Bhullar Khushwant S, Lassalle-Claux Grégoire, Touaibia Mohamed, Rupasinghe H P Vasantha
Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS, Canada B2N 5E3.
Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB, Canada E1A 3E9.
Eur J Pharmacol. 2014 May 5;730:125-32. doi: 10.1016/j.ejphar.2014.02.038. Epub 2014 Mar 11.
Hypertension is a crucial risk factor for cardiovascular diseases and contributes to one third of global mortality. In addition to conventional antihypertensive drugs such as captopril, naturally occurring phytochemicals and their analogs are used for reducing the risk and occurrence of hypertension. Herein, we demonstrate the possible use of caffeic acid and its derivatives in the treatment of hypertension through multi-target modulation of renin-angiotensin-aldosterone system (RAAS). Caffeic acid along with its nineteen novel derivatives, chlorogenic acid, quercetin and captopril were all investigated for the inhibition of renin and angiotensin converting enzyme (ACE) activities and production of aldosterone. Compound 22 with CH2CH(Ph)2 moiety exhibited the strongest renin inhibition (IC50=229µM) among all compounds tested (P≤0.05). Caffeic acid was the weakest renin inhibitor (IC50=5704µM) among all the compounds assayed. Similar to renin inhibition, compound 22 (IC50=9.1µM) also exhibited about 47 times stronger ACE inhibition compared to the parent compound. Analysis of aldosterone revealed that compound 8 with n-Pr moiety was the strongest modulator of aldosterone production among all the derivatives (P≤0.05). Toxicity analysis using human fibroblasts (WI-38 cells) confirmed the non-toxic manifestations of caffeic acid and its derivatives in comparison to clinically used drug captopril.
高血压是心血管疾病的关键危险因素，导致全球三分之一的死亡率。除了卡托普利等传统抗高血压药物外，天然存在的植物化学物质及其类似物也被用于降低高血压的风险和发生率。在此，我们通过对肾素-血管紧张素-醛固酮系统（RAAS）的多靶点调节，证明了咖啡酸及其衍生物在治疗高血压方面的潜在用途。研究了咖啡酸及其19种新型衍生物、绿原酸、槲皮素和卡托普利对肾素和血管紧张素转换酶（ACE）活性以及醛固酮生成的抑制作用。在所有测试化合物中，具有CH2CH(Ph)2部分的化合物22表现出最强的肾素抑制作用（IC50=229µM）（P≤0.05）。咖啡酸是所有测定化合物中最弱的肾素抑制剂（IC50=5704µM）。与肾素抑制作用类似，化合物22（IC50=9.1µM）对ACE的抑制作用也比母体化合物强约47倍。醛固酮分析表明，具有正丙基部分的化合物8是所有衍生物中最强的醛固酮生成调节剂（P≤0.05）。使用人成纤维细胞（WI-38细胞）进行的毒性分析证实，与临床使用的药物卡托普利相比，咖啡酸及其衍生物无毒性表现。
