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Κ-opioid receptor stimulation improves endothelial function in hypoxic pulmonary hypertension.

Wu Q, Wang HY, Li J, Zhou P, Wang QL, Zhao L, Fan R, Wang YM, Xu XZ, Yi DH, Yu SQ, Pei JM - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Chengdu Medical College, Chengdu, P.R. China.

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), gp91(phox) 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 gp91(phox) 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.

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Effect of U50,488H on eNOS and iNOS activity in pulmonary arteries of HPH rats.A, group results for eNOS activity; B, group results for iNOS activity; Con:control; 2 w: 2 wk hypoxia; 2 w+NS: 2 w+normal saline; 2 w+U50: 2 w+U50,488H; 2 w+U50+nor-BNI: 2 w+U50,488H+nor-BNI; 2 w+nor: 2 w+nor-BNI. All values were expressed as means ± SE, n  = 7 in each group. *P<0.05, **P<0.01vs. Con; #P<0.05, ##P<0.01 vs. 2 w; τP<0.05, ττP<0.01 vs. 2 w+NS; $P<0.05, $$P<0.01 vs. 2 w+U50.
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pone-0060850-g005: Effect of U50,488H on eNOS and iNOS activity in pulmonary arteries of HPH rats.A, group results for eNOS activity; B, group results for iNOS activity; Con:control; 2 w: 2 wk hypoxia; 2 w+NS: 2 w+normal saline; 2 w+U50: 2 w+U50,488H; 2 w+U50+nor-BNI: 2 w+U50,488H+nor-BNI; 2 w+nor: 2 w+nor-BNI. All values were expressed as means ± SE, n  = 7 in each group. *P<0.05, **P<0.01vs. Con; #P<0.05, ##P<0.01 vs. 2 w; τP<0.05, ττP<0.01 vs. 2 w+NS; $P<0.05, $$P<0.01 vs. 2 w+U50.

Mentions: In order to elucidate the precise mechanism of the stimulative role of U50,488H on NO release, eNOS and iNOS activity were measured respectively. As demonstrated in Figure 5, chronic hypoxia significantly decreased eNOS activity and elevated iNOS activity, and administration of U50,488H significantly elevated eNOS activity and decreased iNOS activity. These results indicated that U50,488H might stimulate bioactive NO production by dural regulation of eNOS activity and iNOS activity.


Κ-opioid receptor stimulation improves endothelial function in hypoxic pulmonary hypertension.

Wu Q, Wang HY, Li J, Zhou P, Wang QL, Zhao L, Fan R, Wang YM, Xu XZ, Yi DH, Yu SQ, Pei JM - PLoS ONE (2013)

Effect of U50,488H on eNOS and iNOS activity in pulmonary arteries of HPH rats.A, group results for eNOS activity; B, group results for iNOS activity; Con:control; 2 w: 2 wk hypoxia; 2 w+NS: 2 w+normal saline; 2 w+U50: 2 w+U50,488H; 2 w+U50+nor-BNI: 2 w+U50,488H+nor-BNI; 2 w+nor: 2 w+nor-BNI. All values were expressed as means ± SE, n  = 7 in each group. *P<0.05, **P<0.01vs. Con; #P<0.05, ##P<0.01 vs. 2 w; τP<0.05, ττP<0.01 vs. 2 w+NS; $P<0.05, $$P<0.01 vs. 2 w+U50.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646880&req=5

pone-0060850-g005: Effect of U50,488H on eNOS and iNOS activity in pulmonary arteries of HPH rats.A, group results for eNOS activity; B, group results for iNOS activity; Con:control; 2 w: 2 wk hypoxia; 2 w+NS: 2 w+normal saline; 2 w+U50: 2 w+U50,488H; 2 w+U50+nor-BNI: 2 w+U50,488H+nor-BNI; 2 w+nor: 2 w+nor-BNI. All values were expressed as means ± SE, n  = 7 in each group. *P<0.05, **P<0.01vs. Con; #P<0.05, ##P<0.01 vs. 2 w; τP<0.05, ττP<0.01 vs. 2 w+NS; $P<0.05, $$P<0.01 vs. 2 w+U50.
Mentions: In order to elucidate the precise mechanism of the stimulative role of U50,488H on NO release, eNOS and iNOS activity were measured respectively. As demonstrated in Figure 5, chronic hypoxia significantly decreased eNOS activity and elevated iNOS activity, and administration of U50,488H significantly elevated eNOS activity and decreased iNOS activity. These results indicated that U50,488H might stimulate bioactive NO production by dural regulation of eNOS activity and iNOS activity.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Chengdu Medical College, Chengdu, P.R. China.

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), gp91(phox) 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 gp91(phox) 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.

Show MeSH
Related in: MedlinePlus