Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Endocrine Disorders
Published in: BMC Endocrine Disorders 1/2015

Open Access 01-12-2015 | Research article

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

Authors: Xuan Zhou, Dongjuan Wang, Yuyang Zhang, Jinxia Zhang, Dingcheng Xiang, Haichang Wang

Published in: BMC Endocrine Disorders | Issue 1/2015

Login to get access

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.
Literature
1.
Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414(6865):782–7.PubMedCrossRef
2.
Cooper ME, Gilbert RE, Jerums G. Diabetic vascular complications. Clin Exp Pharmacol Physiol. 1997;24(9–10):770–5.PubMedCrossRef
3.
Creager MA, Luscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation. 2003;108(12):1527–32.PubMedCrossRef
4.
Pyorala K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev. 1987;3(2):463–524.PubMedCrossRef
5.
Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science. 1973;179(4077):1011–4.PubMedCrossRef
6.
Corbett AD, Henderson G, McKnight AT, Paterson SJ. 75 years of opioid research: the exciting but vain quest for the Holy Grail. Br J Pharmacol. 2006;147 Suppl 1:S153–162.PubMedPubMedCentral
7.
Simonin F, Gaveriaux-Ruff C, Befort K, Matthes H, Lannes B, Micheletti G, et al. kappa-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci U S A. 1995;92(15):7006–10.PubMedPubMedCentralCrossRef
8.
Sauriyal DS, Jaggi AS, Singh N. Extending pharmacological spectrum of opioids beyond analgesia: multifunctional aspects in different pathophysiological states. Neuropeptides. 2011;45(3):175–88.PubMedCrossRef
9.
Saraiva J, Oliveira SM, Rocha-Sousa A, Leite-Moreira A. Opioid receptors and preconditioning of the heart. Rev Port Cardiol. 2004;23(10):1317–33.PubMed
10.
11.
12.
Tong G, Sun Z, Wei X, Gu C, Kaye AD, Wang Y, et al. U50,488H postconditioning reduces apoptosis after myocardial ischemia and reperfusion. Life Sci. 2011;88(1–2):31–8.PubMedCrossRef
13.
Jin-Cheng L, Wen Y, Zhao Y, Quan-Yu Z, Shu-Miao Z, Hai-Tao G, et al. Anti-arrhythmic effects of kappa-opioid receptor and its changes in ischemia and reperfusion. Arch Med Res. 2008;39(5):483–8.PubMedCrossRef
14.
Li J, Zhang P, Zhang QY, Zhang SM, Guo HT, Bi H, et al. Effects of U50,488H on hypoxia pulmonary hypertension and its underlying mechanism. Vascul Pharmacol. 2009;51(2–3):72–7.PubMedCrossRef
15.
Kivell B, Prisinzano TE. Kappa opioids and the modulation of pain. Psychopharmacology (Berl). 2010;210(2):109–19.CrossRef
16.
Ye RD. Regulation of nuclear factor kappaB activation by G-protein-coupled receptors. J Leukoc Biol. 2001;70(6):839–48.PubMed
17.
Belcheva MM, Clark AL, Haas PD, Serna JS, Hahn JW, Kiss A, et al. Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in astrocytes. J Biol Chem. 2005;280(30):27662–9.PubMedPubMedCentralCrossRef
18.
Bruchas MR, Macey TA, Lowe JD, Chavkin C. Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes. J Biol Chem. 2006;281(26):18081–9.PubMedPubMedCentralCrossRef
19.
20.
de Jager J, Dekker JM, Kooy A, Kostense PJ, Nijpels G, Heine RJ, et al. Endothelial dysfunction and low-grade inflammation explain much of the excess cardiovascular mortality in individuals with type 2 diabetes: the Hoorn Study. Arterioscler Thromb Vasc Biol. 2006;26(5):1086–93.PubMedCrossRef
21.
Vlassara H, Cai W, Crandall J, Goldberg T, Oberstein R, Dardaine V, et al. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci U S A. 2002;99(24):15596–601.PubMedPubMedCentralCrossRef
22.
