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目的评价桂皮酸类化合物咖啡酸和阿魏酸对内皮素(ET_1)生物效应的拮抗作用并初步探讨其拮抗ET_1的作用机理。方法用咖啡酸与阿魏酸腹腔注射及静脉注射给药后观察其对ET_1致小鼠急性死亡以及对大鼠升压效应、对离体主动脉条的收缩效应的拮抗作用 ;口服给药后考察其对醋酸去氧皮质酮(DOCA)_盐高血压大鼠ET_1的作用 ,并对DOCA_盐高血压动物模型ET_1血浆浓度、血压和动物体重变化及心血管组织增生的影响 ;对ET_1、c_fos、热休克蛋白(HSP70)mRNA基因表达的影响。结果咖啡酸和阿魏酸腹腔注射给药后能显著延长ET_1致小鼠急性死亡时间 ,与对照组相比该作用具剂量依赖性 ;静脉注射给药后能拮抗ET_1引起的正常大鼠升压效应 ;在离体器官上可观察到咖啡酸与阿魏酸能拮抗ET_1的缩血管效应 ;咖啡酸和阿魏酸长期口服给药能降低DOCA_盐高血压模型大鼠的血压、对心脏和血管的组织增生有明显的抑制作用 ;可降低血浆中ET_1的浓度并可减少ET_1引起的c_fos、HSP70mRNA基因表达的增加 ;放射性受体 -配体结合实验表明 ,咖啡酸和阿魏酸可竞争性地抑制ET_1与其受体结合。结论咖啡酸和阿魏酸为新的非肽类ET_1拮抗剂。
Objective To evaluate the antagonistic effect of cinnamon acids caffeic acid and ferulic acid on the biological effects of endothelin (ET_1) and to explore the mechanism of its antagonism of ET_1. Methods After intraperitoneal injection and intravenous administration of caffeic acid and ferulic acid, the antagonistic effects on the acute death of ET1-induced mice and on the vasopressors in rats and on the contractions of isolated aortic strips were observed. After oral administration To investigate its effect on ET_1 in DOCA-salt hypertensive rats, and its effect on ET_1 plasma concentration, blood pressure and body weight changes and cardiovascular tissue hyperplasia in DOCA-salt hypertensive animal model; c_fos, heat shock protein (HSP70) mRNA gene expression. Results The intraperitoneal injection of caffeic acid and ferulic acid could significantly prolong the acute death time of mice induced by ET 1, which was dose-dependent compared with the control group. The intravenous injection could antagonize the normal rats induced by ET 1 Effects of caffeic acid and ferulic acid on the vasoconstriction of ET_1 were observed in isolated organs. Long-term oral administration of caffeic acid and ferulic acid could decrease the blood pressure of DOCA-salt hypertensive rats, Vascular tissue hyperplasia significantly inhibited; can reduce plasma concentrations of ET 1 and ET 1 can reduce the c_fos, HSP70mRNA gene expression increased; radioactive receptor - ligand binding experiments show that caffeic acid and ferulic acid competitive Inhibits ET-1 binding to its receptor. Conclusion Caffeic acid and ferulic acid are new non-peptide ET1 antagonists.