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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 T-AOC in pulmonary arteries of HPH rats.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 ± SEM, n  = 7 in each group. **P<0.01 vs. Con; ##P<0.01 vs. 2 w; ττP<0.01 vs. 2 w+NS; $P<0.05 vs. 2 w+U50.
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pone-0060850-g006: Effect of U50,488H on T-AOC in pulmonary arteries of HPH rats.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 ± SEM, n  = 7 in each group. **P<0.01 vs. Con; ##P<0.01 vs. 2 w; ττP<0.01 vs. 2 w+NS; $P<0.05 vs. 2 w+U50.

Mentions: The data presented above indicate that U50,488H can stimulate bioactive NO production by regulation of eNOS and iNOS activity. However, it remains unclear whether U50,488H can prevent NO destruction. As we all know, the decrease of total antioxidant capacity (T-AOC) may lead to NO destruction. As summarized in Figure 6, chronic hypoxia led to a significant reduction of T-AOC in pulmonary arteries, indicating that chronic hypoxia triggered NO destruction. More importantly, administration of U50,488H significantly elevated T-AOC of pulmonary arteries, indicating that U50,488H may prevent NO destruction. To further support this notion, additional experiments were performed. gp91phox, a major source of superoxide, was detected by Western blotting. As showed in Figure 7, consistent with previously published results [19], gp91phox expression was significantly increased in pulmonary arteries of HPH rats. Administration of U50,488H caused a moderate, yet statistically significant, reduction in gp91phox expression. Moreover, this effect was abolished by nor-BNI, indicating that the reducing effect of U50,488H on gp91phox expression was mediated by κ-opioid receptor.


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 T-AOC in pulmonary arteries of HPH rats.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 ± SEM, n  = 7 in each group. **P<0.01 vs. Con; ##P<0.01 vs. 2 w; ττP<0.01 vs. 2 w+NS; $P<0.05 vs. 2 w+U50.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0060850-g006: Effect of U50,488H on T-AOC in pulmonary arteries of HPH rats.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 ± SEM, n  = 7 in each group. **P<0.01 vs. Con; ##P<0.01 vs. 2 w; ττP<0.01 vs. 2 w+NS; $P<0.05 vs. 2 w+U50.
Mentions: The data presented above indicate that U50,488H can stimulate bioactive NO production by regulation of eNOS and iNOS activity. However, it remains unclear whether U50,488H can prevent NO destruction. As we all know, the decrease of total antioxidant capacity (T-AOC) may lead to NO destruction. As summarized in Figure 6, chronic hypoxia led to a significant reduction of T-AOC in pulmonary arteries, indicating that chronic hypoxia triggered NO destruction. More importantly, administration of U50,488H significantly elevated T-AOC of pulmonary arteries, indicating that U50,488H may prevent NO destruction. To further support this notion, additional experiments were performed. gp91phox, a major source of superoxide, was detected by Western blotting. As showed in Figure 7, consistent with previously published results [19], gp91phox expression was significantly increased in pulmonary arteries of HPH rats. Administration of U50,488H caused a moderate, yet statistically significant, reduction in gp91phox expression. Moreover, this effect was abolished by nor-BNI, indicating that the reducing effect of U50,488H on gp91phox expression was mediated by κ-opioid receptor.

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