Abstract
Background
Due to increasing prevalence of diabetes and associated endothelial dysfunction, this study was carried out to investigate the effects of co-administration of adrenoceptor blockers (prazosin and propranolol) and glibenclamide on plasma biomarkers of endothelial functions in diabetic rats.
Methods
Experiments were carried out on 35 male Wistar rats (170–200 g). They were divided into seven groups (n=5) as follows: normal control, diabetic control, diabetic + glibenclamide (GLB-5mg/kg/day), diabetic+ prazosin (PRZ-0.5 mg/kg/day), diabetic + PRZ + GLB, diabetic + propranolol (PRP-10 mg/kg/day), diabetes + PRP + GLB. Experimental diabetes was induced with streptozotocin (60 mg/kg) and drugs were administered orally for 3 weeks. Blood pressure was measured and animals were sacrificed afterwards. Blood samples were collected by cardiac puncture, and major marker of endothelial functions, nitric oxide derivatives (NOx), as well as superoxide dismutase (SOD) and malondialdehyde (MDA) were measured on the plasma. The aorta was harvested for histological examination. Data were subjected to descriptive statistics and analysed using ANOVA at α0.05.
Results
There was a significant increase in levels of NOx and SOD, and a decrease in MDA level in diabetic treated groups compared to diabetic control. Mean blood pressure increased in diabetic control and diabetic + GLB group when compared with normal control, while it was mildly reduced in diabetic group treated with PRZ and PRP, and co-administered GLB. More so, Aorta histology was altered in diabetic control groups when compared with normal control and all diabetic treated groups.
Conclusions
Results from this study suggest that PRZ, PRP, and GLB (singly and in combined therapy) could have a restorative effect on endothelial functions in diabetes.
Acknowledgments
The authors would like to appreciate the technical assistance rendered by Dr. Temidayo Olutayo Omobowale, Dr Olumuyiwa Abiola Adejumobi (Department of Veterinary Medicine, University of Ibadan), and Dr Ademola Adetokunbo Oyagbemi (Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan) during the blood pressure measurement. In addition, the technical assistance rendered by Mr. Adebowale Olabanji (Bridge Bio-Tech limited, Ilorin, Kwara State) during the biochemical analysis is acknowledged. The authors declare no conflict of interest.
Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The local Institutional Review Board deemed the study.
References
1. Levick JR. An introduction to cardiovascular physiology. 4th ed. London: Arnold Publishers; 2003.Search in Google Scholar
2. Yasa M, Turkseven S. Vasoprotective effects of nitric oxide in atherosclerosis. FABAD J Pharm Sci 2005;30:41–3.Search in Google Scholar
3. Roberts AC, Porter KE. Cellular and molecular mechanisms of endothelial dysfunction in diabetes. Diab Vasc Dis Res 2013;10:472–82. https://doi.org/10.1177/1479164113500680.Search in Google Scholar
4. Förstermann U, Mügge A, Alheid U, Haverich A, Frolich JC. Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries. Circ Res 1988;62:185–90. https://doi.org/10.1161/01.res.62.2.185.Search in Google Scholar
5. Werns SW, Walton JA, Hsia HH, Nabel EG, Sanz ML, Pitt B. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation 1989;79:287–91. https://doi.org/10.1161/01.cir.79.2.287.Search in Google Scholar
6. Bossaller C, Habib GB, Yamamoto H, William C, Wells S, Henry PD. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5’-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest 1987;79:170–4. https://doi.org/10.1172/jci112779.Search in Google Scholar
7. Freiman PC, Mitchell GG, Heistad DD, Armstrong ML, Harrison DG. Atherosclerosis impairs endothelium-dependent vascular relaxation to acetylcholine and thrombin in primates. Circ Res 1986;58:783–9. https://doi.org/10.1161/01.res.58.6.783.Search in Google Scholar
8. McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR, et al. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992;35:771–6. https://doi.org/10.1016/s0008-6363(01)00379-0.Search in Google Scholar
9. Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88:2510–6. https://doi.org/10.1161/01.cir.88.6.2510.Search in Google Scholar
10. Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin dependent diabetes mellitus. J Am Coll Cardiol 1996;27:567–74. https://doi.org/10.1016/0735-1097(95)00522-6.Search in Google Scholar
11. Dunford EC, Leclair E, Aiken J, Mandel ER, Haas TL, Birot O, et al. The effects of voluntary exercise and prazosin on capillary rarefaction and metabolism in streptozotocin-induced male rats. J Appl Physiol 2017;122:492–502. https://doi.org/10.1152/japplphysiol.00762.2016.Search in Google Scholar PubMed PubMed Central
12. Romana-Souza B, Nascimento AP, Monte-Alto-Costa A. Propranolol improves cutaneous wound healing in streptozotocin-induced diabetic rats. Eur J Pharma 2009;611:77–84. https://doi.org/10.1016/j.ejphar.2009.03.053.Search in Google Scholar PubMed
13. Gribble FM, Reimann F. Sulphonylurea action revisited: the post-cloning era. Diabetologia 2003;46:875–91. https://doi.org/10.1007/s00125-003-1143-3.Search in Google Scholar
14. Riddle MC. Editorial: Sulphonylureas differ in effects on ischaemic preconditions—is it time to retire glyburide? J Clin Endocrinol Metab 2003;88:528–30. https://doi.org/10.1210/jc.2002-021971.Search in Google Scholar
15. Henquin JC. The fiftieth anniversary of hypogycaemic sulphonamides. How did the mother compound work? Diabetologia 1992;35:907–12. https://doi.org/10.1007/bf00401417.Search in Google Scholar
16. Stuehr DJ, Cho HJ, Kwon NS, Weise MF, Nathan CF. Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. Proc. Natl. Acad. Sci. USA. 1991;88:7773–7. https://doi.org/10.1073/pnas.88.17.7773.Search in Google Scholar
17. Marklund S, Marklund G. Involvement of the superoxide anion radical in the autooxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur. J. Biochem 1974;47:469–4. https://doi.org/10.1111/j.1432-1033.1974.tb03714.x.Search in Google Scholar
18. Magnani L, Gaydou M, Jean CH. Spectrophotometric measurement of antioxidant properties of flavones and flavonols against superoxide anion. Anal. Chim. Acta, 2000;411:209–16. https://doi.org/10.1016/s0003-2670(00)00717-0.Search in Google Scholar
19. Varshney R, Kale RK. Effects of Calmodulin Antagonists on Radiation-induced Lipid Peroxidation in Microsomes. Int. J. Rad. Biol 1990;58:733–43. https://doi.org/10.1080/09553009014552121.Search in Google Scholar
20. Avwioro OG. Textbook of histochemistry and tissue pathology. 2nd ed. Ibadan: Claverianun press; 2010.Search in Google Scholar
21. Pollare T, Lithell H, Selinus I, Berne C. Application of prazosin is associated with an increase in insulin sensitivity in obese patients with hypertension. Diabetologia 1988;31:415–20. https://doi.org/10.1007/bf00271585.Search in Google Scholar
22. Giordano M, Matsuda M, Sanders L, Canessa ML, DeFronzo RA. Effects of angiotensin-converting enzyme inhibitors, Ca2+channel antagonists, and α-adrenergic blockers on glucose and lipid metabolism in NIDDM patients with hypertension. Diabetes 1995;44:665–71. https://doi.org/10.2337/diabetes.44.6.665.Search in Google Scholar
