Abstract
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.
Highlights
Pulmonary hypertension (PH) is a chronic disease characterized by progressively increased pulmonary vascular resistance and vascular remodeling and it has been recognized as ‘cancer of cardiovascular diseases’ because of its high mortality and morbidity
After chronic hypoxia for 2 weeks, mean pulmonary arterial pressure (mPAP) was significantly increased by 57%, and this change was almost abolished by the peritoneal injection of U50,488H, a selective k-opioid receptor agonist during chronic hypoxia
The effect of U50,488H was abolished by nor-BNI, a selective kopioid receptor antagonist, which itself had no effect on these parameters, indicating that U50,488H exerted depressive effect on hypoxic pulmonary hypertension (HPH) and right ventricle (RV) hypertrophy and this effect was mediated by kopioid receptor
Summary
Pulmonary hypertension (PH) is a chronic disease characterized by progressively increased pulmonary vascular resistance and vascular remodeling and it has been recognized as ‘cancer of cardiovascular diseases’ because of its high mortality and morbidity. There has been no magic cure for pulmonary hypertension, and the goal of treatment is to delay or prevent the progression of this disease. Among various types of PH, hypoxic pulmonary hypertension (HPH) which occurs in patients with cardiopulmonary disease and residents at high altitude has aroused great interest from researchers. Many investigators have demonstrated that the pathogenesis of the hypoxic pulmonary vasoconstriction has been associated with Kv channel, endothelin, serotonin and so on [1,2,3], the precise mechanism remains unclear. Deeply investigating the pathogenesis of HPH and seeking effective control strategy are of great significance
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