Angiotensin II Type 1 Receptor Antagonist Azilsartan Restores Vascular Reactivity Through a Perivascular Adipose Tissue-Independent Mechanism in Rats with Metabolic Syndrome
Perivascular adipose tissues (PVAT) are involved in the regulation of vascular tone. In mesenteric arteries, the compensatory vasodilatory effects of PVAT appear when vascular relaxation is impaired and disappear at around 23 weeks of age in SHRSP.Z-Leprfa/IzmDmcr (SHRSP.ZF) rats with metabolic syndrome (MetS). The renin-angiotensin system is involved in the development of endothelium and vascular dysfunction. Therefore, we investigated whether azilsartan, a potent angiotensin II type 1 (AT1) receptor antagonist, can protect against the deterioration of the PVAT compensatory vasodilator function that occurs with aging in MetS.
Two age groups of SHRSP.ZF rats (13 and 20 weeks of age) were administered azilsartan or vehicle through oral gavage once daily for 10 weeks. The vasodilation response of the isolated superior-mesenteric arteries upon addition of endothelium-dependent and -independent agonists was determined in the presence or absence of PVAT using organ bath methods.
In vivo treatment with azilsartan improved the acetylcholine-induced vasodilation in mesenteric arteries with and without PVAT at both time-points. The mRNA levels of AT1 receptor and AT1 receptor-associated protein were unchanged in PVAT upon azilsartan treatment. Furthermore, in vitro treatment with azilsartan (0.1 and 0.3 μM for 30 min) did not affect the compensatory effect of PVAT on vasodilation in response to acetylcholine in SHRSP.ZF rat mesenteric arteries.
Our results provide evidence supporting the use of azilsartan for the long-term protection against vascular dysfunctions in MetS. Azilsartan did not improve the dysfunction of PVAT-mediated modulation of vascular tone during MetS. The protective effect of azilsartan is mediated by restoring the endothelium- and vascular smooth muscle-mediated mechanisms.
KeywordsAdipose tissue AT1 receptor Angiotensin II Azilsartan Metabolic syndrome Vasodilation
Azilsartan used in in vivo treatment was a generous gift from Takeda Pharmaceutical Co. Ltd. (Tokyo, Japan). The authors wish to thank Ms. Saki Iwata, Ms. Rui Yamada, Ms. Maho Mizuno, Ms. Shiori Koyanagi, and Ms. Yayoi Shiokawa in Mukogawa Women’s University for their technical support.
Conceptualization of study, Satomi Kagota; Experimental design, Satomi Kagota; Performed the experiments and data analysis, Satomi Kagota, Kana Maruyama-Fumoto, and Miho Shimari; Data interpretation, Satomi Kagota and John J. McGuire; Funding acquisition and supervision, Satomi Kagota and Kazumasa Shinozuka; Original manuscript draft preparation, Satomi Kagota and John J. McGuire; Reviewing and editing the manuscript, Satomi Kagota and John J. McGuire. All authors have read and approved the final manuscript.
This work was partly supported by JSPS KAKENHI (grant number JP16K08563) to SK.
Compliance with Ethical Standards
This study was approved by the Animal Experimentation Committee at Mukogawa Women’s University (protocol numbers: P-12-2016-01-A, P-12-2017-01-A, and P-12-2018-01-A), and all animal experiments were performed in accordance with the guidelines for the Care and Use of Laboratory Animals at Mukogawa Women’s University.
Conflict of Interest
The authors declare that they have no conflict of interest.
Research Involving Animals
All protocols involving the care and use of animals were approved by the animal ethics committee and performed in accordance with the Guidelines for the Care and Use of Laboratory Animals at Mukogawa Women’s University (protocol numbers: P-12-2016-01-A, P-12-2017-01-A, and P-12-2018-01-A).
