Vasorelaxing effect of U50,488H in pulmonary artery and underlying mechanism in rats

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

doi:10.1016/j.lfs.2005.10.042

Cited by 19 publications

(14 citation statements)

References 17 publications

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“…Seelhorst and Starke (1986) showed that it was likely that receptors in the pulmonary artery of the rabbits are at least, predominantly kappa‐type. Our previous study demonstrated for the first time that a selective κ‐opioid receptor agonist, U50,488H, relaxed pulmonary arteries in vitro , and decreased pulmonary pressure in vivo in rats (Pei et al,2006; Sun et al,2006), indicating that κ‐ORs may exist in pulmonary arteries (PAs) in rats. However, the exact distribution of κ‐ORs in PAs and how they change during hypoxia still remains largely uncertain.…”

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confidence: 99%

Distribution of κ‐Opioid Receptor in the Pulmonary Artery and its Changes During Hypoxia

Peng

Huang

et al. 2009

The Anatomical Record

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The present study evaluated the distribution of j-opioid receptors (j-ORs) in pulmonary arteries (PAs) in rats and investigated whether j-ORs are altered in PAs during hypoxia. An animal model of hypobaric/ hypoxic pulmonary hypertension and a pulmonary artery smooth muscle cell (PASMC) model of hypoxia were utilized. Distribution of j-ORs was determined by fluorescence immunohistochemistry and changes in j-ORs expression in PAs and PASMCs were determined by fluorescence immunohistochemistry or Western blot techniques. The j-ORs were primarily distributed in the smooth muscle layer of the PAs and in the nucleus of PASMCs. The expression of the j-ORs were increased in PAs of rats subjected to hypoxia for 1-4 week (P < 0.01). Accordingly, the expression of j-ORs in PASMCs were also increased when subjected to hypoxia for 12-36 hr (P < 0.05). The present study has provided evidence for the first time of the precise location of j-ORs in PAs and PASMCs of rats and that hypoxia upregulates expression of j-ORs.

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confidence: 99%

Distribution of κ‐Opioid Receptor in the Pulmonary Artery and its Changes During Hypoxia

Peng

Huang

et al. 2009

The Anatomical Record

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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].…”

Section: Discussionmentioning

confidence: 67%

“…κ-opioid receptors have been identified in pulmonary arteries and their expression levels increase during hypoxia [18]. Our previous studies showed that U50, 488H (trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacet-amidel), a selective κ-opioid receptor agonist, relaxed the pulmonary artery in a dose-dependent manner and inhibited PASMC proliferation [19,20]. In addition, we found that double membrane vacuolar structures, which display the morphological features of autophagosomes, appeared in U50, 488H-treated pulmonary artery endothelial cells under hypoxic conditions (for all online suppl.…”

Section: Introductionmentioning

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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“…Although there was no direct or solid evidence that U50,488H ameliorated hypoxia-induced endothelial dysfunction by stimulating NO production, we have no reason to deny its close relationship. Additionally, our previous study has demonstrated that the relaxing effect of U50,488H on pulmonary artery was partially blunted by L-NAME, an eNOS inhibitor [21], indicating that the relaxing effect may be related to NO. Based on these findings, we believe that U50,488H-induced elevation of NO may contribute to its role in the improvement of endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 92%

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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Vasorelaxing effect of U50,488H in pulmonary artery and underlying mechanism in rats

Cited by 19 publications

References 17 publications

Distribution of κ‐Opioid Receptor in the Pulmonary Artery and its Changes During Hypoxia

Distribution of κ‐Opioid Receptor in the Pulmonary Artery and its Changes During Hypoxia

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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