title: Role of dynorphin in hypoxic pulmonary hypertension.
abstract: Previously study showed κ-opioid receptor stimulation with exogenous κ-opioid receptor agonist elicited a protective effect against hypoxic pulmonary hypertension (HPH). However, the effect of endogenous κ-opioid receptor agonist dynorphin A on HPH remains unclear. This study was to determine the role of dynorphin in HPH. Hypoxia for 2 weeks induced HPH. Compared with the HPH group, the HPH + nor-BNI (a selective κ-opioid receptor antagonist) group showed a significant increase in mean pulmonary arterial pressure (mPAP). Exogenous treatment with dynorphin A 1-13 significantly decreased mPAP in HPH rat. In addition, we evaluated the effect of exogenous κ-opioid receptor agonist U50,488H on mPAP. The anti-HPH effect of dynorphin A was less than that of U50,488H. Meanwhile, level of dynorphin A in serum and lung was increased during hypoxia for 2 weeks, while it decreased after hypoxia for 4 weeks. In addition, both the level of ET-1 and AngII were increased during hypoxia. Dynorphin A 1-13 and U50,488H time-dependently relaxed pulmonary artery from both normal and HPH rats. The relaxation of dynorphin A was less than that of U50,488H. Dynorphin A 1-13 inhibited the proliferation of pulmonary artery smooth muscle cells (PASMCs) during hypoxia, which was blocked by nor-BNI. κ-opioid receptor expression increased in PASMCs in both normoxia exposed to dynorphin A 1-13 and during hypoxia. Hypoxia-induced increase was enhanced by dynorphin A 1-13 and abolished by nor-BNI. In conclusion, endogenous dynorphin A released in the early stage of hypoxia plays a protective effect against HPH via stimulation of κ-opioid receptor.
authors: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors: Juan
authors: J
authors: Li
authors: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors: Xiaojie
authors: X
authors: Liang
authors: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors: Yaguang
authors: Y
authors: Zhou
authors: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors: Shumiao
authors: S
authors: Zhang
authors: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors: Fan
authors: F
authors: Yang
authors: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors: Haitao
authors: H
authors: Guo
authors: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors: Rong
authors: R
authors: Fan
authors: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors: Na
authors: N
authors: Feng
authors: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors: Min
authors: M
authors: Jia
authors: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors: Yueming
authors: Y
authors: Wang
authors: Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. Electronic address: lmclmc@fmmu.edu.cn.
authors: Mingchao
authors: M
authors: Liu
authors: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. Electronic address: jmpei8@fmmu.edu.cn.
authors: Jianming
authors: J
authors: Pei
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004399:Dynorphins / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D019332:Endothelin-1 / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D017473:Receptors, Opioid, kappa; D000804:Angiotensin II; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins
keywords: Dynorphin A; Hypoxia; Opioid receptor; Pulmonary artery hypertension