Widlansky ME, Gokce N, Keaney Jr JF, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003;42(7):1149–60.PubMedCrossRef
23.
Blankenberg S, Barbaux S, Tiret L. Adhesion molecules and atherosclerosis. Atherosclerosis. 2003;170(2):191–203.PubMedCrossRef
24.
Weglarz L, Dzierzewicz Z, Skop B, Orchel A, Parfiniewicz B, Wisniowska B, et al. Desulfovibrio desulfuricans lipopolysaccharides induce endothelial cell IL-6 and IL-8 secretion and E-selectin and VCAM-1 expression. Cell Mol Biol Lett. 2003;8(4):991–1003.PubMed
25.
Esper RJ, Nordaby RA, Vilarino JO, Paragano A, Cacharron JL, Machado RA. Endothelial dysfunction: a comprehensive appraisal. Cardiovasc Diabetol. 2006;5:4.PubMedPubMedCentralCrossRef
26.
Duprez DA. Role of the renin-angiotensin-aldosterone system in vascular remodeling and inflammation: a clinical review. J Hypertens. 2006;24(6):983–91.PubMedCrossRef
27.
De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone Jr MA, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96(1):60–8.PubMedPubMedCentralCrossRef
28.
Puntmann VO, Taylor PC, Mayr M. Coupling vascular and myocardial inflammatory injury into a common phenotype of cardiovascular dysfunction: systemic inflammation and aging - a mini-review. Gerontology. 2011;57(4):295–303.PubMedCrossRef
29.
30.
Lin J, Wang H, Li J, Wang Q, Zhang S, Feng N, et al. kappa-Opioid receptor stimulation modulates TLR4/NF-kappaB signaling in the rat heart subjected to ischemia-reperfusion. Cytokine. 2013;61(3):842–8.PubMedCrossRef
31.
Wang D, Luo P, Wang Y, Li W, Wang C, Sun D, et al. Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism. Diabetes. 2013;62(5):1697–708.PubMedPubMedCentralCrossRef
32.
Rodriguez A, Becerril S, Valenti V, Moncada R, Mendez-Gimenez L, Ramirez B, et al. Short-term effects of sleeve gastrectomy and caloric restriction on blood pressure in diet-induced obese rats. Obes Surg. 2012;22(9):1481–90.PubMedCrossRef
33.
Wang D, Wang H, Luo P, Hwang A, Sun D, Wang Y, et al. Effects of ghrelin on homocysteine-induced dysfunction and inflammatory response in rat cardiac microvascular endothelial cells. Cell Biol Int. 2012;36(6):511–7.PubMedCrossRef
34.
Ross GR, Lichtman A, Dewey WL, Akbarali HI. Evidence for the putative cannabinoid receptor (GPR55)-mediated inhibitory effects on intestinal contractility in mice. Pharmacology. 2012;90(1–2):55–65.PubMedPubMedCentralCrossRef
35.
Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 1999;22(2):233–40.PubMedCrossRef
36.
Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006;113(15):1888–904.PubMedCrossRef
37.
38.
O’Brien BA, Harmon BV, Cameron DP, Allan DJ. Beta-cell apoptosis is responsible for the development of IDDM in the multiple low-dose streptozotocin model. J Pathol. 1996;178(2):176–81.PubMedCrossRef
39.
Chen D, Wang MW. Development and application of rodent models for type 2 diabetes. Diabetes Obes Metab. 2005;7(4):307–17.PubMedCrossRef
40.
41.
Shi QX, Zhang LJ, Yao Y, Zhang QY, Wang W, Li J, et al. kappa-opioid receptor activation prevents against arrhythmias by preserving Cx43 protein via alleviation of intracellular calcium. Am J Ther. 2013;20(5):493–501.PubMedCrossRef
42.
Zhang L, Li J, Shi Q, Fan R, Kaye AJ, Wang Y, et al. Role of kappa-opioid receptor in hypoxic pulmonary artery hypertension and its underlying mechanism. Am J Ther. 2013;20(4):329–36.PubMedCrossRef
43.
Barton M. Prevention and endothelial therapy of coronary artery disease. Curr Opin Pharmacol. 2013;13(2):226–41.PubMedCrossRef
44.
Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J. 2013;34(31):2436–43.PubMedPubMedCentralCrossRef
45.
Singh KK, Shukla PC, Quan A, Al-Omran M, Lovren F, Pan Y, et al. BRCA1 is a novel target to improve endothelial dysfunction and retard atherosclerosis. J Thorac Cardiovasc Surg. 2013;146(4):949–60. e944.PubMedCrossRef
46.
Patel BM, Mehta AA. Aldosterone and angiotensin: role in diabetes and cardiovascular diseases. Eur J Pharmacol. 2012;697(1–3):1–12.PubMedCrossRef
47.
Umbrello M, Dyson A, Feelisch M, Singer M. The key role of nitric oxide in hypoxia: hypoxic vasodilation and energy supply–demand matching. Antioxid Redox Signal. 2013;19(14):1690–710.PubMedCrossRef
48.
Park K, Li Q, Rask-Madsen C, Mima A, Mizutani K, Winnay J, et al. Serine phosphorylation sites on IRS2 activated by angiotensin II and protein kinase C to induce selective insulin resistance in endothelial cells. Mol Cell Biol. 2013;33(16):3227–41.PubMedPubMedCentralCrossRef
49.
Pacurari M, Kafoury R, Tchounwou PB, Ndebele K. The Renin-Angiotensin-aldosterone system in vascular inflammation and remodeling. Int J Inflam. 2014;2014:689360.PubMedPubMedCentralCrossRef
50.
Nakane H, Miller Jr FJ, Faraci FM, Toyoda K, Heistad DD. Gene transfer of endothelial nitric oxide synthase reduces angiotensin II-induced endothelial dysfunction. Hypertension. 2000;35(2):595–601.PubMedCrossRef
51.
Wu Q, Wang HY, Li J, Zhou P, Wang QL, Zhao L, et al. Kappa-opioid receptor stimulation improves endothelial function in hypoxic pulmonary hypertension. PLoS One. 2013;8(5):e60850.PubMedPubMedCentralCrossRef
52.
Wu X, Zhang B, Fan R, Zhao L, Wang Y, Zhang S, et al. U50,488H inhibits neutrophil accumulation and TNF-alpha induction induced by ischemia-reperfusion in rat heart. Cytokine. 2011;56(2):503–7.PubMedCrossRef
53.
Tona F, Serra R, Di Ascenzo L, Osto E, Scarda A, Fabris R, et al. Systemic inflammation is related to coronary microvascular dysfunction in obese patients without obstructive coronary disease. Nutr Metab Cardiovasc Dis. 2014;24(4):447–53.PubMedCrossRef
Metadata
Title
Activation of κ-opioid receptor by U50,488H improves vascular dysfunction in streptozotocin-induced diabetic rats
Authors
Xuan Zhou
Dongjuan Wang
Yuyang Zhang
Jinxia Zhang
Dingcheng Xiang
Haichang Wang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Endocrine Disorders / Issue 1/2015
Electronic ISSN: 1472-6823
DOI
https://doi.org/10.1186/s12902-015-0004-7

Other articles of this Issue 1/2015

BMC Endocrine Disorders 1/2015 Go to the issue

Research article

Evaluation of efficacy, safety, pain perception and health-related quality of life of percutaneous ethanol injection as first-line treatment in symptomatic thyroid cysts

Research article

Assessing fear of hypoglycemia in a population-based study among parents of children with type 1 diabetes – psychometric properties of the hypoglycemia fear survey – parent version

Research article

Subclinical and clinical hypothyroidism and non-alcoholic fatty liver disease: a cross-sectional study of a random population sample aged 18 to 65 years

Research article

New insight into ectopic thyroid glands between the neck and maxillofacial region from a 42-case study

Research article

Association between lipids profile and thyroid parameters in euthyroid diabetic subjects: a cross-sectional study

Case report

Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion from a Meckel diverticulum neuroendocrine tumor: case report
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits