Cardiovascular Research Institute and Department of Medicine, University of Vermont College of Medicine, Colchester, VT.
J Cardiovasc Pharmacol. 2013 Oct;62(4):381-7. doi: 10.1097/FJC.0b013e31829f0c1b.
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.
血管紧张素 II 受体阻滞剂（ARBs）被广泛用于治疗心力衰竭。然而，它们在肥胖和胰岛素抵抗患者中的应用仍存在争议。为了阐明它们在这些情况下的潜在疗效，我们给喂食高脂肪饮食（HFD）并伴有左心室（LV）压力超负荷（主动脉缩窄）的小鼠施用血管紧张素 II 受体阻滞剂的前体药物——阿齐沙坦酯（azilsartan）。评估了 LV 纤维化（羟脯氨酸）、心脏纤溶酶原激活物抑制剂-1（PAI-1；纤维化标志物）和肌酸激酶（心肌存活和能量标志物）。通过超声心动图评估 LV 壁厚度和心功能。给予 HFD 的小鼠肥胖且胰岛素抵抗。与正常饮食对照组相比，它们的 LV 肥大伴有更高的 LV PAI-1 和更低的 LV 肌酸激酶。与 HFD 载体对照组相比，药物治疗可减少主动脉缩窄后 LV 壁厚度、肥大和 PAI-1，并增加心输出量。因此，阿齐沙坦对接受 LV 压力超负荷的肥胖胰岛素抵抗小鼠的心脏产生了有利的生物学作用，这与其在具有类似情况的患者中的潜在用途一致。
