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Vasculoprotective effect of U50,488H in rats exposed to chronic hypoxia: role of Akt-stimulated NO production.

Abstract
Impairment of pulmonary endothelium function in the pulmonary artery is a direct result of chronic hypoxia. This study is to investigate the vasculoprotective effects of U50,488H (a selective κ-opioid receptor agonist) and its underlying mechanism in hypoxia-induced pulmonary artery endothelial functional injury. Chronic hypoxia was simulated by exposing the rats to 10% oxygen for 2 wk. After hypoxia, right ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI) were measured. The pulmonary vascular dysfunction, effect of nitric oxide synthase inhibitor (l-NAME) on the relaxation of U50,488H, and level of nitric oxide (NO) were determined. In vitro, the signaling pathway involved in the anti-apoptotic effect of U50,488H was investigated. Cultured endothelial cells were subjected to simulated hypoxia, and cell apoptosis was determined by TUNEL staining. U50,488H (1.25 mg/kg) significantly reduced RVP and RVHI in hypoxia. U50,488H markedly improved both pulmonary endothelial function (maximal vasorelaxation in response to ACh: 74.9 ± 1.8%, n = 6, P <0.01 vs. hypoxia for 2 wk group) and increased total NO production (1.65 fold). U50,488H relaxed the pulmonary artery rings of the hypoxic rats. This effect was partly abolished by l-NAME. In cells, U50,488H both increased NO production and reduced hypoxia-induced apoptosis. Moreover, pretreatment with nor-binaltorphimine (nor-BNI, a selective κ-opioid receptor antagonist), PI3K inhibitor, Akt inhibitor or l-NAME almost abolished anti-apoptotic effect exerted by U50,488H. U50,488H resulted in increases in Akt and eNOS phosphorylation. These results demonstrate that pretreatment with U50,488H attenuates hypoxia-induced pulmonary vascular endothelial dysfunction in an Akt-dependent and NO-mediated fashion.
AuthorsJuan Li, Quan-Xing Shi, Rong Fan, Li-Jun Zhang, Shu-Miao Zhang, Hai-Tao Guo, Yue-Min Wang, Aaron Joshua Kaye, Alan David Kaye, Franklin Rivera Bueno, Xue-Zeng Xu, Shi-Qiang Yu, Ding-Hua Yi, Jian-Ming Pei
JournalJournal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 114 Issue 2 Pg. 238-44 (Jan 15 2013) ISSN: 1522-1601 [Electronic] United States
PMID23139366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Receptors, Opioid, kappa
  • Nitric Oxide
  • norbinaltorphimine
  • Naltrexone
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • Nitric Oxide Synthase Type III
  • Proto-Oncogene Proteins c-akt
Topics
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer (pharmacology)
  • Animals
  • Apoptosis (drug effects, physiology)
  • Cells, Cultured
  • Endothelium, Vascular (cytology, drug effects, metabolism)
  • Hypoxia (metabolism)
  • In Vitro Techniques
  • Male
  • Models, Animal
  • Naltrexone (analogs & derivatives, pharmacology)
  • Nitric Oxide (metabolism)
  • Nitric Oxide Synthase Type III (metabolism)
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Pulmonary Artery (cytology, drug effects, metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, kappa (agonists, antagonists & inhibitors)

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