Synergistic Effect of Ferulic Acid and Z-Ligustilide, Major Components of A. sinensis, on Regulating Cold-Sensing Protein TRPM8 and TPRA1 In Vitro.

Angelica sinensis has been used to attenuate cold-induced cutaneous vasospasm syndrome, such as Raynaud's disease and frostbite, in China for many years. Ferulic acid (PubChem CID: 445858) and Z-ligustilide (PubChem CID: 529865), two major components extracted from Angelica sinensis, had been reported to inhibit vasoconstriction induced by vasoconstrictors. In this study, the pharmacological interaction in regulating cold-induced vascular smooth muscle cell contraction via cold-sensing protein TRPM8 and TRPA1 was analyzed between ferulic acid and Z-ligustilide. Pharmacological interaction on inhibiting [Ca2+]i influx evoked by TRPM8 agonist WS-12 or TRPA1 agonist ASP 7663 as well as cold-induced upregulation of TRPM8 was determined using isobolographic analysis. The isobolograms demonstrated that the combinations investigated in this study produced a synergistic interaction. Combination effect of two components in inhibiting RhoA activation and phosphorylation of MLC20 induced by WS-12 or ASP 7663 was also being quantified. These findings suggest that the therapeutic effect of Angelica sinensis on cold-induced vasospasm may be partially attributed to combinational effect, via TRPM8 and TPRA1 way, between ferulic acid and Z-ligustilide.

当归在中国多年来一直被用于缓解寒冷诱发的皮肤血管痉挛综合征，如雷诺氏病和冻伤。阿魏酸（PubChem CID：445858）和Z - 藁本内酯（PubChem CID：529865）是从当归中提取的两种主要成分，据报道它们可抑制血管收缩剂诱导的血管收缩。在本研究中，分析了阿魏酸和Z - 藁本内酯在通过冷觉感受蛋白TRPM8和TRPA1调节寒冷诱导的血管平滑肌细胞收缩方面的药理相互作用。采用等效线图分析确定了在抑制由TRPM8激动剂WS - 12或TRPA1激动剂ASP 7663诱发的[Ca2+]i内流以及寒冷诱导的TRPM8上调方面的药理相互作用。等效线图表明本研究中所研究的组合产生了协同作用。还对两种成分在抑制由WS - 12或ASP 7663诱导的RhoA激活和MLC20磷酸化方面的联合作用进行了量化。这些发现表明当归对寒冷诱发的血管痉挛的治疗作用可能部分归因于阿魏酸和Z - 藁本内酯之间通过TRPM8和TRPA1途径的联合作用。