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Activation of κ-opioid receptor by U50,488H improves vascular dysfunction in streptozotocin-induced diabetic rats.

Zhou X, Wang D, Zhang Y, Zhang J, Xiang D, Wang H - BMC Endocr Disord (2015)

Bottom Line: U50,488H treatment resulted in reduction in ANG II, sICAM-1, IL-6 and IL-8 levels and elevation in NO levels, while these effects were abolished by nor-BNI treatment.Further more, eNOS phosphorylation was increased, and NF-κB p65 translocation was decreased after U50,488H treatment.Our study demonstrated that U50,488H may have therapeutic effects on diabetic vascular dysfunction by improving endothelial dysfunction and attenuating chronic inflammation, which may be dependent on phosphorylation of eNOS and downstream inhibition of NF-кB.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. zhouxuanxuan2007@126.com.

ABSTRACT

Background: Evidence suggests that activation of κ-opioid receptor (KOR) by U50,488H exhibits potential cardiovascular protective properties. However, the effects of U50,488H on vascular dysfunction in diabetes mellitus (DM) are still not clear. The present study was designed to investigate the effects of U50,488H on vascular dysfunction in diabetic rats and explore the underlying mechanisms involved.

Methods: Rats were randomly divided into control, DM, DM + vehicle, DM + U50,488H and DM + nor-binaltorphimine (nor-BNI) groups. Streptozotocin injection was used to induce DM. Weight, blood glucose, blood pressure and plasma insulin for each group were measured. Arterial functions were assessed with isolated vessels mounted for isometric tension recordings. Angiotensin II (ANG II), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin (IL)-6 and IL-8 levels were measured by ELISA, and endothelial nitric oxide synthase (eNOS) phosphorylation and NF-κB p65 translocation were measured by Western blot.

Results: Activation of KOR by U50,488H reduced the enhanced contractility of aortas to KCl and noradrenaline and increased acetylcholine-induced vascular relaxation, which could also protect the aortal ultrastructure in DM. U50,488H treatment resulted in reduction in ANG II, sICAM-1, IL-6 and IL-8 levels and elevation in NO levels, while these effects were abolished by nor-BNI treatment. Further more, eNOS phosphorylation was increased, and NF-κB p65 translocation was decreased after U50,488H treatment.

Conclusions: Our study demonstrated that U50,488H may have therapeutic effects on diabetic vascular dysfunction by improving endothelial dysfunction and attenuating chronic inflammation, which may be dependent on phosphorylation of eNOS and downstream inhibition of NF-кB.

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Related in: MedlinePlus

U50,488H increased serum NO levels and reduced ANG II levels in DM rats. (A) ELISA analysis showed significant decreases in serum NO levels in DM rats as compared with CON group. Treatment with U50,488H increased NO levels in DM. (B) ELISA analysis showed significant increases in serum ANG II levels in DM rats as compared with CON group, and U50,488H treatment blocked this elevation. (C) eNOS phosphorylation in DM rats was decreased in DM group and markedly increased after U50,488H treatment. *P < 0.05 vs. CON group, #P < 0.05 vs. DM group. (n = 5).
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Fig4: U50,488H increased serum NO levels and reduced ANG II levels in DM rats. (A) ELISA analysis showed significant decreases in serum NO levels in DM rats as compared with CON group. Treatment with U50,488H increased NO levels in DM. (B) ELISA analysis showed significant increases in serum ANG II levels in DM rats as compared with CON group, and U50,488H treatment blocked this elevation. (C) eNOS phosphorylation in DM rats was decreased in DM group and markedly increased after U50,488H treatment. *P < 0.05 vs. CON group, #P < 0.05 vs. DM group. (n = 5).

Mentions: Serum NO concentrations in the DM group were significantly decreased compared with the CON group (Figure 4A). Treatment with U50,488H enhanced NO secretion, while treatment with vehicle did not have this positive effect. Additionally, nor-BNI treatment resulted in less NO secretion. ANG II levels in the DM group were higher compared with the CON group, while U50,488H treatment attenuated ANG II production, and nor-BNI treatment further aggravated ANG II production (Figure 4B). We also investigated the effect of U50,488H on eNOS phosphorylation in thoracic aortas. The DM group showed decreased eNOS phosphorylation, while U50,488H treatment increased eNOS phosphorylation (Figure 4C). Furthermore, in the DM + U50,488H group, NO levels and eNOS phosphorylation were lower and ANG II levels were higher compared with the CON group.Figure 4


Activation of κ-opioid receptor by U50,488H improves vascular dysfunction in streptozotocin-induced diabetic rats.

