The impact of perindopril and metformin on the markers of endothelial dysfunction in rats with acute intracerebral hemorrhage and type 2 diabetes mellitus

V.I. Zhyliuk; A.E. Lievykh; A.I. Shevtsova; V.A. Tkachenko; Yu.V.  Kharchenko

doi:10.26641/2307-0404.2021.4.248055

Authors

V.I. Zhyliuk Dnipro State Medical University V. Vernadskyi str., 9, Dnipro, 49044, Ukraine, Ukraine https://orcid.org/0000-0003-2259-0622
A.E. Lievykh Dnipro State Medical University, V. Vernadskyi str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0002-0615-5092
A.I. Shevtsova Dnipro State Medical University, V. Vernadskyi str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0003-0409-6030
V.A. Tkachenko Dnipro State Medical University, V. Vernadskyi str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0003-2231-2913
Yu.V. Kharchenko Dnipro State Medical University, V. Vernadskyi str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0002-4136-3495

DOI:

https://doi.org/10.26641/2307-0404.2021.4.248055

Keywords:

type 2 diabetes mellitus, endothelial dysfunction, intracerebral hemorrhage, perindopril, metformin

Abstract

This comparative research is aimed to study the effect of perindopril and metformin on the levels of biochemical markers of endothelial dysfunction in rats with type 2 diabetes mellitus (T2DM) complicated by a brain hemorrhage. The study was carried out on 30 white male Wistar rats. T2DM was simulated by a single intraperitoneal injection of nicotinamide and streptozotocin (NA/STZ). Intracerebral hemorrhage (ICH) was induced by microinjection of 1 μL of bacterial collagenase 0.2 IU/μL into the striatum on the 60th day of the experiment. Animals were randomized into 5 groups: A – negative control (intact, n=6); B – positive control 1 (NA/STZ, n=6); C – positive control 2 (NA/STZ+ICH, n=6); D – perindopril (“Prestarium”, 2 mg/kg+NA/STZ+ICH, n=6); E – metformin (“Siofor”, 250 mg/kg+NA/STZ+ICH, n=6). The studied drugs were administered intragastrically for 20 days, starting from the 50th day after the induction of T2DM. Endothelial function was assessed by the content of homocysteine (Hcy), advanced glycation end products (AGEs), endothelin-1 (ET-1), and von Willebrand factor (vWF) in blood serum. It was found that long-term separate T2DM is accompanied by hyperhomocysteinemia, as well as an increase in AGEs, ET-1, and vWF levels, indicating dysregulation of the hemostasis system and vascular tone. It should be noted that brain hemorrhage in T2DM can enhance these manifestations, although the obtained differences were characterized only by a persistent trend. At the same time, the effect of perindopril was limited only by a significant decrease in AGEs levels by 31.2% (p<0.05). In turn, the action of metformin was characterized by a positive glycemic control, as well as an effect on the state of the vascular endothelium, namely, a significant decrease in AGEs, ET-1 and vWF levels by 37.6% (p<0.05); 5.5% (p<0.05) and 9.5% (p<0.05), respectively. It was also found that the endotheliotropic properties of the studied drugs were not associated with an effect on homocysteine levels. Thus, metformin in conditions of diabetes mellitus complicated by acute intracerebral hemorrhage has advantages over perindopril in relation to endothelial dysfunction.

References

Antomonov MYu. [Mathematical processing and analysis of medical and biological data]. Kyiv: Malyi druk; 2006. p. 558. Russian.

Ancion A, Tridetti J, Nguyen Trung ML, Oury C, Lancellotti P. A Review of the Role of Bradykinin and Nitric Oxide in the Cardioprotective Action of Angio¬tensin-Converting Enzyme Inhibitors: Focus on Perindopril. Cardiol Ther. 2019;8(2):179-91. doi: https://doi.org/10.1007/s40119-019-00150-w

Ren X, Ren L, Wei Q, Shao H, Chen L, Liu N. Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Cardiovasc Diabetol. 2017;16(1):52. doi: https://doi.org/10.1186/s12933-017-0531-9

Saliba W, Barnett-Griness O, Gronich N, Molad J, Naftali J, Rennert G, Auriel E. Association of Diabetes and Glycated Hemoglobin With the Risk of Intracerebral Hemorrhage: A Population-Based Cohort Study. Diabetes Care. 2019;42(4):682-8. doi: https://doi.org/10.2337/dc18-2472

Chen J, Xu X-M, Xu Z, Zhang J. Animal Models of Acute Neurological Injuries. Springer International Publishing. 2nd ed. Editors J Chen, X-M Xu, Z Xu. J Zhang. 2019. p. 544.

doi: https://doi.org/10.1007/978-3-030-16082-1

Nafisa A, Gray SG, Cao Y, Wang T, Xu S, Wat¬too FH, Barras M, Cohen N, Kamato D, Little PJ. Endothelial function and dysfunction: Impact of metformin. Pharmacol Ther. 2018;192:150-62. doi: https://doi.org/10.1016/j.pharmthera.2018.07.007

Potârniche AV, Dreancă AI, Sarpataki O, Sevastre B, Marcus I. Experimental model of Streptozotocin-Nicotinamide induced Diabetes Mellitus type II in Sprague-Dawley rats: Step by step protocol and the encountered issues Rev Rom Med Vet. 2018;28(2):22-26.

Gabbay KH, Sosenko JM, Banuchi GA, Mininsohn MJ, Flückiger R. Glycosylated hemoglobins: increa¬sed glycosylation of hemoglobin A in diabetic patients. Diabetes. 1979;28(4):337-40. doi: https://doi.org/10.2337/diab.28.4.337

Nair D, Nedungadi D, Mishra N, Nair BG, Nair SS. Identification of carbonylated proteins from monocytic cells under diabetes-induced stress conditions. Biomed Chromatogr. 2021;35(6):e5065. doi: https://doi.org/10.1002/bmc.5065

Lancellotti P, Ancion A, D'Orio V, Gach O, Maréchal P, Krzesinski JM. [Bradykinin and cardiovascular protection. Role of perindopril, an inhibitor of angiotensin conversion enzyme]. Rev Med Liege. 2018;73(4):197-205. French.

An H, Wei R, Ke J, Yang J, Liu Y, Wang X, Wang G, Hong T. Metformin attenuates fluctuating glu¬cose-induced endothelial dysfunction through enhancing GTPCH1-mediated eNOS recoupling and inhibiting NADPH oxidase. J Diabetes Complications. 2016;30(6):1017-24. doi: https://doi.org/10.1016/j.jdiacomp.2016.04.018

Münch G, Keis R, Wessels A, Riederer P, Bahner U, Heidland A, Niwa T, Lemke HD, Schinzel R. De¬termination of advanced glycation end products in serum by fluorescence spectroscopy and competitive ELISA. Eur J Clin Chem Clin Biochem. 1997;35(9):669-77. doi: https://doi.org/10.1515/cclm.1997.35.9.669

Shi Y, Vanhoutte PM. Macro- and microvascular endothelial dysfunction in diabetes. J Diabetes. 2017;9(5):434-49.

doi: https://doi.org/10.1111/1753-0407.12521

Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol. 2015;7(11):719-41. doi: https://doi.org/10.4330/wjc.v7.i11.719

Yaribeygi H, Sathyapalan T, Atkin SL, Sahebkar A. Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus. Oxid Med Cell Longev. 2020;2020:8609213. doi: https://doi.org/10.1155/2020/8609213