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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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U50,488H improved vasoconstrictive and vasodilative functions of thoracic aortas in DM rats. Concentration-response curves for KCl (0–100 mmol/L) (A) or NE (10−9-10−4 mol/L) (B) induced vasoconstriction. U50,488H administration induced a rightward shift in the concentration-response curves, while nor-BNI administration induced a leftward shift in the concentration-response curves. (C) Concentration-response curves for ACh-induced vasodilation showed that U50,488H treatment improved vasodilative function of thoracic aortas. (D) Concentration-response curves for SNP-induced vasodilation showed no statistical differences among all five groups. *P < 0.05 vs. CON group, #P < 0.05 vs. DM group. (n = 5).
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Fig2: U50,488H improved vasoconstrictive and vasodilative functions of thoracic aortas in DM rats. Concentration-response curves for KCl (0–100 mmol/L) (A) or NE (10−9-10−4 mol/L) (B) induced vasoconstriction. U50,488H administration induced a rightward shift in the concentration-response curves, while nor-BNI administration induced a leftward shift in the concentration-response curves. (C) Concentration-response curves for ACh-induced vasodilation showed that U50,488H treatment improved vasodilative function of thoracic aortas. (D) Concentration-response curves for SNP-induced vasodilation showed no statistical differences among all five groups. *P < 0.05 vs. CON group, #P < 0.05 vs. DM group. (n = 5).

Mentions: To determine the effects of KOR activation on vasoconstrictive function of thoracic aortas in DM rats, isometric tension recordings were performed. The concentration-response curves for KCl (0–100 mmol/L) and NE (10−9-10−4 mol/L) are shown in Figure 2A-B. The vasoconstrictive function of thoracic aortas was significantly greater for the DM group compared with CON group. U50,488H administration induced a marked rightward shift in concentration-response curves, while nor-BNI administration induced a marked leftward shift in concentration-response curves, indicating that KOR activation was involved in attenuation of the vasoconstrictive abnormalities in DM rats. However, we also found that U50,488H administration could not restore the vasoconstrictive function to the normal level.Figure 2


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 improved vasoconstrictive and vasodilative functions of thoracic aortas in DM rats. Concentration-response curves for KCl (0–100 mmol/L) (A) or NE (10−9-10−4 mol/L) (B) induced vasoconstriction. U50,488H administration induced a rightward shift in the concentration-response curves, while nor-BNI administration induced a leftward shift in the concentration-response curves. (C) Concentration-response curves for ACh-induced vasodilation showed that U50,488H treatment improved vasodilative function of thoracic aortas. (D) Concentration-response curves for SNP-induced vasodilation showed no statistical differences among all five groups. *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

Fig2: U50,488H improved vasoconstrictive and vasodilative functions of thoracic aortas in DM rats. Concentration-response curves for KCl (0–100 mmol/L) (A) or NE (10−9-10−4 mol/L) (B) induced vasoconstriction. U50,488H administration induced a rightward shift in the concentration-response curves, while nor-BNI administration induced a leftward shift in the concentration-response curves. (C) Concentration-response curves for ACh-induced vasodilation showed that U50,488H treatment improved vasodilative function of thoracic aortas. (D) Concentration-response curves for SNP-induced vasodilation showed no statistical differences among all five groups. *P < 0.05 vs. CON group, #P < 0.05 vs. DM group. (n = 5).
Mentions: To determine the effects of KOR activation on vasoconstrictive function of thoracic aortas in DM rats, isometric tension recordings were performed. The concentration-response curves for KCl (0–100 mmol/L) and NE (10−9-10−4 mol/L) are shown in Figure 2A-B. The vasoconstrictive function of thoracic aortas was significantly greater for the DM group compared with CON group. U50,488H administration induced a marked rightward shift in concentration-response curves, while nor-BNI administration induced a marked leftward shift in concentration-response curves, indicating that KOR activation was involved in attenuation of the vasoconstrictive abnormalities in DM rats. However, we also found that U50,488H administration could not restore the vasoconstrictive function to the normal level.Figure 2

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