The Efficacy and Tolerability of Azilsartan in Obese Insulin-Resistant Mice with Left Ventricular Pressure Overload

Abstract

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.

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

“…In the soleus muscle of KKAy, mRNA expression levels of TNFα, MCP1, and Nox2 were increased and IRS-1 was decreased, but this overexpression was not attenuated by either candesartan cilexetil or azilsartan. It has been shown that azilsartan reduced left ventricular hypertrophy, cardiac fibrosis, plasminogen activator inhibitor-1 (PAI-1; a marker of profibrosis) in aortic banding mice fed high-fat diet [55], indicating that azilsartan may exert favorable biological effects in non-diabetic obese insulin-resistant condition, which shares a common mechanism such as enhanced ROS/inflammation signals with the current model.…”

Updating Experimental Models of Diabetic Cardiomyopathy

“…In contrast, ZDF and GK rats usually exhibited a significant increase of the septum and LVPW thicknesses, reduced LV diastolic and systolic diameters, enlarged cardiomyocyte volume, and higher expression rates of ANP, in spite of the fact that contractile function was frequently preserved [ 10 , 12 , 28 – 31 ]. Finally, the limited body of evidence on diet-induced T2DM rather pointed hypertrophy as the only morphological alteration constantly present, independently of its high-fat of high-sugar diet origin [ 13 , 32 – 34 ]. However, a recent work reported no difference in heart weight and cardiomyocyte size but overexpression of ANP, BNP, and β -MHC after a 16-week-long high-fat diet [ 35 ].…”

Antihypertensive Drug Use in Diabetics: A Drug Utilization Study

“…Thus, it has been suggested that all diabetic patients with BP greater than 130/80 mm Hg should begin ACEI treatment unless contraindicated. 15,16,17,18,19,20,21 Our study indicated a limited congruency to this principle.…”