23. Herings RM, de Boer A, Striker BH, Leufkens HG, Porsius A. Hypoglycemia associated with use of inhibitors of angiotensin converting enzyme. Lancet 1995;345:1195–8.10.1016/S0140-6736(95)91988-0Search in Google Scholar
24. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Antihypertensives and the risk of serious hypoglycemia in older persons using insulin or sulfonylureas. JAMA 1997;278:40–3. https://doi.org/10.1001/jama.1997.03550010054039.Search in Google Scholar
25. Pournaghi P, Sadrkhanlou R, Hasanzadeh S, Foroughi A. An investigation on body weights, blood glucose levels and pituitary-gonadal axis hormones in diabetic and metformin-treated diabetic female rats. Veterinary Research Forum 2012;3:79–84.Search in Google Scholar
26. Segal P, Feig P, Schernthaner G, Ratzmann KP, Rybka J, Petzinna D, et al. The efficacy and safety of miglitol therapy compared with glibenclimide in patients with NIDDM inadequately controlled by diet alone. Diabetes Care 1997;20:687–91. https://doi.org/10.2337/diacare.20.5.687.Search in Google Scholar PubMed
27. Gottdiener JS, Reda DJ, Massie BM, Materson BJ, Williams DW, Anderson RJ. Effect of single-drug therapy on reduction of left ventricular mass in mild to moderate hypertension: comparison of six antihypertensive agents. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Circulation 1997;95:2007–14. https://doi.org/10.1161/01.cir.95.8.2007.Search in Google Scholar PubMed
28. Berglund G, Andersson O, Widgren B. Low-dose antihypertensive treatment with a thiazide diuretic is not diabetogenic: A 10-year controlled trial with bendroflumethiazide. Acta med Scand 1986;220:419–24. https://doi.org/10.1111/j.0954-6820.1986.tb02790.x.Search in Google Scholar PubMed
29. Rossner S, Taylor CL, Byington RP, Furberg CD. Long term propranolol treatment and changes in body weight after myocardial infarction. Br Med J 1990;300:902–3. https://doi.org/10.1136/bmj.300.6729.902.Search in Google Scholar PubMed PubMed Central
30. Murray RK, Graner DK, Mayer PA, Rodwell VW. Hormones of pancreas and gastrointestinal tract. Hapers Biochemistry. 24th edition. Stamford: Appleton & Lange; 1996:586–7p.Search in Google Scholar
31. Amiri I, Karimi J, Piri H, Goodarzi MT, Tavilani H, Khodadadi I, et al. Association between nitric oxide and 8-hydroxydeoxyguanosine levels in semen of diabetic men. Syst Biol Reprod Med. 2011;57:292–5. https://doi.org/10.3109/19396368.2011.621508.Search in Google Scholar PubMed
32. Adela R, Nethi SK, Bagul PK, Barui AK, Mattapally S, Kuncha M, et al. Hyperglycaemia enhances nitric oxide production in diabetes: a study from South Indian patients. PLoS One. 2015;10:e0125270. https://doi.org/10.1371/journal.pone.0125270.Search in Google Scholar PubMed PubMed Central
33. Shiekh GA, Ayub T, Khan SN, Dar R, Andrabi KI. Reduced nitrate level in individuals with hypertension and diabetes. J Cardiovasc Dis Res. 2011;2:172–6. https://doi.org/10.4103/0975-3583.85264.Search in Google Scholar PubMed PubMed Central
34. Tatsch E, Bochi GV, Piva SJ, De Carvalho JA, Kober H, Torbitz VD, et al. Association between DNA strand breakage and oxidative, inflammatory and endothelial biomarkers in type 2 diabetes. Mutat Res. 2012;732:16–20. https://doi.org/10.1016/j.mrfmmm.2012.01.004.Search in Google Scholar PubMed
35. Zhang G, Lin X, Zhang S., Xiu H, Pan C, Wei Cui W. A Protective Role of Glibenclamide in Inflammation-Associated Injury. Mediators of Inflammation 2017;2017:3578702. https://doi.org/10.1155/2017/3578702.Search in Google Scholar PubMed PubMed Central
