Losartan and Metformin Prevent Abnormalities in Perivascular Adipose Tissue and in Mesenteric Vascular Bed Prostanoid Release Induced by High-fat High-fructose Diet in Rats

Hyun Jin Lee, María Álvarez Primo, Miguel A. Allo, Silvana M. Cantú, Adriana S. Donoso, Horacio A. Peredo, Marcelo R. Choi, Ana M. Puyó


Objective: The aim of this study was to analyze the effects of losartan (30 mg/kg/day) and metformin (500 mg/kg/day) on the adiposityindex and the mesenteric vascular bed prostanoid release, and their relationship with systolic blood pressure in a metabolicsyndrome model induced by high-fat high fructose-diet in male Sprague-Dawley rats for 9 weeks..Methods: Mesenteric vascular beds were extracted and incubated and prostanoids were measured by high-performance liquid chromatography.Systolic blood pressure was measured by an indirect method.Results: High-fat high-fructose diet produced a significant increase in systolic blood pressure and mesenteric vascular bed adiposityindex and in the release of vasoconstrictor prostanoids as thromboxane B2 and prostaglandin F2α and of prostaglandin E2, a markerof inflammation. The PGI2/TXA2 ratio was significantly reduced. The administration of losartan and metformin prevented all thesechanges.Conclusion: Both drugs have beneficial effects on mesenteric perivascular adipose tissue by improving endothelial dysfunction inducedby an imbalance of vasoactive substances.


Kim SH, Després JP, Koh KK. Obesity and cardiovascular disease: friend or foe? Eur Heart J 2016;37:3560- 8 http://doi.org/10.1093/eurheartj/ehv509.

Bays HE. Central obesity as a clinical marker of adiposopathy; increased visceral adiposity as a surrogate marker for global fat dysfunction. Curr Opin Endocrinol Diabetes Obes 2014;21:345-51. https://doi.org/10.1097/MED.0000000000000093

Szasz T, Bomfim GF, Webb RC. The influence of perivascular adipose tissue on vascular homeostasis. Vasc Health Risk Manag. 2013;9:105-16.10.2147/VHRM.S33760. https://doi.org/10.2147/VHRM.S33760

Zaman MQ, Leray V, Le Bloc’h J, Thorin C, Ouguerram K, Nguyen P (2011). Lipid profile and insulin sensitivity in rats fed with highfat or high-fructose diets. Br J Nutr 2011;106 (Suppl 1):S206-210.https:// doi.org/10.1017/S0007114511004454

Pereira-Lancha LO, Campos-Ferraz PL, Lancha AH Jr (2012). Obesity: considerations about etiology, metabolism, and the use of experimental models. Diabetes Metab Syndr Obes 2012;5:75-87. https://doi.org/10.2147/DMSO.S25026

Peredo HA, Lee HJ, Donoso AS, Andrade V, Sánchez Eluchans NM, Puyó AM. A high-fat plus fructose diet produces a vascular prostanoid alterations in the rat. Auton Autocoid Pharmacol 2015;34:35-40. https://doi.org/10.1111/aap.12021

Fellmann L, Nascimento AR, Tibiriça E, Bousquet P (2013).

Murine models for pharmacological studies of the metabolic syndrome. Pharmacology &Therapeutics, 2013; 137:331-40. https://doi.org/10.1016/j. pharmthera.2012.11.004

Frontini A, Cinti S. Distribution and development of brown

adipocytes in the murine and human adipose organ. Cell Metab

;11:253-6. https://doi.org/10.1016/j.cmet.2010.03.004

Mendizábal Y, Llorens S, Nava E. Vasoactive effects of prostaglandins from the perivascular fat of mesenteric resistance arteries in WKY and SHROB rats. Life Sci 2013; 93:1023-32. https://doi.org/10.1016/j.lfs.2013.10.021

Peredo HA, Lee HJ, Donoso AS, Andrade V, Sánchez Eluchans NM, Puyó AM. A high-fat plus fructose diet produces a vascular prostanoid alterations in the rat. Auton Autocoid Pharmacol 2015;34:35-40. https://doi.org/10.1111/aap.12021

Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002;137:25-33. https://doi.org/10.7326/0003-4819- 137-1-200207020-00009

Sivasubramaniam S, Kumarasamy B. Pleiotropic Effects

of Losartan in Hypertensive Patients with Dyslipidemia. J

Clin Diagn Res 2017;11:FC05-FC08. https://doi.org/10.7860/


Verma S, Banhot S, McNeill JH. Antihypertensive effect of metformin in fructose-fed hyperinsulinemic, hypertensive rats. J Pharmacol Exp Ther 1994;271:1334-7.

