U50,488H Depresses Pulmonary Pressure in Rats Subjected to Chronic Hypoxia

Pei, Jianming; Sun, Xin; Guo, Hongwei; Ma, Sai; Zang, Yi-Min; Lu, Shun-Yan; Bi, Hui; Wang, Yuemin; Ma, Heng; Ma, Xin‐Liang

doi:10.1097/01.fjc.0000211737.55583.15

Cited by 15 publications

(22 citation statements)

References 2 publications

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“…The oxygen fraction inside the chamber was kept at 10 ± 0.5%. This method of developing pulmonary hypertension following exposure to chronic hypoxia has been well established [23,24]. Age-matched normoxic controls were kept in room air for the same period of time.…”

Section: Preparation Of Animals: Chronically Hypoxic Ratsmentioning

confidence: 99%

Chronic hypoxia inhibits the antihypertensive effect of melatonin on pulmonary artery

Das

Balonan

Ballard

et al. 2008

International Journal of Cardiology

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Section: Preparation Of Animals: Chronically Hypoxic Ratsmentioning

confidence: 99%

Chronic hypoxia inhibits the antihypertensive effect of melatonin on pulmonary artery

Das

Balonan

Ballard

et al. 2008

International Journal of Cardiology

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“…Previously, we demonstrated ex vivo that U50, 488H relaxed rat pulmonary vessel rings in a dose-dependent manner [19]. Our laboratory has also demonstrated in vivo the preventive and therapeutic effects of U50, 488H on HPH [20,31,32]. Although autophagy seems to be an adaptive process necessary in HPH, it is still unclear whether autophagy is involved in U50, 488H-mediated protection.…”

Section: Discussionmentioning

confidence: 99%

“…An automatic hypoxia equipment was used to generate hypobaric and hypoxic pulmonary hypertension in these animals [18,20,31,32]. Rats were exposed to both low pressure and low oxygen (air pressure 50 kpa, oxygen concentration 10%) for 8 hours every day.…”

Section: Animal Groups and Rat Hph Modelmentioning

confidence: 99%

The Protective Effects of Κ-Opioid Receptor Stimulation in Hypoxic Pulmonary Hypertension Involve Inhibition of Autophagy Through the AMPK-MTOR Pathway

Zhou

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: In a previous study, we showed that κ-opioid receptor stimulation with the selective agonist U50,488H ameliorated hypoxic pulmonary hypertension (HPH). However, the roles that pulmonary arterial smooth muscle cell (PASMC) proliferation, apoptosis, and autophagy play in κ-opioid receptor-mediated protection against HPH are still unknown. The goal of the present study was to investigate the role of autophagy in U50,488H-induced HPH protection and the underlying mechanisms. Methods: Rats were exposed to 10% oxygen for three weeks to induce HPH. After hypoxia, the mean pulmonary arterial pressure (mPAP) and the right ventricular pressure (RVP) were measured. Cell viability was monitored using the Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was detected by flow cytometry and Western blot. Autophagy was assessed by means of the mRFP-GFP-LC3 adenovirus transfection assay and by Western blot. Results: Inhibition of autophagy by the administration of chloroquine prevented the development of HPH in the rat model, as evidenced by significantly reduced mPAP and RVP, as well as decreased autophagy. U50,488H mimicked the effects of chloroquine, and the effects of U50,488H were blocked by nor-BNI, a selective κ-opioid receptor antagonist. In vitro experiments showed that the inhibition of autophagy by chloroquine was associated with decreased proliferation and increased apoptosis of PASMCs. Under hypoxia, U50,488H also significantly inhibited autophagy, reduced proliferation and increased apoptosis of PASMCs. These effects of U50,488H were blocked by nor-BNI. Moreover, exposure to hypoxic conditions significantly increased AMPK phosphorylation and reduced mTOR phosphorylation, and these effects were abrogated by U50,488H. The effects of U50,488H on PASMC autophagy were inhibited by AICAR, a selective AMPK agonist, or by rapamycin, a selective mTOR inhibitor. Conclusion: Our data provide evidence for the first time that κ-opioid receptor stimulation protects against HPH by inhibiting PASMCs autophagy via the AMPK-mTOR pathway.

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“…Rat HPH model was produced as described previously [11], [12]. Briefly, rats were subjected to hypoxia for 8 h every day in a homemade automodulating cabin (air pressure 50 kPa, oxygen concentration 10%).…”

Section: Methodsmentioning

confidence: 99%

κ-Opioid Receptor Stimulation Improves Endothelial Function in Hypoxic Pulmonary Hypertension

Wang

et al. 2013

PLoS ONE

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The present study was designed to investigate the effect of κ-opioid receptor stimulation with U50,488H on endothelial function and underlying mechanism in rats with hypoxic pulmonary hypertension (HPH). Chronic hypoxia-induced HPH was simulated by exposing the rats to 10% oxygen for 2 wk. After hypoxia, mean pulmonary arterial pressure (mPAP), right ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI) were measured. Relaxation of pulmonary artery in response to acetylcholine (ACh) was determined. Expression and activity of endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) with NO production, total antioxidant capacity (T-AOC), gp91phox expression and nitrotyrosine content were measured. The effect of U50,488H administration during chronic hypoxia was investigated. Administration of U50,488H significantly decreased mPAP and right ventricular hypertrophy as evidenced by reduction in RVP and RVHI. These effects were mediated by κ-opioid receptor. In the meantime, treatment with U50,488H significantly improved endothelial function as evidenced by enhanced relaxation in response to ACh. Moreover, U50,488H resulted in a significant increase in eNOS phosphorylation, NO content in serum, and T-AOC in pulmonary artery of HPH rats. In addition, the activity of eNOS was enhanced, but the activity of iNOS was attenuated in the pulmonary artery of chronic hypoxic rats treated with U50,488H. On the other hand, U50,488H markedly blunted HPH-induced elevation of gp91phox expression and nitrotyrosine content in pulmonary artery, and these effects were blocked by nor-BNI, a selective κ-opioid receptor antagonist. These data suggest that κ-opioid receptor stimulation with U50,488H improves endothelial function in rats with HPH. The mechanism of action might be attributed to the preservation of eNOS activity, enhancement of eNOS phosphorylation, downregulation of iNOS activity and its antioxidative/nitrative effect.

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U50,488H Depresses Pulmonary Pressure in Rats Subjected to Chronic Hypoxia

Cited by 15 publications

References 2 publications

Chronic hypoxia inhibits the antihypertensive effect of melatonin on pulmonary artery

Chronic hypoxia inhibits the antihypertensive effect of melatonin on pulmonary artery

The Protective Effects of Κ-Opioid Receptor Stimulation in Hypoxic Pulmonary Hypertension Involve Inhibition of Autophagy Through the AMPK-MTOR Pathway

κ-Opioid Receptor Stimulation Improves Endothelial Function in Hypoxic Pulmonary Hypertension

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