Cytochrome P450 Epoxygenase-Dependent Activation of TRPV4 Channel Participates in Enhanced Serotonin-Induced Pulmonary Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension

Yang, Xia; Xia, Lei; Zhou, Jin; Jin, Rui; Paudel, Omkar; Sham, James S.K.

doi:10.1155/2020/8927381

Cited by 5 publications

(3 citation statements)

References 51 publications

(67 reference statements)

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“…TRPV4 expression is increased in CH rat PASMC [23,65] associated with enhanced responses, providing evidence that TRPV4 is important in the development of the pathology. Indeed, the TRPV4 upregulation in PASMC is consistent with the higher basal [Ca 2+ ] i observed after CH, an enhanced myogenic tone and 5-HT-induced vasoconstriction via the cytochrome P450 epoxygenase-epoxyeicosatrienoic acid pathway CH PA [23,121]. Nevertheless, whereas culturing PASMC in CH (1% O 2 during 48 h) does not affect TRPV4 expression, the amplitude of the TRPV4-induced Ca 2+ elevation and migratory response are more elevated [21], suggesting a direct role of hypoxia on TRPV4 channel function.…”

Section: Trpv4supporting

confidence: 75%

Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension

et al. 2021

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A variety of cell types in pulmonary arteries (endothelial cells, fibroblasts, and smooth muscle cells) are continuously exposed to mechanical stimulations such as shear stress and pulsatile blood pressure, which are altered under conditions of pulmonary hypertension (PH). Most functions of such vascular cells (e.g., contraction, migration, proliferation, production of extracellular matrix proteins, etc.) depend on a key event, i.e., the increase in intracellular calcium concentration ([Ca2+]i) which results from an influx of extracellular Ca2+ and/or a release of intracellular stored Ca2+. Calcium entry from the extracellular space is a major step in the elevation of [Ca2+]i, involving a variety of plasmalemmal Ca2+ channels including the superfamily of stretch-activated channels (SAC). A common characteristic of SAC is that their gating depends on membrane stretch. In general, SAC are non-selective Ca2+-permeable cation channels, including proteins of the TRP (Transient Receptor Potential) and Piezo channel superfamily. As membrane mechano-transducers, SAC convert physical forces into biological signals and hence into a cell response. Consequently, SAC play a major role in pulmonary arterial calcium homeostasis and, thus, appear as potential novel drug targets for a better management of PH.

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Section: Trpv4supporting

confidence: 75%

Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension

et al. 2021

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“…Согласно литературным данным [8,9], серотонин является одним из главных суживающих факторов при развитии ЛГ, кроме того, он участвует в ремоделинге сосудистой стенки легочных сосудов. Известно, что суживающий эффект серотонина реализуется через активацию в основном 5НТ1В-и 5НТ2В-рецепторов [10] и цитохром 450-эпоксизависимую активацию TRP4-каналов [11]. На рис.…”

Section: материалы и методы исследованияunclassified

Sex-dependent change in the reactivity of isolated pulmonary arteries of gonadectomized rats under the intermittent hypoxia of different degree

Панькова

Артемьева

Medvedeva

2021

Regional blood circulation and microcirculation

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Introduction. Pulmonary vasoconstriction is one of factors of hypoxic pulmonary hypertension (HPH). The progression of this disease depends on the degree of hypoxiа and seх. The aim of this study was to investigate the reactivity of isolated pulmonary vessels of male and female rats with HPH to vasoactive factors. Materials and methods. The experiments were on male and female of Wistar rats 190–200 g, which were gonadectomized. All animals were divided into 4 groups. One group of males and female rats was kept in a vivarium (21 % О2 ). To simulate HPH, other rats were exposed to hypobaric hypoxia for 10 hours a day at an oxygen content in the inhaled air equal to 13 % (pP O2 103.7 mmHg) or 10 % (pP O2 78,2 mmHg), or 8 % (pP O2 63,5 mmHg) as compared to its content at 21 % (pP О2 159 mmHg). After that, a third-order pulmonary vessel was perfused at a constant flow rate with vasoconstrictors and vasodilators. The reaction was recorded by the change in perfusion pressure. Results. In females with HРН 10 %O2 , constricting response to serotonin were greater than in males. In normotensive males, the dilatory response to sodium nitroprusside (NP) was less than in female. Exposure to hypoxia induced an increase in NP responses. Conclusion. Increased reactivity of pulmonary vessels to serotonin is a factor of pathogenesis of HPH in females, in contrast to males. Increased reactivity to NO donor in males exposed to hypoxia сan be used for a pharmacological target for HPH.

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“…Simvastatin, sildenafil, bosentan, and nifedipine are metabolized by CYP3A4 in humans and by CYP3A1 in rats [ 27 , 28 , 29 , 30 , 31 ]. Studies have demonstrated that hypoxia significantly alters the activity and expression of the drug-metabolizing enzyme CYP450 [ 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. Therefore, it is inferred that CYP3A4 activity may change under hypoxia and then affects the metabolism of these four cardiovascular system drugs.…”

Section: Introductionmentioning

confidence: 99%

High-altitude Hypoxia Influences the Activities of the Drug-Metabolizing Enzyme CYP3A1 and the Pharmacokinetics of Four Cardiovascular System Drugs

et al. 2022

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(1) Background: High-altitude hypoxia has been shown to affect the pharmacokinetic properties of drugs. Although there is a high incidence of cardiovascular disease among individuals living in high-altitude areas, studies on the effect of high-altitude hypoxia on the pharmacokinetic properties of cardiovascular drugs are limited. (2) Methods: The aim of this study was to evaluate the pharmacokinetics of nifedipine, bosentan, simvastatin, sildenafil, and their respective main metabolites, dehydronifedipine, hydroxybosentan, simvastatin hydroxy acid, and N-desmethyl sildenafil, in rats exposed to high-altitude hypoxia. Additionally, the protein and mRNA expression of cytochrome P450 3A1 (CYP3A1), a drug-metabolizing enzyme, were examined. (3) Results: There were significant changes in the pharmacokinetic properties of the drugs in rats exposed to high-altitude hypoxia, as evidenced by an increase in the area under the curve (AUC) and the half-life (t1/2z) and a decrease in total plasma clearance (CLz/F). However, most of these changes were reversed when the rats returned to a normoxic environment. Additionally, there was a significant decrease in CYP3A1 expression in rats exposed to high-altitude hypoxia at both the protein and mRNA levels. (4) Conclusions: High-altitude hypoxia suppressed the metabolism of the drugs, indicating that the pharmacokinetics of the drugs should be re-examined, and the optimal dose should be reassessed in patients living in high-altitude areas.

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Cytochrome P450 Epoxygenase-Dependent Activation of TRPV4 Channel Participates in Enhanced Serotonin-Induced Pulmonary Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension

Cited by 5 publications

References 51 publications

Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension

Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension

Sex-dependent change in the reactivity of isolated pulmonary arteries of gonadectomized rats under the intermittent hypoxia of different degree

High-altitude Hypoxia Influences the Activities of the Drug-Metabolizing Enzyme CYP3A1 and the Pharmacokinetics of Four Cardiovascular System Drugs

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