- 1.Michel MC, Brunner HR, Foster C, Huo Y. Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease. Pharmacol Ther. 2016;164:1–81.Google Scholar
- 2.Kizilirmak P, Uresin Y, Ozdemir O, Kilickiran Avci B, Tokgozoglu L, Ongen Z. Renin-angiotensin-aldosterone system blockers and cardiovascular outcomes: a meta-analysis of randomized clinical trials. Turk Kardiyol Dern Ars. 2017;45(1):49–66.Google Scholar
- 3.Angeloni E. Azilsartan medoxomil in the management of hypertension: an evidence-based review of its place in therapy. Core Evid. 2016;11:1–10.Google Scholar
- 4.Zaiken K, Cheng JW. Azilsartan medoxomil: a new angiotensin receptor blocker. Clin Ther. 2011;33(11):1577–89.Google Scholar
- 5.Ojima M, Igata H, Tanaka M, Sakamoto H, Kuroita T, Kohara Y, et al. In vitro antagonistic properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and function studies. J Pharmacol Exp Ther. 2011;336(3):801–8.Google Scholar
- 6.Takai S, Jin D, Sakonjo H, Takubo T, Nakanishi T. Significance of the vascular concentration of angiotensin II-receptor blockers on the mechanism of lowering blood pressure in spontaneously hypertensive rats. J Pharmacol Sci. 2013;123(4):371–9.Google Scholar
- 7.Sueta D, Kataoka K, Koibuchi N, Toyama K, Uekawa K, Katayama T, et al. Novel mechanism for disrupted circadian blood pressure rhythm in a rat model of metabolic syndrome—the critical role of angiotensin II. J Am Heart Assoc. 2013;2(3):e000035.Google Scholar
- 8.Hye Khan MA, Neckar J, Cummens B, Wahl GM, Imig JD. Azilsartan decreases renal and cardiovascular injury in the spontaneously hypertensive obese rat. Cardiovasc Drugs Ther. 2014;28(4):313–22.Google Scholar
- 9.Hye Khan MA, Neckar J, Haines J, Imig JD. Azilsartan improves glycemic status and reduces kidney damage in zucker diabetic fatty rats. Am J Hypertens. 2014;27(8):1087–95.Google Scholar
- 10.Takami T, Okada S, Saito Y, Nishijima Y, Kobori H, Nishiyama A. Effects of olmesartan and azilsartan on albuminuria and the intrarenal renin-angiotensin system. World J Res Rev. 2018;6(1):7–10.Google Scholar
- 11.Abdelsaid M, Coucha M, Ergul A. Cerebrovasculoprotective effects of azilsartan medoxomil in diabetes. Transl Res. 2014;164(5):424–32.Google Scholar
- 12.Xia N, Li H. The role of perivascular adipose tissue in obesity-induced vascular dysfunction. Br J Pharmacol. 2017;174(20):3425–42.Google Scholar
- 13.Nosalski R, Guzik TJ. Perivascular adipose tissue inflammation in vascular disease. Br J Pharmacol. 2017;174(20):3496–513.Google Scholar
- 14.Kagota S, Fukushima K, Umetani K, Tada Y, Nejime N, Nakamura K, et al. Coronary vascular dysfunction promoted by oxidative-nitrative stress in SHRSP.Z-Lepr(fa) /IzmDmcr rats with metabolic syndrome. Clin Exp Pharmacol Physiol. 2010;37(11):1035–43.Google Scholar
- 15.Ueno T, Takagi H, Fukuda N, Takahashi A, Yao EH, Mitsumata M, et al. Cardiovascular remodeling and metabolic abnormalities in SHRSP.Z-Lepr(fa)/IzmDmcr rats as a new model of metabolic syndrome. Hypertens Res. 2008;31(5):1021–31.Google Scholar
- 16.Hiraoka-Yamamoto J, Nara Y, Yasui N, Onobayashi Y, Tsuchikura S, Ikeda K. Establishment of a new animal model of metabolic syndrome: SHRSP fatty (fa/fa) rats. Clin Exp Pharmacol Physiol. 2004;31(1–2):107–9.Google Scholar
- 17.Kagota S, Iwata S, Maruyama K, McGuire JJ, Shinozuka K. Time-dependent differences in the influence of perivascular adipose tissue on vasomotor functions in metabolic syndrome. Metab Syndr Relat Disord. 2017;15(5):233–9.Google Scholar
- 18.Kagota S, Maruyama-Fumoto K, Iwata S, Shimari M, Koyanagi S, Shiokawa Y, et al. Perivascular adipose tissue-enhanced vasodilation in metabolic syndrome rats by apelin and N-acetyl(−)l-cysteine-sensitive factor(s). Int J Mol Sci. 2018;20(1).Google Scholar