Zhou X, Wang D, Zhang Y, Zhang J, Xiang D, Wang H - BMC Endocr Disord (2015)

U50,488H increased serum NO levels and reduced ANG II levels in DM rats. (A) ELISA analysis showed significant decreases in serum NO levels in DM rats as compared with CON group. Treatment with U50,488H increased NO levels in DM. (B) ELISA analysis showed significant increases in serum ANG II levels in DM rats as compared with CON group, and U50,488H treatment blocked this elevation. (C) eNOS phosphorylation in DM rats was decreased in DM group and markedly increased after U50,488H treatment. *P < 0.05 vs. CON group, #P < 0.05 vs. DM group. (n = 5).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4355970&req=5

Fig4: U50,488H increased serum NO levels and reduced ANG II levels in DM rats. (A) ELISA analysis showed significant decreases in serum NO levels in DM rats as compared with CON group. Treatment with U50,488H increased NO levels in DM. (B) ELISA analysis showed significant increases in serum ANG II levels in DM rats as compared with CON group, and U50,488H treatment blocked this elevation. (C) eNOS phosphorylation in DM rats was decreased in DM group and markedly increased after U50,488H treatment. *P < 0.05 vs. CON group, #P < 0.05 vs. DM group. (n = 5).
Mentions: Serum NO concentrations in the DM group were significantly decreased compared with the CON group (Figure 4A). Treatment with U50,488H enhanced NO secretion, while treatment with vehicle did not have this positive effect. Additionally, nor-BNI treatment resulted in less NO secretion. ANG II levels in the DM group were higher compared with the CON group, while U50,488H treatment attenuated ANG II production, and nor-BNI treatment further aggravated ANG II production (Figure 4B). We also investigated the effect of U50,488H on eNOS phosphorylation in thoracic aortas. The DM group showed decreased eNOS phosphorylation, while U50,488H treatment increased eNOS phosphorylation (Figure 4C). Furthermore, in the DM + U50,488H group, NO levels and eNOS phosphorylation were lower and ANG II levels were higher compared with the CON group.Figure 4

Bottom Line: U50,488H treatment resulted in reduction in ANG II, sICAM-1, IL-6 and IL-8 levels and elevation in NO levels, while these effects were abolished by nor-BNI treatment.Further more, eNOS phosphorylation was increased, and NF-κB p65 translocation was decreased after U50,488H treatment.Our study demonstrated that U50,488H may have therapeutic effects on diabetic vascular dysfunction by improving endothelial dysfunction and attenuating chronic inflammation, which may be dependent on phosphorylation of eNOS and downstream inhibition of NF-кB.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. zhouxuanxuan2007@126.com.

ABSTRACT

Background: Evidence suggests that activation of κ-opioid receptor (KOR) by U50,488H exhibits potential cardiovascular protective properties. However, the effects of U50,488H on vascular dysfunction in diabetes mellitus (DM) are still not clear. The present study was designed to investigate the effects of U50,488H on vascular dysfunction in diabetic rats and explore the underlying mechanisms involved.

Methods: Rats were randomly divided into control, DM, DM + vehicle, DM + U50,488H and DM + nor-binaltorphimine (nor-BNI) groups. Streptozotocin injection was used to induce DM. Weight, blood glucose, blood pressure and plasma insulin for each group were measured. Arterial functions were assessed with isolated vessels mounted for isometric tension recordings. Angiotensin II (ANG II), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin (IL)-6 and IL-8 levels were measured by ELISA, and endothelial nitric oxide synthase (eNOS) phosphorylation and NF-κB p65 translocation were measured by Western blot.

Results: Activation of KOR by U50,488H reduced the enhanced contractility of aortas to KCl and noradrenaline and increased acetylcholine-induced vascular relaxation, which could also protect the aortal ultrastructure in DM. U50,488H treatment resulted in reduction in ANG II, sICAM-1, IL-6 and IL-8 levels and elevation in NO levels, while these effects were abolished by nor-BNI treatment. Further more, eNOS phosphorylation was increased, and NF-κB p65 translocation was decreased after U50,488H treatment.

Conclusions: Our study demonstrated that U50,488H may have therapeutic effects on diabetic vascular dysfunction by improving endothelial dysfunction and attenuating chronic inflammation, which may be dependent on phosphorylation of eNOS and downstream inhibition of NF-кB.

Show MeSH
Related in: MedlinePlus