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: Juan Li, Xiaojie Liang, Yaguang Zhou, Shumiao Zhang, Fan Yang, Haitao Guo, Rong Fan, Na Feng, Min Jia, Yueming Wang, Mingchao Liu, Jianming Pei
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 791 Pg. 78-84 (Nov 15 2016) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 27568355 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Endothelin-1
• Receptors, Opioid, kappa
• Angiotensin II
• 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
• Dynorphins

Topics

• 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer (pharmacology)
• Angiotensin II (blood)
• Animals
• Blood Pressure (drug effects)
• Cell Hypoxia (drug effects)
• Cell Proliferation (drug effects)
• Dynorphins (blood, metabolism, pharmacology)
• Endothelin-1 (blood)
• Gene Expression Regulation (drug effects)
• Humans
• Hypertension, Pulmonary (blood, metabolism, pathology, physiopathology)
• Lung (drug effects, metabolism)
• Male
• Myocytes, Smooth Muscle (drug effects, pathology)
• Pulmonary Artery (drug effects, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid, kappa (metabolism)