title: Κ-opioid receptor stimulation improves endothelial function in hypoxic pulmonary hypertension.
abstract: 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), gp91(phox) 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 gp91(phox) 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.
authors.affiliation: Department of Cardiology, Chengdu Medical College, Chengdu, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
authors.forename: Qiu-Lin
authors.initials: QL
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.forename: Yue-Min
authors.initials: YM
authors.lastname: Wang
authors.forename: Xue-Zeng
authors.initials: XZ
authors.lastname: Xu
authors.forename: Ding-Hua
authors.initials: DH
authors.lastname: Yi
authors.forename: Shi-Qiang
authors.initials: SQ
authors.lastname: Yu
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Pei
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology* / Q000627:therapeutic use; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000188:drug therapy; D000860:Hypoxia / Q000150:complications*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D017473:Receptors, Opioid, kappa; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine