κ-Opioid Receptor Stimulation Improves Endothelial Function in Hypoxic Pulmonary HypertensionReportar como inadecuado




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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, gp91phox 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 gp91phox 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.



Autor: Qi Wu , Hai-Yan Wang , Juan Li , Peng Zhou, Qiu-Lin Wang, Lei Zhao, Rong Fan, Yue-Min Wang, Xue-Zeng Xu, Ding-Hua Yi, Shi-Qiang Y

Fuente: http://plos.srce.hr/



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