Role of dynorphin in hypoxic pulmonary hypertension

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• 作者：Juan Li^a ; ¹ ; Xiaojie Liang^a ; ¹ ; Yaguang Zhou^a ; Shumiao Zhang^a ; Fan Yang^a ; Haitao Guo^a ; Rong Fan^a ; Na Feng^a ; Min Jia^a ; Yueming Wang^a ; Mingchao Liu^b ; ^{lmclmc@fmmu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Jianming Pei^a ; ^{jmpei8@fmmu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Dynorphin A ; Opioid receptor ; Pulmonary artery hypertension ; Hypoxia
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：791
• 期：Complete
• 页码：78-84
• 全文大小：1134 K

文摘

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.