Functional state of the mesenteric arteries with higt fat intake in rats with streptozotocin-induced diabetes

• Galina T. Ivanova

Abstract

An increase in the incidence of diabetes mellitus (DM) is associated with excessive consumption of fats and carbohydrates, while DM leads to the development of cardiovascular diseases.

The aim of the research was to evaluate the effect of a high-fat diet (HFD) on the functional state of the mesenteric arteries in vivo in Wistar rats with DM.

Material and methods. The study was conducted on 45 male Wistar rats with an initial body weight of 220–240 g, which were divided into 3 equal groups. Animals of the control group received a standard diet for 3 months. Rats of the second group (STZ) were fed a standard diet, after 8 weeks the animals were intraperitoneally injected with streptozotocin (STZ, 35 mg/kg body weight). Animals in the STZ+HFD group received HFD (50% beef tallow), and an injection of STZ (35 mg/kg). We assessed the effect of HFD on endothelium-dependent and endothelium-free reactions of phenylephrine (PE) precontracted mesenteric arteries under the action of agonists in the absence and use of blockers of NO-synthase (L-NAME), cyclooxygenase (indomethacin), and K⁺-channels (tetraethylammonium), using microphoto- and videorecording of vessel diameter in vivo.

Results. DM in rats led to an increase in the constrictor reaction to FE; in animals of the STZ+HFD group, the diameter of the vessel decreased by 63.7±4.7%; in the STZ group, by 60.4±3.8%; and in the control group, by 48.9±4.1%. HFD and DM induction had no effect on the amount of relaxation under the action of sodium nitroprusside. The amplitude of acetylcholine-induced relaxation of the mesenteric arteries of rats with DM in the absence of blockers was significantly lower (by 27.1% on average in the STZ+HFD group, by 14.6% in the STZ group) compared with control animals. After NO synthase inhibition, the relaxation amplitude decreased in the STZ+HFD group by 48.6±3.2%, in the STZ group by 56.1±2.8%, and in control animals by 58.3±3.1% compared with the dilatation amplitude without the use of a blocker. Acetylcholine-induced vascular dilatation under conditions of simultaneous use of a complex of three blockers – L-NAME, indomethacin and tetraethylammonium was reduced in rats with DM treated with HFD by an average of 18.9% and in animals of the STZ group by 22.1% compared with control animals.

Conclusion. Thus, excessive fat intake in rats with STZ-induced DM enhances the impairment of the functional state of the mesenteric arteries compared to animals with DM that received a standard diet. In HFD in rats with DM, a decrease in endothelium-dependent vasodilation was mediated as a failure of NO-dependent relaxation mechanisms and a decrease in the efficiency of the mechanism of endothelial hyperpolarization, whereas in rats with DM fed a standard diet, it was predominantly a disturbance in the mechanism of endothelial hyperpolarization.

Keywords:high-fat diet; diabetes mellitus; mesenteric artery; endothelium; acetylcholine-induced dilatation; vasoconstriction; phenylephrine; Wistar

References

1. Wondmkun Y.T. Obesity, Insulin Resistance, and Type 2 Diabetes: Associations and Therapeutic Implications // Diabetes Metab. Syndr. Obes. 2020. Vol. 13. P. 3611-3616. https://doi.org/10.2147/DMSO.S275898

2. Marzoog B.A. Recent advances in molecular biology of metabolic syndrome pathophysiology: endothelial dysfunction as a potential therapeutic target // J. Diabetes Metab. Disord. 2022. Vol. 21, N 2. P. 1903-1911. https://doi.org/10.1007/s40200-022-01088-y

3. Forouhi N.G., Misra A., Mohan V., Taylor R., Yancy W. Dietary and nutritional approaches for prevention and management of type 2 diabetes // B.M.J. 2018. Vol. 361. P. k2234. https://doi.org/10.1136/bmj.k2234

4. Wong N.D., Sattar N. Cardiovascular risk in diabetes mellitus: epidemiology, assessment and prevention // Nat. Rev. Cardiol. 2023. Vol. 20, N 10. P. 685-695. https://doi.org/10.1038/s41569-023-00877-z

5. Gvazava I.G., Rogovaya O.S., Borisov M.A., Vorotelyak E.A., Vasiliev A.V. Pathogenesis of Type 1 Diabetes Mellitus and Rodent Experimental Models // Acta Naturae. 2018. Vol. 10, N 1. P. 24-33. PMID: 29713516; PMCID: PMC5916731

