摘要
目的探讨硝苯地平与组蛋白去乙酰化酶8抑制剂PCI-34051联合用药对左旋硝基精氨酸诱导的高血压大鼠模型的降压效果,并探讨其降压机制。方法选用7周龄,SPF级,重量165~210g,雄性Wistar大鼠50只,采用腹腔注射左旋硝基精氨酸方法复制高血压大鼠模型,设立正常组、模型组、硝苯地平组(0.5 mg/Kg)、PCI-34051组(0.7 mg/Kg)、硝苯地平与PCI-34051联合用药组(0.5 mg/Kg+0.7 mg/Kg),每组10只。采用无创性套尾法测定大鼠清醒状态下尾动脉血压及心率,酶联免疫吸附法测定大鼠血清内皮素(ET-1)、一氧化氮(NO)、肾素(Renin)、血管紧张素Ⅱ(AngⅡ)和醛固酮(ALD)的含量;H&E染色评估主要器官的毒性情况。结果与模型组比较,单次给药24 h和连续给予4周后,硝苯地平组、PCI-34051和联合用药组均降低收缩压和舒张压,并降低血清ET-1、Ang Ⅱ和ALD水平,提高NO水平(均P<0.05),其中联合用药的降压效果显著强于单用硝苯地平组或PCI-34051组(P<0.05)。此外,与正常组比较,硝苯地平组加快了实验大鼠的心率(P<0.05),而PCI-34051组和联合用药组则对心率无显著性影响(P>0.05);硝苯地平组对肾素没有影响(P>0.05),而PCI-34051组和联合用药组能够降低血清肾素(P<0.05)。结论硝苯地平与组蛋白去乙酰化酶8抑制剂PCI-34051联合用药对左旋硝基精氨酸诱导的高血压大鼠有明显的协同降压作用,其机制与降低血清ET-1,升高NO水平以改善血管内皮功能障碍,降低血清肾素、AngⅡ和ALD水平以抑制肾素-血管紧张素-醛固酮系统活性有关。
Objective To study the effect and its mechanism of anti-hypertensive of combination of nifedipine and histone deacetylase 8 inhibitor PCI-34051 on hypertension rats induced by L-nitro-arginine.Methods Rats for hypertension were induced by injection of L-nitro-arginine,which were treated by nifedipine(0.5 mg/Kg),histone deacetylases inhibitor PCI-34051(0.7 mg/Kg),and nifedipine(0.5 mg/Kg)combined with the PCI-34051(0.7 mg/Kg).The blood pressure and heart rate were measured by tail-cuff,and the contents of serum endothelin(ET-1),nitric oxide(NO),renin,angiotensin Ⅱ(AngⅡ)and aldosterone(ALD)were detected by enzyme-linked immunosorbent assay(ELISA).Results Compared with mode group,nifedipine,PCI-34051 and combination groups had antihypertensive effect.The contents of ET-1,Ang Ⅱ,ALD were decreased and NO was enhanced(P<0.05)after 24 h of single administration or successive administration for 4 weeks.Among the three groups,the anti-hypertensive effect of combination group was significantly stronger than that of nifedipine or PCI-34051 alone(P<0.05).In addition,compared with the normal group,nifedipine group accelerated the heart rate of experimental rats(P<0.05),while there was no significant effect in PCI-34051 and combination groups(P>0.05).The nifedipine group had no effect on renin(P>0.05),but which was decreased in PCI-34051 and combination groups(P<0.05).Conclusion Nifedipine combined with histone deacetylase 8 inhibitor PCI-34051 has a synergistic antihypertensive effect on rats induced by L-nitro-arginine.The mechanism is related to the improvement in dysfunction of blood vessel endothelium by lowering serum ET-1,elevating serum NO contents,and the inhibition of RAAS system activity by reducing serum renin,Ang Ⅱ and ALD contents.
作者
王晓媚
陈丽
韩兆洋
卫娜
徐阳
艾美梅
WANG Xiaomei;CHEN Li;HAN Zhaoyang;WEI Na;XU Yang;AI Meimei(Department of Emergency,Xijing Hospital,The First Affiliated Hospital of Air Force Medical University,Xi’an 710032,China)
出处
《西部医学》
2019年第12期1851-1855,1861,共6页
Medical Journal of West China
