The efficacy and tolerability of azilsartan in obese insulin-resistant mice with left ventricular pressure overload.
Angiotensin II receptor blockers (ARBs) are used widely for the treatment of heart failure. However, their use in obese and insulin-resistant patients remains controversial. To clarify their potential efficacy in these conditions, we administered azilsartan medoxomil (azilsartan), a prodrug of an angiotensin II receptor blocker to mice fed a high-fat diet (HFD) with left ventricular (LV) pressure overload (aortic banding). LV fibrosis (hydroxyproline), cardiac plasminogen activator inhibitor-1 (PAI-1; a marker of profibrosis), and creatine kinase (a marker of myocardial viability and energetics) were assessed. LV wall thickness and cardiac function were assessed echocardiographically. Mice given a HFD were obese and insulin resistant. Their LV hypertrophy was accompanied by greater LV PAI-1 and reduced LV creatine kinase compared with normal diet controls. Drug treatment reduced LV wall thickness, hypertrophy, and PAI-1 and increased cardiac output after aortic banding compared with results in HFD vehicle controls. Thus, azilsartan exerted favorable biological effects on the hearts of obese insulin-resistant mice subjected to LV pressure overload consistent with its potential utility in patients with analogous conditions.
Cardiovascular Research Institute and Department of Medicine, University of Vermont College of Medicine, Colchester, VT.
A K M
AK
Tarikuz Zaman
Danielle L
DL
McLean
Burton E
BE
Sobel
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000633:toxicity; D002302:Cardiac Output / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D059305:Diet, High-Fat; D004452:Echocardiography; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000503:physiopathology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000503:physiopathology*; D010069:Oxadiazoles / Q000494:pharmacology* / Q000633:toxicity; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017725:Ventricular Pressure / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D010069:Oxadiazoles; D017395:Plasminogen Activator Inhibitor 1; D003402:Creatine Kinase; C557413:azilsartan medoxomil