6. Gvazava I.G., Karimova M.V., Vasiliev A.V., Vorotelyak E.A. Type 2 Diabetes Mellitus: Pathogenic Features and Experimental Models in Rodents // Acta Naturae. 2022. Vol. 14, N 3. P. 57-68. https://doi.org/10.32607/actanaturae.11751

7. Gao L., Liu Y., Guo S., Xiao L., Wu L., Wang Z., et al. LAZ3 protects cardiac remodeling in diabetic cardiomyopathy via regulating miR-21/PPARa signaling // Biochim. Biophys. Acta Mol. Basis Dis. 2018. Vol. 1864, N 10. P. 3322-3338. https://doi.org/10.1016/j.bbadis.2018.07.019

8. Li J.C., Velagic A., Qin C.X., Li M., Leo C.H., Kemp-Harper B.K., et al. Diabetes Attenuates the Contribution of Endogenous Nitric Oxide but Not Nitroxyl to Endothelium Dependent Relaxation of Rat Carotid Arteries // Front. Pharmacol. 2021. Vol. 11. P. 585740. doi: 10.3389/fphar.2020.585740

9. Park Y., Capobianco S., Gao X., Falck J.R., Dellsperger K.C., Zhang C. Role of EDHF in type 2 diabetes-induced endothelial dysfunction // Am. J. Physiol. Heart Circ. Physiol. 2008. Vol. 295, N 5. P. H1982-H1988. https://doi.org/10.1152/ajpheart.01261.2007

10. David S.R., Lai P.P.N., Chellian J., Chakravarthi S., Rajabalaya R. Influence of rutin and its combination with metformin on vascular functions in type 1 diabetes // Sci. Rep. 2023. Vol. 13, N 1. P. 12423. https://doi.org/10.1038/s41598-023-39442-6

11. Wee C.L., Mokhtar S.S., Singh K.K.B., Yahaya S., Leung S.W.S., Rasool A.H.G. Calcitriol Supplementation Ameliorates Microvascular Endothelial Dysfunction in Vitamin D-Deficient Diabetic Rats by Upregulating the Vascular eNOS Protein Expression and Reducing Oxidative Stress. Oxid. Med. Cell. Longev. 2021. Vol. 2021. P. 3109294. https://doi.org/10.1155/2021/3109294

12. Wardani G., Nugraha J., Kurnijasanti R., Mustafa M.R., Sudjarwo S.A. Molecular Mechanism of Fucoidan Nanoparticles as Protector on Endothelial Cell Dysfunction in Diabetic Rats’ Aortas // Nutrients. 2023. Vol. 15, N 3, P. 568. https://doi.org/10.3390/nu15030568

13. Makino A., Ohuchi K., Kamata K. Mechanisms underlying the attenuation of endothelium-dependent vasodilatation in the mesenteric arterial bed of the streptozotocin-induced diabetic rat // Br. J. Pharmacol. 2000. Vol. 130. Р. 549–556. https://doi.org/10.1038/sj.bjp.0703354

14. Ivanova G.T. Reactivity of Mesenteric Arteries in the Development of Metabolic Syndrome in Rats Fed on a High-Fat Diet // J. Evol. Biochem. Phys. 2023. Vol. 59, N 1. P. 154–164. https://doi.org/10.1134/S0022093023010131

15. Sharma M., Chan H.K., Lavilla C.A. Jr., Uy M.M., Froemming G.R.A., Okechukwu P.N. Induction of a single dose of streptozotocin (50 mg) in rat model causes insulin resistance with type 2 diabetes mellitus // Fundam. Clin. Pharmacol. 2023. Vol. 37, N 4. P. 769-778. https://doi.org/10.1111/fcp.12892

16. Preciado-Saldaña A.M., López-Díaz J.A., Domínguez-Avila J.A., Ayala-Zavala J.F., Astiazaran-García H.F., González-Aguilar G.A., Wall-Medrano A. Revisiting the high-fat diet/low streptozotocin prediabetic rat model: A bioanalytical adjustment // J. Pharmacol. Toxicol. Methods. 2023. Vol. 120. P. 107252. https://doi.org/10.1016/j.vascn.2023.107252

17. Kleinert M., Clemmensen C., Hofmann S. Animal models of obesity and diabetes mellitus // Nat. Rev. Endocrinol. 2018. Vol. 14. Р. 140–162. https://doi.org/10.1038/nrendo.2017.161

