The Efficacy and Tolerability of Azilsartan in Mice With Left Ventricular Pressure Overload or Acute Myocardial Infarction

Abstract

Angiotensin II receptor blockers (ARBs) are used for the treatment of patients with heart failure and hypertension. Yet their safety has been questioned by some who observed delayed cardiac healing and scar thinning after myocardial infarction (MI). To clarify potential efficacy and safety of ARBs, we administered Azilsartan medoxomil, a prodrug of an ARB (Takeda Pharmaceutical Company Limited), assessed cardiac fibrosis (hydroxyproline content), left ventricular (LV) wall thickness (premortem echocardiography and caliper measurement at necropsy), and LV mass and cardiac function with high-resolution ultrasound in mice with either surgically induced LV pressure overload (aortic banding) or acute MI. Drug-treated aortic-banded mice exhibited less LV wall thickness, hypertrophy, and dilation compared with that exhibited by controls. Survival in drug-treated MI mice was greater though not significantly. Drug-treated mice with acute MI exhibited less cardiomyocyte injury reflected by LV creatine kinase content and less LV hypertrophy and dilation. Thus, Azilsartan exerted favorable biological effects on the hearts of mice subjected to LV pressure overload or MI without compromising survival consistent with its potential utility and tolerability in patients with analogous conditions.

Azilsartan Modulates HMGB1/NF-κB/p38/ERK1/2/JNK and Apoptosis Pathways during Renal Ischemia Reperfusion Injury

“…Additionally, azilsartan attenuated LPS-induced inflammation and oxidative stress in U937 macrophages and lung injury through the modulation of Nr2/HO-1 pathway [39,40]. Furthermore, it showed promising activity in acute myocardial infarction [41] and exerted a potential protective effect against cisplatin-induced cytotoxicity [42]. The present study aimed to examine the effect of azilsartan on renal IR injury in rats and the possible molecular mechanisms implied this effect by inspecting apoptosis and HMGB1/NF-κB/p38/ERK1/2/JNK signaling pathways.…”

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

“…This is consistent with previous reports of reduced hypertrophy in patients (without diabetes) treated with ARBs. 41 Thus, the decrease in hypertrophy noted in this study may have been attributable in part to reduced pressure after load secondary to suppression of activity of the RAAS. Improved cardiac function, reflected by increased CO and stroke volume, was observed as well in mice treated with azilsartan.…”

“…ACE inhibitors are standard therapy in patients with hypertension 50 and heart failure. 41 In addition, we have found that azilsartan was safe and well tolerated in normal mice subjected to aortic banding. Increased activity of RAAS in both laboratory animals 25,26 and patients 27,29 with the metabolic syndrome is well established.…”

“…51 The utilization of ARBs for treatment of such patients has steadily increased 52 partially because of the absence of the unwanted side effects associated with ACE inhibition. 41 In this study, we characterized the efficacy of azilsartan in the setting of metabolic dysfunction. Inhibition of RAAS in such patients has reduced cardiovascular comorbidities and insulin resistance and also the incidence of new onset type 2 diabetes.…”