- 19.Galvez-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(1):55–64.Google Scholar
- 20.Zhao M, Li Y, Wang J, Ebihara K, Rong X, Hosoda K, et al. Azilsartan treatment improves insulin sensitivity in obese spontaneously hypertensive Koletsky rats. Diabetes Obes Metab. 2011;13(12):1123–9.Google Scholar
- 21.Kubota Y, Umegaki K, Kagota S, Tanaka N, Nakamura K, Kunitomo M, et al. Evaluation of blood pressure measured by tail-cuff methods (without heating) in spontaneously hypertensive rats. Biol Pharm Bull. 2006;29(8):1756–8.Google Scholar
- 22.Kagota S, Tada Y, Nejime N, Nakamura K, Kunitomo M, Shinozuka K. Telmisartan provides protection against development of impaired vasodilation independently of metabolic effects in SHRSP.Z-Lepr(fa)/IzmDmcr rats with metabolic syndrome. Can J Physiol Pharmacol. 2011;89(5):355–64.Google Scholar
- 23.Matsumoto S, Shimabukuro M, Fukuda D, Soeki T, Yamakawa K, Masuzaki H, et al. Azilsartan, an angiotensin II type 1 receptor blocker, restores endothelial function by reducing vascular inflammation and by increasing the phosphorylation ratio Ser(1177)/Thr(497) of endothelial nitric oxide synthase in diabetic mice. Cardiovasc Diabetol. 2014;13:30.Google Scholar
- 24.Huang F, Lezama MA, Ontiveros JA, Bravo G, Villafana S, del-Rio-Navarro BE, et al. Effect of losartan on vascular function in fructose-fed rats: the role of perivascular adipose tissue. Clin Exp Hypertens. 2010;32(2):98–104.Google Scholar
- 25.Wang T, Lian G, Cai X, Lin Z, Xie L. Effect of prehypertensive losartan therapy on AT1R and ATRAP methylation of adipose tissue in the later life of highfatfed spontaneously hypertensive rats. Mol Med Rep. 2018;17(1):1753–61.Google Scholar
- 26.Maeda A, Tamura K, Wakui H, Ohsawa M, Azushima K, Uneda K, et al. Effects of the angiotensin receptor blocker olmesartan on adipocyte hypertrophy and function in mice with metabolic disorders. Biomed Res Int. 2014;2014:946492.Google Scholar
- 27.Tamura K, Wakui H, Maeda A, Dejima T, Ohsawa M, Azushima K, et al. The physiology and pathophysiology of a novel angiotensin receptor-binding protein ATRAP/Agtrap. Curr Pharm Des. 2013;19(17):3043–8.Google Scholar
- 28.Maeda A, Tamura K, Wakui H, Dejima T, Ohsawa M, Azushima K, et al. Angiotensin receptor-binding protein ATRAP/Agtrap inhibits metabolic dysfunction with visceral obesity. J Am Heart Assoc. 2013;2(4):e000312.Google Scholar
- 29.Maeda A, Tamura K, Wakui H, Ohsawa M, Azushima K, Uneda K, et al. Effects of Ang II receptor blocker irbesartan on adipose tissue function in mice with metabolic disorders. Int J Med Sci. 2014;11(6):646–51.Google Scholar
- 30.Lu C, Su LY, Lee RM, Gao YJ. Mechanisms for perivascular adipose tissue-mediated potentiation of vascular contraction to perivascular neuronal stimulation: the role of adipocyte-derived angiotensin II. Eur J Pharmacol. 2010;634(1–3):107–12.Google Scholar
- 31.Nobrega N, Araujo NF, Reis D, Facine LM, Miranda CAS, Mota GC, et al. Hydrogen peroxide and nitric oxide induce anticontractile effect of perivascular adipose tissue via renin angiotensin system activation. Nitric Oxide. 2019;84:50–9.Google Scholar
- 32.Tsukuda K, Mogi M, Iwanami J, Kanno H, Nakaoka H, Wang XL, et al. Enhancement of adipocyte browning by angiotensin II type 1 receptor blockade. PLoS One. 2016;11(12):e0167704.Google Scholar
- 33.Kong LR, Zhou YP, Chen DR, Ruan CC, Gao PJ. Decrease of perivascular adipose tissue browning is associated with vascular dysfunction in spontaneous hypertensive rats during aging. Front Physiol. 2018;9:400.Google Scholar