目的:观察积雪草苷对大鼠血压和胸主动脉舒张功能的影响,并探讨其作用机制。
方法:SD大鼠每日灌胃50和100mg/kg积雪草苷2周,监测收缩压变化,采用HE染色评价胸主动脉的组织学变化。在孤立的大鼠内皮完整和内皮裸露的胸主动脉环中,在基线和去甲肾上腺素(NE)-和KCl-诱导的收缩后,测试积雪草苷对主动脉环舒张的影响.在用L-硝基精氨酸甲酯预处理的NE刺激的内皮完整大鼠主动脉环中进一步观察到积雪草苷的血管舒张作用,吲哚美辛,锌原卟啉IX,四乙基氯化铵,格列本脲,氯化钡,伊比利亚毒素,4-氨基吡啶,或TASK-1-IN-1。用KCl和NE处理主动脉环,然后增加CaCl2的浓度,以研究积雪草苷对外部钙内流和内部钙释放引起的血管收缩的影响。
结果:50和100mg/kg的积雪草苷可显著降低大鼠的收缩压,而不影响胸主动脉的组织形态学。虽然没有明显影响完整内皮的静息主动脉环,100mg/kg的积雪草苷诱导了KCl和NE收缩的环的显着松弛,但是它的作用在内皮完整环和内皮剥脱环之间有所不同。在用吲哚美辛预处理的内皮完整主动脉环中,ZnPPIX,氯化钡,格列本脲,TASK-1-IN-1和4-氨基吡啶,积雪草苷对NE诱导的血管收缩没有显著影响,和四乙基铵,伊比利亚毒素和L-硝基精氨酸甲酯均抑制积雪草苷的松弛作用。在KClandNE处理过的戒指中,积雪草苷明显抑制CaCl2诱导的血管收缩。
结论:积雪草苷通过介导高电导钙激活钾通道开放诱导胸主动脉舒张,促进内皮细胞释放一氧化氮,调节Ca2+流入和流出,从而降低大鼠的收缩压。
OBJECTIVE: To investigate the effect of
asiaticoside on blood pressure and relaxation of thoracic aorta in rats and explore the underlying mechanism.
METHODS: SD rats treated with 50 and 100 mg/kg
asiaticoside by daily gavage for 2 weeks were monitored for systolic blood pressure changes, and histological changes of the thoracic aorta were evaluated using HE staining. In isolated rat endothelium-intact and endothelium-denuded thoracic aorta rings, the effects of asiaticoside on relaxation of the aortic rings were tested at baseline and following norepinephrine (NE)- and KCl-induced constriction. The vascular relaxation effect of
asiaticoside was further observed in NE-stimulated endothelium-intact rat aortic rings pretreated with L-nitroarginine methyl ester, indomethacin, zinc protoporphyrin Ⅸ, tetraethyl ammonium chloride, glibenclamide, barium chloride, Iberiotoxin, 4-aminopyridine, or TASK-1-IN-1. The aortic rings were treated with KCl and NE followed by increasing concentrations of CaCl2 to investigate the effect of asiaticoside on vasoconstriction induced by external calcium influx and internal calcium release.
RESULTS: Asiaticoside at 50 and 100 mg/kg significantly lowered systolic blood pressure in rats without affecting the thoracic aorta histomorphology. While not obviously affecting resting aortic rings with intact endothelium, asiaticoside at 100 mg/kg induced significant relaxation of the rings constricted by KCl and NE, but its effects differed between endothelium-intact and endothelium-denuded rings. In endothelium-intact aortic rings pretreated with indomethacin, ZnPP Ⅸ, barium chloride, glyburide, TASK-1-IN-1 and 4-aminopyridine, asiaticoside did not produce significant effect on NE-induced vasoconstriction, and tetraethylammonium, Iberiotoxin and L-nitroarginine methyl ester all inhibited the relaxation effect of asiaticoside. In KCland NE-treated rings,
asiaticoside obviously inhibited CaCl2-induced vascular contraction.
CONCLUSIONS: Asiaticoside induces thoracic aorta relaxation by mediating high-conductance calcium-activated potassium channel opening, promoting nitric oxide release from endothelial cells and regulating Ca2+ influx and outflow, thereby reducing systolic blood pressure in rats.