18. Alsenosy A.A., El-Far A.H., Sadek K.M., Ibrahim S.A., Atta M.S., Sayed-Ahmed A., et al. Graviola (Annona muricata) attenuates behavioural alterations and testicular oxidative stress induced by streptozotocin in diabetic rats // PLoS One. 2019. Vol. 14, N 9. Р. e0222410. https://doi.org/10.1371/journal.pone.0222410

19. Mediani A., Abas F., Maulidiani M., Abu Bakar Sajak A., Khatib A., Tan C.P., et al. Metabolomic analysis and biochemical changes in the urine and serum of streptozotocin-induced normal- and obese-diabetic rats // J. Physiol. Biochem. 2018. Vol. 74, N 3. Р. 403-416. https://doi.org/10.1007/s13105-018-0631-3

20. Tare M., Kalidindi R.S., Bubb K.J., Parkington H.C., Boon W.M., Li X., et al. Vasoactive actions of nitroxyl (HNO) are preserved in resistance arteries in diabetes // Naunyn Schmiedebergs Arch. Pharmacol. 2017. Vol. 390, N 4. Р. 397-408. https://doi.org/10.1007/s00210-016-1336-1

21. Punithavathi V.R., Prince P.S., Kumar R., Selvakumari J. Antihyperglycaemic, antilipid peroxidative and antioxidant effects of gallic acid on streptozotocin induced diabetic Wistar rats // Eur. J. Pharmacol. 2011. Vol. 650, N 1. Р. 465-471. https://doi.org/10.1016/j.ejphar.2010.08.059

22. Wickramasinghe A.S.D., Attanayake A.P., Kalansuriya P. Biochemical characterization of high fat diet fed and low dose streptozotocin induced diabetic Wistar rat model // J. Pharmacol. Toxicol. Methods. 2022. Vol. 113. P. 107144. https://doi.org/10.1016/j.vascn.2021.107144

23. Han X., Zhang R., Anderson L., Rahimian R. Sexual dimorphism in rat aortic endothelial function of streptozotocin-induced diabetes: possible involvement of superoxide and nitric oxide production // Eur. J. Pharmacol. 2014. Vol. 723. Р. 442-450. https://doi.org/10.1016/j.ejphar.2013.10.052

24. Musial D.C., da Silva E.J.D., da Silva R.M., Miranda-Ferreira R., Lima-Landman M.T.R., Jurkiewicz A., et al. Increase of angiotensin-converting enzyme activity and peripheral sympathetic dysfunction could contribute to hypertension development in streptozotocin-induced diabetic rats // Diabetes Vasc. Dis. Res. 2013. Vol. 10, N 6. Р. 498-504. https://doi.org/10.1177/1479164113496441

25. Jahn L.A., Logan B., Love K.M., Horton W.B., Eichner N.Z., Hartline L.M., et al. Nitric oxide-dependent micro- and macrovascular dysfunction occurs early in adolescents with type 1 diabetes // Am. J. Physiol. Endocrinol. Metab. 2022. Vol. 322, N 2. P. E101-E108. https://doi.org/10.1152/ajpendo.00267.2021

26. Leo C.H., Hart J.L., Woodman O.L. Impairment of both nitric oxide-mediated and EDHF-type relaxation in small mesenteric arteries from rats with streptozotocin-induced diabetes // Br. J. Pharmacol. 2011. Vol. 162, N 2. Р. 365-377. https://doi.org/10.1111/j.1476-5381.2010.01023.x

27. Vanhoutte P.M., Shimokawa H., Tang E.H., Feletou M. Endothelial dysfunction and vascular disease // Acta Physiol. (Oxf). 2009. Vol. 196, N 2. Р. 193-222. https://doi.org/10.1111/j.1748-1716.2009.01964.x

28. Zhao L.M., Wang Y., Yang Y., Guo R., Wang N.P., Deng X.L. Metformin Restores Intermediate-Conductance Calcium-Activated K⁺ Channel- and Small-Conductance Calcium-Activated K⁺ Channel-Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery // Mol. Pharmacol. 2014. Vol. 86, N 5. Р. 580-591. https://doi.org/10.1124/mol.114.092874

29. Lee H.J., Peredo H.A., Cantú S.M., Donoso A.S., Puyó A.M., Choi M.R. Effects of sodium tungstate and vanadyl sulphate on the liberation of prostanoids of the mesenteric vascular bed in diabetic rats // Clin. Investig. Arterioscler. 2018. Vol. 30, N 6. P. 249-257. https://doi.org/10.1016/j.arteri.2018.04.001

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