Li Yong-Qi, Ji Hui, Zhang Yi-Hua, Shi Wei-Bing, Meng Zhao-Ke, Chen Xiu-Ying, Du Guan-Tao, Tian Jide
Department of Pharmacology, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, PR China.
Eur J Pharmacol. 2007 Dec 22;577(1-3):100-8. doi: 10.1016/j.ejphar.2007.08.008. Epub 2007 Aug 14.
Angiotensin converting enzyme (ACE) inhibitors usually cause severe coughing and intolerance while antagonists for angiotensin AT(1) receptor do not stimulate the production of nitric oxide (NO). NO has been shown to regulate arterial hypertension and insulin resistance. Hence, new hybrids of antagonist for angiotensin AT(1) receptor and a NO donor may have potent anti-hypertensive effect and regulate glucose metabolism and insulin resistance. Herein, the effects of [6-(nitrooxymethyl)pyridin-2-yl] methyl 4'-[1-(1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzo[d]imidazol-3'-yl)ethyl] biphenyl-2-carboxylate (WB1106), a novel NO-releasing derivative of telmisartan newly synthesized, on the vasocontraction, hypertension and diet-induced insulin resistance were examined in vitro using rat aortic strips and in normotensive and spontaneous hypertension rats (SHR rats). Apparently, WB1106 induced the vasorelaxation of contracted rat aortic strips in a dose- and time-dependent manner, which depended on the activity of guanylate cyclase, a characteristic of NO-related function. Furthermore, WB1106 reduced the contractile and blood pressure responses to angiotensin II, which relied on the release of telmisartan. Moreover, treatment with WB1106 significantly reduced the blood pressure with similar potency to telmitarsan and increased the contents of cGMP in SHR rats. Therefore, WB1106 possesses both the angiotensin AT(1) receptor antagonist activity of telmisartan and the NO-releasing property of a 'slow NO donor'. Importantly, in contrast to equimolar telmisartan, treatment with WB1106 significantly attenuated body weight gains and improved glucose tolerance in high-fat and carbohydrate-fed rats, reflecting a synergistic effect of NO and telmisartan. Potentially, WB1106 may be a potent anti-hypertensive drug for treatment of hypertension and diabetes-related cardiovascular diseases in the clinic.
血管紧张素转换酶（ACE）抑制剂通常会引起严重咳嗽和不耐受，而血管紧张素AT（1）受体拮抗剂不会刺激一氧化氮（NO）的产生。NO已被证明可调节动脉高血压和胰岛素抵抗。因此，血管紧张素AT（1）受体拮抗剂与NO供体的新型杂合物可能具有强大的抗高血压作用，并调节葡萄糖代谢和胰岛素抵抗。在此，使用大鼠主动脉条在体外以及在正常血压和自发性高血压大鼠（SHR大鼠）中，研究了新合成的替米沙坦新型NO释放衍生物[6 - （硝基氧甲基）吡啶 - 2 - 基]甲基4'-[1 - （1,7'-二甲基 - 2'-丙基 - 1H，3'H - 2,5'-联苯并[d]咪唑 - 3'-基）乙基]联苯 - 2 - 羧酸酯（WB1106）对血管收缩、高血压和饮食诱导的胰岛素抵抗的影响。显然，WB1106以剂量和时间依赖性方式诱导收缩的大鼠主动脉条血管舒张，这取决于鸟苷酸环化酶的活性，这是NO相关功能的一个特征。此外，WB1106降低了对血管紧张素II的收缩和血压反应，这依赖于替米沙坦的释放。而且，用WB1106治疗可显著降低血压，其效力与替米沙坦相似，并增加SHR大鼠中cGMP的含量。因此，WB1106兼具替米沙坦的血管紧张素AT（1）受体拮抗剂活性和“慢NO供体”的NO释放特性。重要的是，与等摩尔的替米沙坦相比，用WB1106治疗可显著减轻高脂和高碳水化合物喂养大鼠的体重增加并改善葡萄糖耐量，这反映了NO和替米沙坦的协同作用。潜在地，WB1106可能是一种有效的抗高血压药物，用于临床治疗高血压和糖尿病相关的心血管疾病。
