Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Diabetes Obes Metab. 2011 Dec;13(12):1123-9. doi: 10.1111/j.1463-1326.2011.01471.x.
Hypertension often coexists with insulin resistance. However, most metabolic effects of the antihypertensive agents have been investigated in nomotensive animals, in which different conclusions may arise. We investigated the metabolic effects of the new angiotensin II type 1 receptor blocker azilsartan using the obese Koletsky rats superimposed on the background of the spontaneously hypertensive rats.
Male Koletsky rats were treated with azilsartan (2 mg/kg/day) over 3 weeks. Blood pressure was measured by tail-cuff. Blood biochemical and hormonal parameters were determined by enzymatic or ELISA methods. Gene expression was assessed by RT-PCR.
In Koletsky rats, azilsartan treatment lowered blood pressure, basal plasma insulin concentration and the homeostasis model assessment of insulin resistance index, and inhibited over-increase of plasma glucose and insulin concentrations during oral glucose tolerance test. These effects were accompanied by decreases in both food intake and body weight (BW) increase. Although two treatments showed the same effect on BW gain, insulin sensitivity was higher after azilsartan treatment than pair-feeding. Azilsartan neither affected plasma concentrations of triglyceride and free fatty acids, nor increased adipose mRNA levels of peroxisome proliferator-activated receptor (PPAR)γ and its target genes such as adiponectin, aP2. In addition, azilsartan downregulated 11β-hydroxysteroid dehydrogenase type 1 expression.
These results show the insulin-sensitizing effect of azilsartan in obese Koletsky rats. This effect is independent of decreases in food intake and BW increase or of the activation of adipose PPARγ. Our findings indicate the possible usefulness of azilsartan in the treatment of metabolic syndrome.
高血压常伴有胰岛素抵抗。然而，大多数降压药物的代谢作用都是在非高血压动物中进行研究的，可能会得出不同的结论。我们使用肥胖的科列索斯基大鼠（Koletsky rats）叠加自发性高血压大鼠（spontaneously hypertensive rats）的背景，研究了新型血管紧张素 II 型 1 型受体阻滞剂阿齐沙坦的代谢作用。
雄性科列索斯基大鼠用阿齐沙坦（2mg/kg/天）治疗 3 周。通过尾套测量血压。通过酶法或 ELISA 法测定血液生化和激素参数。通过 RT-PCR 评估基因表达。
在 Koletsky 大鼠中，阿齐沙坦治疗降低了血压、基础血浆胰岛素浓度和胰岛素抵抗评估的稳态模型，抑制了口服葡萄糖耐量试验期间血浆葡萄糖和胰岛素浓度的过度增加。这些作用伴随着食物摄入量和体重增加的减少。尽管两种治疗方法对体重增加都有相同的作用，但阿齐沙坦治疗后的胰岛素敏感性高于配对喂养。阿齐沙坦既不影响甘油三酯和游离脂肪酸的血浆浓度，也不增加脂肪组织过氧化物酶体增殖物激活受体（PPAR）γ及其靶基因如脂联素、aP2 的 mRNA 水平。此外，阿齐沙坦下调了 11β-羟甾类脱氢酶 1 的表达。
这些结果表明阿齐沙坦在肥胖科列索斯基大鼠中具有胰岛素增敏作用。这种作用独立于食物摄入量和体重增加的减少或脂肪组织 PPARγ 的激活。我们的发现表明阿齐沙坦在治疗代谢综合征方面可能有用。
