title: Role of κ-opioid receptor in hypoxic pulmonary artery hypertension and its underlying mechanism.
abstract: The objective of this study were to determine the mechanism of action and role of the κ-opioid receptor (κ-OR) on hypoxic pulmonary artery hypertension (HPH) in the rat and its underlying mechanisms. The effect of U50,488H, a selective κ-OR agonist, on the proliferation of pulmonary arterial smooth muscle cells (PASMCs) under hypoxic conditions were measured by monotetrazolium assay and [H]-thymidine incorporation. Effects of U50,488H and nor-BNI, a highly selective κ-OR antagonist, on expression of κ-ORs were determined by Western blot technique. The results of our study demonstrated that U50,488H significantly lowered both mean pulmonary artery pressure and right ventricular pressure in HPH rats (P < 0.01). Further, this effect was abolished by nor-BNI (P < 0.01). Further, the effect of the agonist U50,488H was abolished by the antagonist nor-BNI (P < 0.01). mean pulmonary artery pressure and right ventricular pressure were both significantly upregulated in HPH rats treated with nor-BNI versus HPH control group rats (P < 0.01). Moreover, U50,488H inhibited proliferation of the PASMCs that were induced by hypoxia, and this inhibition lasted for 48 hours in a dose-dependent manner (P < 0.01). The inhibitory effect that U50,488H exerted on PASMC proliferation was also abolished by nor-BNI. During hypoxia, the expression of κ-ORs increased in the pulmonary artery. This increase of κ-OR expression was both enhanced by U50,488H and abolished by nor-BNI. The results demonstrate that U50,488H attenuates HPH through both the stimulation and upregulation of κ-ORs.
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Quanxing
authors.initials: Q
authors.lastname: Shi
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.forename: Aaron Joshua
authors.initials: AJ
authors.lastname: Kaye
authors.forename: Yuemin
authors.initials: Y
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.forename: Franklin Bueno
authors.initials: FB
authors.lastname: Rivera
authors.forename: Alan David
authors.initials: AD
authors.lastname: Kaye
authors.forename: Jianming
authors.initials: J
authors.lastname: Pei
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065627:Familial Primary Pulmonary Hypertension; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer