiovascular disease [ 30 ] including hypertension [ 31 ]. A role for BH 4 in BP control is further supported by the finding that BH 4 supplementation lowers BP in a male rat model of pulmonary arterial hypertension [ 32 ] and male mice with disrupted BH 4 synthesis are hypertensive [ 33 ]. Despite growing interest and evidence for the role of BH 4 in the pathogenesis of hypertension, there is a scarcity of data in the literature examining the impact of sex on the BH 4 system.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress induces BH4 deficiency in male, but not female, SHR

et al. 2018

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We previously published that female spontaneously hypertensive rats (SHR) have significantly greater nitric oxide (NO) bioavailability and NO synthase (NOS) enzymatic activity in the renal inner medulla (IM) compared with age-matched males, although the mechanism responsible remains unknown. Tetrahydrobiopterin (BH4) is a critical cofactor required for NO generation, and decreases in BH4 as a result of increases in oxidative stress have been implicated in the pathogenesis of hypertension. As male SHR are known to have higher levels of oxidative stress compared with female SHR, we hypothesized that relative BH4 deficiency induced by oxidative stress in male SHR results in lower levels of NOS activity in renal IM compared with females. Twelve-week-old male and female SHR were randomized to receive tempol (30 mg/kg/day via drinking water) or vehicle for 2 weeks. Tempol treatment did not affect blood pressure (BP) in either sex, but reduced peroxynitrite levels only in males. Females had more total biopterin, dihydrobiopterin (BH2), and BH4 levels in renal IMs than males, and tempol treatment eliminated these sex differences. Females had greater total NOS activity in the renal IM than males, and adding exogenous BH4 to the assay increased NOS activity in both sexes. This sex difference in total NOS and the effect of exogenous BH4 were abolished with tempol treatment. We conclude that higher oxidative stress in male SHR results in a relative deficiency of BH4 compared with females, resulting in diminished renal NOS activity in the male.

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Section: Discussionmentioning

confidence: 99%

Oxidative stress induces BH4 deficiency in male, but not female, SHR

et al. 2018

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“…Consistent with evidence that supplementation of BH4 [ 116 , 123 , 124 , 125 , 126 ] and an increased BH4/oxidized BH4 ratio [ 31 , 121 , 123 ] enhance eNOS activity, oral BH4 administration promotes eNOS activity, lowers lung O 2 .− levels, and reverses established CH-induced PH [ 34 ]. Additionally, BH4 is shown to be beneficial in the treatment of a rat PAH model [ 127 ].…”

Section: Ros In the Pathogenesis Of Phmentioning

confidence: 99%

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

2020

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Elevated resistance of pulmonary circulation after chronic hypoxia exposure leads to pulmonary hypertension. Contributing to this pathological process is enhanced pulmonary vasoconstriction through both calcium-dependent and calcium sensitization mechanisms. Reactive oxygen species (ROS), as a result of increased enzymatic production and/or decreased scavenging, participate in augmentation of pulmonary arterial constriction by potentiating calcium influx as well as activation of myofilament sensitization, therefore mediating the development of pulmonary hypertension. Here, we review the effects of chronic hypoxia on sources of ROS within the pulmonary vasculature including NADPH oxidases, mitochondria, uncoupled endothelial nitric oxide synthase, xanthine oxidase, monoamine oxidases and dysfunctional superoxide dismutases. We also summarize the ROS-induced functional alterations of various Ca2+ and K+ channels involved in regulating Ca2+ influx, and of Rho kinase that is responsible for myofilament Ca2+ sensitivity. A variety of antioxidants have been shown to have beneficial therapeutic effects in animal models of pulmonary hypertension, supporting the role of ROS in the development of pulmonary hypertension. A better understanding of the mechanisms by which ROS enhance vasoconstriction will be useful in evaluating the efficacy of antioxidants for the treatment of pulmonary hypertension.

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“…The present investigation showed that pre-incubation of rat aortic rings with LA and BH 4 in combination caused the marked increase in BQ-123 efficacy and potency. Schreiber et al (2017) recorded that LA is the main substrate in the production of NO. Binding BH 4 exert allosteric action to stabilize the active dimeric form of eNOS (Shinozaki et al, 2000) and increases the enzymatic turnover of LA.…”

Section: Discussionmentioning

confidence: 99%

L-arginine and tetrahydrobiopterin modulate endothelin-1A receptor activity in isolated rat aorta

2019

ZJPAS

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Endothelin-1 (ET-1), is a potent endogenous vasoconstrictor secreted by endothelial cells. It acts as the natural counterpart of the vasodilator effect of nitric oxide (NO). ET-1 exert it is the vasoconstrictor activity through two types of receptors, ET-1A and ET-1B receptors that are located on vascular smooth muscle cells (VSMCs). The present study was designed to evaluate the effect of L-arginine (LA), tetrahydrobiopterin (BH4), and their combination on ET-1A receptor activity in rat aortic rings. The study involved pre-incubation of rat aortic rings with LA, BH4, and their combination. Then, the vascular response to a cumulative dose of the ET-1A receptor antagonist (BQ-123) and in the second set of experiment cumulative doses of Acetylcholine (ACh) were applied to each group. BQ-123 potency increased after LA pre-incubation, but LA and BH4 in combination significantly potentiated BQ-123 potency and maximum response. In the second set of experiment, ACh potency does not change, while ACh efficacy markedly increased during pre-incubation of LA, BH4, and their combination. In conclusion, LA and BH4 may offer some pharmacological tools to modulate the ET-1A receptor activity and treat cardiovascular disease beyond pulmonary arterial hypertension.

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

Cited by 12 publications

References 37 publications

Oxidative stress induces BH4 deficiency in male, but not female, SHR

Oxidative stress induces BH4 deficiency in male, but not female, SHR

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

L-arginine and tetrahydrobiopterin modulate endothelin-1A receptor activity in isolated rat aorta

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