κ-Opioid Receptor Stimulation Improves Endothelial Function in Hypoxic Pulmonary Hypertension

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.

Calorie Restriction Attenuates Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

“…Although different mechanisms, such as different neointimal proliferative changes, are involved in the development of MCT-induced and hypoxia-induced PAH, similar molecular mechanisms, such as decreased eNOS phosphorylation, have been reported to play an important role in the development of both MCT-induced and hypoxia-induced PAH. 25 , 30 , 46 It was demonstrated that SIRT1 overexpression also attenuated the increase in mPAP in hypoxia-induced PAH animals in which the mechanisms may be related to the restoration of eNOS phosphorylation. One of the limitations of this study was that we could not prevent the increase of SIRT1 expression in the CR rats to confirm that the protective effects of CR on PAH are dependent on SIRT1.…”

“…The homogenate was centrifuged at 12,000 g for 10 minutes at 4°C, the supernatant was decanted, and eNOS activity was determined using an eNOS activity assay kit (Nanjing Jiancheng Bioengineering Institute) following the manufacturer instructions as previously described. 24 , 25 Total NO production by pulmonary artery tissues was measured by NO assay kit (Nanjing Jiancheng Bioengineering Institute) strictly according to the instruction of production as previously reported. 24 , 25 …”

“… 24 , 25 Total NO production by pulmonary artery tissues was measured by NO assay kit (Nanjing Jiancheng Bioengineering Institute) strictly according to the instruction of production as previously reported. 24 , 25 …”

Functional pharmacological characterization of SER100 in cardiovascular health and disease

“…Indeed, monocrotaline‐induced PH is attenuated by over‐expression of VEGF (Campbell et al , ) and angiopoietin‐1 (Zhao et al , ), both of which are essential for growth and survival of endothelial cells, and are associated with increased endothelial cell migration and proliferation (Lamalice et al , ). Moreover, κ‐opioid agonists attenuate hypoxia‐induced PH as a result of improved endothelial function, illustrated by higher eNOS expression and enhanced NO bioavailability (Wu et al , ). Together, these data hint that SER100 may be of benefit in PH by supporting endothelial survival and function.…”

Calorie Restriction Attenuates Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

“…The homogenate was centrifuged at 12,000g for 10 minutes at 48C, the supernatant was decanted, and eNOS activity was determined using an eNOS activity assay kit (Nanjing Jiancheng Bioengineering Institute) following the manufacturer instructions as previously described. 24,25 Total NO production by pulmonary artery tissues was measured by NO assay kit (Nanjing Jiancheng Bioengineering Institute) strictly according to the instruction of production as previously reported. 24,25…”