Verma S, Yao L, Dumont AS, McNeill JH. Metformin treatment corrects vascular insulin resistance in hypertension. J Hypertens 2000;18:1445-50. https://doi.org/10.1097/00004872-200018100-00012

Peredo H, Mayer M, Carranza, Puyó A. Pioglitazone and losartan modify hemodynamic and metabolic parameters and vascularprostanoids in fructose-overloaded rats. Clin Exp Hypertens 2008;30:159- 69. https://doi.org/10.1080/10641960801946889

Boshra V, El Wakeel G, Nader M. Effect of celecoxib on the antihypertensive effect of losartan in a rat model of renovascular hypertension.Can J Physiol. Pharmacol 2011;89: 103-7. https://doi.org/10.1139/Y10-112

Smith P, Hindmarch C, Murphy D, Ferguson A. AT1 receptor

blockade alters nutritional and biometric development in obesity resistant and obesity-prone rats submitted to a high fat diet. Front Psychol. 2014;5:832. https://doi.org/10.3389/fpsyg.2014.00832

Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentration in man. Diabetologia. 1985;28:412-9. https://doi.org/10.1007/BF00280883

Mourad AA, Heeba GH, Taye A, El-Moselhy MA. Comparative study between atorvastatin and losartan on high fat diet induced type 2 diabetes mellitus in rats. Fundam Clin Pharmacol 2013;27:489-97. https://doi.org/10.1111/j.1472-8206.2012.01048.x

Tikoo K, Sharma E, Amara VR, Pamulapati H, Dhawale VS. Metformin improves metabolic memory in high fat diet (HFD)-induced renal dysfunction. J Biol Chem. 2016; 291:21848-21856, pii: jbc.C116.732990. https://doi.org/10.1074/jbc.C116.732990

Wang T, Lian G, Cai X, Lin Z, Xie L. Effect of prehypertensive losartán therapy on AT1R and ATRAP methylation of adipose tissue in the later life of high fat fed spontaneously hypertensive rats. Mol Med Rep 2018;17:1753-61.10.1097/01.hjh. https://doi.org/10.3892/mmr.2017.8081

Yudkin JS, Eringa E, Stehouwer CD. ‘Vasocrine’ signaling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet 2005;365:1817-20. https://doi.org/10.1016/S0140-


Marchesi C, Ebrahimian T, Angulo O, Paradis P, Schiffrin EL.

Endothelial nitric oxide synthase uncoupling and perivascular

adipose oxidative stress and inflammation contribute to vascular

dysfunction in a rodent model of metabolic syndrome. Hypertension 2009;54:1384-92. https://doi.org/10.1161/HYPERTENSIONAHA.


Ma L, Ma S, He H, et al. Perivascular fat-mediated vascular

dysfunction and remodeling through the AMPK/mTOR pathway

in high-fat diet-induced obese rats. Hypertens Res 2010;33:446-53.https://doi.org/10.1038/hr.2010.11

Ketonen J, Pilvi T, Mervaala E. Caloric restriction reverses high fat diet-induced endothelial dysfunction and vascular superoxide production in C57Bl/6 mice. Heart Vessels. 2010;25:254-62. https://doi.org/10.1007/s00380-009-1182-x

Tang EH, Vanhoutte PM. Prostanoids and reactive oxygen

species: team players in endothelium-dependent contractions.

Pharmacol Ther 2009;122:140-9. https://doi.org/10.1016/j.pharmthera.2009.02.006

Ketonen J, Shi J, Martonen E, Mervaala E. Periadventitial adipose tissue promotes endothelial dysfunction via oxidative stress in diet-induced obese C57Bl/6 mice. Circ J. 2010;74:1479-87. https://doi. org/10.1253/circj.CJ-09-0661

Hernanz R, Briones AM, Salaices M, Alonso MJ. New roles for old pathways? A circuitous relationship between reactive oxygen species and cyclo-oxygenase in hypertension. Clin Sci 2014;126:111-21. https://doi.org/10.1042/CS20120651

Matsumoto T, Noguchi E, Ishida K, Kobayashi T, Yamada N,

Kamata K. Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes. Am J Physiol Heart Circ Physiol 2008;295:H1165-H1176. https://doi.org/10.1152/ajpheart.00486.2008

Matsumoto T, Ishida K, Nakayama N, Taguchi K, Kobayashi T,

Kamata K. Mechanisms underlying the losartan treatment-induced improvement in the endothelial dysfunction seen in mesenteric arteries from type 2 diabetic rats. Pharmacol Res 2010;62:271-81.https:// doi.org/10.1016/j.phrs.2010.03.003

Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 2010;11:554-65. https:// doi.org/10.1016/j.cmet.2010.04.001

Nagata D, Hirata Y. The role of AMP-activated protein kinase in the cardiovascular system. Hypertens Res 2010; 33:22-8. https://doi.org/10.1038/hr.2009.187

Hardie DG. AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochem SocTrans 2011;39:113. https://doi.org/10.1042/BST0390001

Hildebrand S, Stümer J, Pfeifer A. PVAT and Its Relation

to Brown, Beige, and White Adipose Tissue in Development

and Function. Front Physiol 2018;9:70. https://doi.org/10.3389/


Gálvez-Prieto B, Bolbrinker J, Stucchi P, de Las Heras AI, Merino B, Arribas S, et al. Comparative expression analysis of the renin-angiotensin system components between white and brown perivascular adipose tissue. J Endocrinol 2008;197:55-64. https://doi. org/10.1677/JOE-07-0284

Cassis LA, Fettinger MJ, Roe AL, Shenoy UR, Howard G. Characterization and regulation of angiotensin II receptors in rat adipose tissue. Angiotensin receptors in adipose tissue. Adv Exp Med Biol1996;396:39-47. https://doi.org/10.1007/978-1- 4899-1376-0_5

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