Department of Cardiology, Fukuoka University School of Medicine, Jonan-ku, Fukuoka, Japan.
J Renin Angiotensin Aldosterone Syst. 2012 Mar;13(1):76-83. doi: 10.1177/1470320311417478. Epub 2011 Aug 8.
Angiotensin II (Ang II) binds to Ang II type 1 (AT(1)) receptor and evokes cell signaling, and subsequently stimulates vasoconstriction and cell proliferation, which eventually lead to cardiovascular disease. Since most AT(1) receptor blockers (ARBs) have molecular (differential) effects, we evaluated the specific features of candesartan and compared the abilities of candesartan and other ARBs (olmesartan, telmisartan, valsartan, irbesartan and losartan) to bind to and activate AT(1) receptors using a cell-based wash-out assay. Each ARB blocked Ang II-induced extracellular signal-regulated kinase (ERK) activation and inositol phosphate production to different degrees after wash-out. In addition, a small difference in the molecular structure, i.e. a carboxyl group, between candesartan and candesartan-7H was associated with a difference in the degree of this blocking effect. In addition, interaction between Gln(257) in the AT(1) receptor and the carboxyl group of candesartan may be partially associated with the effect of candesartan after wash-out. Although our findings regarding the molecular effects of ARB are based on basic research, these findings may lead to an exciting new area in the clinical application of ARBs.
血管紧张素 II（Ang II）与血管紧张素 II 型 1（AT(1)）受体结合并引发细胞信号转导，随后刺激血管收缩和细胞增殖，最终导致心血管疾病。由于大多数 AT(1)受体阻滞剂（ARB）具有分子（差异）作用，我们评估了坎地沙坦的特异性，并使用基于细胞的洗脱测定法比较了坎地沙坦和其他 ARB（奥美沙坦、替米沙坦、缬沙坦、厄贝沙坦和氯沙坦）与 AT(1)受体结合和激活的能力。在洗脱后，每种 ARB 都不同程度地阻断了 Ang II 诱导的细胞外信号调节激酶（ERK）激活和肌醇磷酸生成。此外，坎地沙坦和坎地沙坦-7H 之间分子结构上的微小差异，即羧基，与这种阻断作用的程度差异有关。此外，AT(1)受体中的 Gln(257)与坎地沙坦的羧基之间的相互作用可能与洗脱后坎地沙坦的作用部分相关。尽管我们关于 ARB 分子作用的发现基于基础研究，但这些发现可能会为 ARB 的临床应用开辟一个令人兴奋的新领域。
