Storka A, Vojtassakova E, Mueller M, Kapiotis S, Haider D G, Jungbauer A, Wolzt M
Department of Clinical Pharmacology, Medical University of Vienna, Austria.
Eur J Clin Invest. 2008 Nov;38(11):820-6. doi: 10.1111/j.1365-2362.2008.02025.x.
Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) exhibit beneficial antidiabetic effects in patients with type 2 diabetes independent of their blood pressure-lowering effects. Some antidiabetic properties of ARB and ACE-I might by exerted by activation of peroxisome proliferator-activated receptor gamma (PPARgamma). However, it is not clear whether this action is drug specific.
The binding affinity of telmisartan, valsartan, lisinopril, rosiglitazone and angiotensin II to PPARgamma was assessed in a cell-free assay system. PPARgamma signalling was studied in isolated skeletal muscle cells using Western blot analysis of phosphorylated protein kinase B (pAKT) and phosphorylated insulin like growth factor-1 receptor (pILGF-1R). Further, the ability of the drugs under study to stimulate the release of the adipocytokine visfatin was investigated in isolated human adipocytes, skeletal muscle cells, and umbilical vein endothelial cells (HUVEC).
The binding affinity to PPARgamma was highest for telmisartan with a half-maximal effective concentration of 463 nM, followed by lisinopril (2.9 microM) and valsartan (6.2 microM). In skeletal muscle cells phosphorylation of ILGF-1R was 2-fold increased after incubation with telmisartan or valsartan and 1.7-fold with lisinopril. pAKT expression was enhanced after incubation with telmisartan, valsartan and with lisinopril. The release of visfatin from adipocytes was 1.6-fold increased after treatment with lisinopril and about 2.0-fold increased with telmisartan and valsartan. Similar results were obtained in skeletal muscle cells and HUVEC.
Our data confirm agonism of telmisartan, valsartan and lisinopril on PPARgamma. Pharmacokinetic differences may explain different potencies of PPARgamma stimulation by drugs acting on the renin-angiotensin system in clinical settings.
血管紧张素转换酶抑制剂（ACE-I）和血管紧张素受体阻滞剂（ARB）在2型糖尿病患者中表现出有益的抗糖尿病作用，与其降压作用无关。ARB和ACE-I的一些抗糖尿病特性可能是通过激活过氧化物酶体增殖物激活受体γ（PPARγ）发挥的。然而，尚不清楚这种作用是否具有药物特异性。
在无细胞检测系统中评估替米沙坦、缬沙坦、赖诺普利、罗格列酮和血管紧张素II与PPARγ的结合亲和力。使用磷酸化蛋白激酶B（pAKT）和磷酸化胰岛素样生长因子-1受体（pILGF-1R）的蛋白质印迹分析，在分离的骨骼肌细胞中研究PPARγ信号传导。此外，在分离的人脂肪细胞、骨骼肌细胞和脐静脉内皮细胞（HUVEC）中研究了所研究药物刺激脂肪细胞因子内脂素释放的能力。
替米沙坦与PPARγ的结合亲和力最高，半数有效浓度为463 nM，其次是赖诺普利（2.9 microM）和缬沙坦（6.2 microM）。在骨骼肌细胞中，与替米沙坦或缬沙坦孵育后，ILGF-1R的磷酸化增加2倍，与赖诺普利孵育后增加1.7倍。与替米沙坦、缬沙坦和赖诺普利孵育后，pAKT表达增强。赖诺普利治疗后，脂肪细胞内脂素的释放增加1.6倍，替米沙坦和缬沙坦增加约2.0倍。在骨骼肌细胞和HUVEC中也获得了类似的结果。
我们的数据证实了替米沙坦、缬沙坦和赖诺普利对PPARγ的激动作用。药代动力学差异可能解释了临床环境中作用于肾素-血管紧张素系统的药物对PPARγ刺激的不同效力。
