PMID- 24485356
OWN - NLM
STAT- MEDLINE
DCOM- 20140826
LR  - 20220408
IS  - 1475-2840 (Electronic)
IS  - 1475-2840 (Linking)
VI  - 13
DP  - 2014 Jan 31
TI  - 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.
PG  - 30
LID - 10.1186/1475-2840-13-30 [doi]
AB  - BACKGROUND: Azilsartan, 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. METHODS: We 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 TNFalpha in the 
      perivascular fat were strongly attenuated by azilsartan compared to candesartan 
      cilexetil. CONCLUSIONS: These 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.
FAU - Matsumoto, Sachiko
AU  - Matsumoto S
FAU - Shimabukuro, Michio
AU  - Shimabukuro M
AD  - Department of Cardio-Diabetes Medicine, The University of Tokushima Graduate 
      School of Health Biosciences, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. 
      mshimabukuro-ur@umin.ac.jp.
FAU - Fukuda, Daiju
AU  - Fukuda D
FAU - Soeki, Takeshi
AU  - Soeki T
FAU - Yamakawa, Ken
AU  - Yamakawa K
FAU - Masuzaki, Hiroaki
AU  - Masuzaki H
FAU - Sata, Masataka
AU  - Sata M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140131
PL  - England
TA  - Cardiovasc Diabetol
JT  - Cardiovascular diabetology
JID - 101147637
RN  - 0 (Angiotensin II Type 1 Receptor Blockers)
RN  - 0 (Benzimidazoles)
RN  - 0 (Oxadiazoles)
RN  - 2ZD004190S (Threonine)
RN  - 452VLY9402 (Serine)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 1.14.13.39 (Nos3 protein, mouse)
RN  - F9NUX55P23 (azilsartan)
SB  - IM
MH  - Angiotensin II Type 1 Receptor Blockers/pharmacology/*therapeutic use
MH  - Animals
MH  - Benzimidazoles/pharmacology/*therapeutic use
MH  - Diabetes Mellitus, Experimental/drug therapy/*metabolism
MH  - Endothelium, Vascular/drug effects/*metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nitric Oxide Synthase Type III/*metabolism
MH  - Organ Culture Techniques
MH  - Oxadiazoles/pharmacology/*therapeutic use
MH  - Phosphorylation/drug effects/physiology
MH  - Serine/metabolism
MH  - Threonine/metabolism
MH  - Vasculitis/drug therapy/*metabolism
MH  - Vasodilation/drug effects/physiology
PMC - PMC3916073
EDAT- 2014/02/04 06:00
MHDA- 2014/08/27 06:00
PMCR- 2014/01/31
CRDT- 2014/02/04 06:00
PHST- 2013/11/25 00:00 [received]
PHST- 2014/01/23 00:00 [accepted]
PHST- 2014/02/04 06:00 [entrez]
PHST- 2014/02/04 06:00 [pubmed]
PHST- 2014/08/27 06:00 [medline]
PHST- 2014/01/31 00:00 [pmc-release]
AID - 1475-2840-13-30 [pii]
AID - 10.1186/1475-2840-13-30 [doi]
PST - epublish
SO  - Cardiovasc Diabetol. 2014 Jan 31;13:30. doi: 10.1186/1475-2840-13-30.