Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARγ-modulating activity
Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARγ-modulating activity
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DOI：
10.1161/01.hyp.0000123072.34629.57
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发表时间：
2004-05-01
期刊：
影响因子：
8.3
通讯作者：
Kurtz, TW
中科院分区：
文献类型：
--
作者：
Benson, SC;Pershadsingh, HA;Kurtz, TW
代谢综合征是心血管疾病和 2 型糖尿病的常见先兆，其特征是胰岛素抵抗、血脂异常和血压升高。据报道，在人类中，过氧化物酶体增殖物激活受体-γ (PPARγ) 的突变会导致全面的代谢综合征，而激活 PPARγ 的药物已被证明是预防和治疗胰岛素抵抗和 2 型糖尿病的有效药物。在这里，我们报道了替米沙坦（telmisartan），一种结构独特的血管紧张素 II 受体拮抗剂，用于治疗高血压，可以作为 PPARgamma 的部分激动剂；影响参与碳水化合物和脂质代谢的 PPARgamma 靶基因的表达；并降低喂食高脂肪、高碳水化合物饮食的大鼠的葡萄糖、胰岛素和甘油三酯水平。当以常规口服给药通常在血浆中达到的浓度进行测试时，其他市售血管紧张素 II 受体拮抗剂似乎都没有激活 PPARgamma。与普通抗高血压和抗糖尿病药物相比，能够同时阻断血管紧张素II受体和激活PPARγ的分子具有治疗代谢综合征的血流动力学和生化特征的潜力，并且可以为高危人群的糖尿病和心血管疾病的预防和治疗提供独特的机会。
The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-gamma (PPARgamma) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARgamma have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPARgamma; influence the expression of PPARgamma target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet. None of the other commercially available angiotensin II receptor antagonists appeared to activate PPARgamma when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPARgamma have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations.