Azilsartan, an angiotensin II type 1 receptor blocker, restores endothelial function by reducing vascular inflammation and by increasing the phosphorylation ratio Ser1177/Thr497 of endothelial nitric oxide synthase in diabetic mice

Cardiovascular Diabetology

Original Investigation

Michio Shimabukuro¹  Daiju Fukuda¹  Takeshi Soeki²  Masataka Sata²  Sachiko Matsumoto²  Hiroaki Masuzaki³  Ken Yamakawa³ 

[1] Department of Cardio-Diabetes Medicine, The University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto, 770-8503, Tokushima, Japan;Department of Cardiovascular Medicine, The University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto, 770-8503, Tokushima, Japan;Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan;

关键词: Telmisartan;    Olmesartan;    Candesartan Cilexetil;    Insulin Tolerance Test;    Reactive Oxidant Species;   

DOI  :  10.1186/1475-2840-13-30

 received in 2013-11-25, accepted in 2014-01-23,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundAzilsartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), has a higher affinity for and slower dissociation from AT1 receptors and shows stronger inverse agonism compared to other ARBs. Possible benefits of azilsartan in diabetic vascular dysfunction have not been established.MethodsWe measured vascular reactivity of aortic rings in male KKAy diabetic mice treated with vehicle, 0.005% azilsartan, or 0.005% candesartan cilexetil for 3 weeks. Expression of markers of inflammation and oxidative stress was measured using semiquantitative RT-PCR in the vascular wall, perivascular fat, and skeletal muscle. Phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and Thr495 was measured using Western blotting, and the ratio of phosphorylation at Ser1177 to phosphorylation at Thr495 was used as a putative indicator of vascular eNOS activity.Results(1) Vascular endothelium–dependent relaxation with acetylcholine in KKAy mice was improved by azilsartan treatment compared to candesartan cilexetil; (2) the ratio of Ser1177/Thr495 phosphorylation of eNOS was impaired in KKAy and was effectively restored by azilsartan; (3) anomalies in the expression levels of monocyte chemotactic protein 1 (MCP1), F4/80, NAD(P)H oxidase (Nox) 2, and Nox4 of the aortic wall and in the expression of TNFα in the perivascular fat were strongly attenuated by azilsartan compared to candesartan cilexetil.ConclusionsThese results provide evidence that azilsartan prevents endothelial dysfunction in diabetic mice, more potently than does candesartan cilexetil. Azilsartan’s higher affinity for and slower dissociation from AT1 receptors may underlie its efficacy in diabetic vascular dysfunction via a dual effect on uncoupled eNOS and on Nox.

【 授权许可】

Unknown   
© Matsumoto et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.