Angiotensin II Type 1 Receptor Antagonist Azilsartan Restores Vascular Reactivity Through a Perivascular Adipose Tissue-Independent Mechanism in Rats with Metabolic Syndrome

  • Satomi Kagota
  • Kana Maruyama-Fumoto
  • Miho Shimari
  • John J. McGuire
  • Kazumasa Shinozuka



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.


Adipose 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.

Author Contributions

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.

Funding Information

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).

Supplementary material

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ESM 1 (DOCX 266 kb)
10557_2019_6900_MOESM2_ESM.docx (23 kb)
ESM 2 (DOCX 23 kb)


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, School of Pharmacy and Pharmaceutical SciencesMukogawa Women’s UniversityNishinomiyaJapan
  2. 2.Department of Medical Biophysics, Schulich School of Medicine & DentistryWestern UniversityLondonCanada

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