36. Tesfamariam B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol 1992;263:H321–6. https://doi.org/10.1152/ajpheart.1992.263.2.h321.Search in Google Scholar
37. Pieper GM, Langenstroer P, Siebeneich W. Diabetic-induced endothelial dysfunction in rat aorta: role of hydroxyl radicals. Cardiovasc Res 1997;34:145–56. https://doi.org/10.1016/s0008-6363(96)00237-4.Search in Google Scholar
38. Sorriento D, De Luca N, Trimarco B, Iaccarino G. The Antioxidant Therapy: New Insights in the Treatment of Hypertension. Front. Physiol. 2018;9:258. https://doi.org/10.3389/fphys.2018.00258.Search in Google Scholar
39. Hashimoto Y. Effect of alloxan diabetes induced in spontaneously hypertensive rats. Jpn Circ J 1969;33:1315–38. https://doi.org/10.1253/jcj.33.1315.Search in Google Scholar
40. Christlieb, A.R.. Diabetes and hypertensive vascular disease. Am J Cardiol 1973;32:592–606. https://doi.org/10.1016/s0002-9149(73)80051-7.Search in Google Scholar
41. Cavaliere TA, Taylor DG, Kerwin LJ, Antonaccio MJ. Cardiovascular effects of alloxan diabetes in normotensive and spontaneously hypertensive rats. Pharmacology 1980;20:211–23. https://doi.org/10.1159/000137367.Search in Google Scholar
42. Kawashima H, Igarashi T, Nakajima Y, Akiyama Y, Usuki K, Ohtake S. Chronic hypertension induced by streptozotocin in rats. Naunyn Schmiedebergs Arch Pharmacol 1978;305:123–6. https://doi.org/10.1007/bf00508281.Search in Google Scholar
43. Somani P, Singh H, Saini R, Rabinovitch A. Streptozotocin-induced diabetes in the spontaneously hypertensive rat. Metabolism 1979;28:1075–7. https://doi.org/10.1016/0026-0495(79)90144-6.Search in Google Scholar
44. Kohler L, Boillat N, Luthi P, Atkinson J, Peters-Haefeli L. Influence of streptozotocin-induced diabetes on blood pressure and on renin formation and release. Naunyn Schmiedebergs Arch Pharmacol 1980;313:257–61. https://doi.org/10.1007/bf00505742.Search in Google Scholar
45. Pfaffman MA. The effects of streptozotocin-induced diabetes and insulin-treatment on the cardiovascular system of the rat. Res Commun Chem Pathol Pharmacol 1980;28:27–41. https://doi.org/10.2337/diabetes.47.12.1967.Search in Google Scholar PubMed
46. Muthaian R, Pakirisamy RM, Parasuraman S, Raveendran R. Hypertension influences the exponential progression of inflammation and oxidative stress in streptozotocin-induced diabetic kidney. J Pharmacol Pharmacother 2016;7:159–64. https://doi.org/10.4103/0976-500x.195898.Search in Google Scholar
47. Makino A, Scott BT, Dillmann WH. Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes. Diabetologia 2010;53:1783–94. https://doi.org/10.1007/s00125-010-1770-4.Search in Google Scholar PubMed PubMed Central
48. Shen GX. Oxidative stress and diabetic cardiovascular disorders: roles of mitochondria and NADPHoxidase. Can J Phys Pharma 2010;88:241–8. https://doi.org/10.1139/y10-018.Search in Google Scholar PubMed
49. Mokini Z, Marcovecchio ML, Chiarelli F. Molecular pathology of oxidative stress in diabetic angiopathy: role of mitochondrial and cellular pathways. Diab Res Clini Pra 2010;87:313–21. https://doi.org/10.1016/j.diabres.2009.11.018.Search in Google Scholar PubMed
50. Wilhelm B. Weber M. Kreisselmeier H, Kugler M, Ries C, Pfutzner A, et al. Endothelial function and arterial stiffness in uncomplicated type 1 diabetes and healthy controls and the impact of insulin on these parameters during an euglycemic clamp. J Diabetes Sci Technolo 2007;1:582–9. https://doi.org/10.1177/193229680700100417.Search in Google Scholar PubMed PubMed Central
© 2020 Walter de Gruyter GmbH, Berlin/Boston
