摘要
目的 研究藏红花酸(crocetin acid, CA)对大鼠实验性房颤(atrial fibrillation, AF)的影响,并探究其离子通道层面的作用机制。方法 用氯化钙-乙酰胆碱给药法诱导体内阵发性AF大鼠模型;使用Langendorff逆行灌流、单酶解消化急性分离大鼠心房肌细胞,应用全细胞膜片钳技术记录、观察和分析不同浓度CA对大鼠心房肌细胞瞬时外向钾通道电流(I_(to))的影响。结果 与对照组相比,不同剂量的CA预处理组均延长了模型动物AF诱导时间,降低了AF持续时间。膜片钳实验结果表明,25μmol·L^(-1)的CA对I_(to)无显著影响,当其剂量增加到50μmol·L^(-1)以上时则能显著抑制I_(to)。其中50、100、200μmol·L^(-1)的CA可使I_(to)峰值由给药前(71.10±7.28)pA/pF分别降为(55.49±2.34)pA/pF、(35.56±7.57)pA/pF和(14.69±1.95)pA/pF(P<0.01),表现出明显的浓度依赖性抑制。动力学研究方面,各浓度的CA可使I_(to)的电流-电压关系曲线(I-V曲线)明显下移,但不改变其激活电位、峰值电位和反转电位。能使稳态激活曲线显著右移,半数激活电压(V_(1/2-active))降低(P<0.01)。稳态失活曲线显著左移,半数失活电压(V_(1/2-inactive))降低(P<0.01),而失活后恢复曲线则右移,恢复时间常数(τ)延长(P<0.05)。以上结果显示,CA能够抑制大鼠实验性AF的产生,并抑制I_(to)的激活、失活及失活后动力学过程。结论 CA具有抗药物诱导的AF作用,此效应可能与其抑制I_(to),并改变其动力学过程有关。
OBJECTIVE To study the effect of crocetin acid(CA)on experimental atrial fibrillation in rats and the mechanism of effect at the ion channel level.METHODS Rat model of paroxysmal atrial fibrillation(AF)was induced by administration of calcium chloride⁃acetylcholine.Atrial myocardial was digested by single enzymatic perfusate on the Langendorff device.Whole⁃cell patch clamp techniques was used to record the effects of different concentrations of CA onI_(to)and its kinetics in rat atrial myocytes.RESULTS Com⁃pared with the control group,all groups of CA pretreatment prolonged the induction of AF and reduced the duration of AF.The results of the patch clamp experiment showed that CA had no significant effect onI_(to)at 25μmol·L^(-1).When the concentration of CA was increased to above 50μmol·L^(-1),the peak ofI_(to)was significantly inhibited,decreasing from(71.10±7.28)pA/pF to(55.49±2.34)pA/pF,(35.56±7.57)pA/pF,and(14.69±1.95)pA/pF by CA of 50μmol·L^(-1),100μmol·L^(-1),and 200μmol·L^(-1),respectively(P<0.01),in a concentration⁃dependent manner.CA down⁃regulated the current⁃voltage relationship(I⁃V)curve ofI_(to),but activation potential,peak potential,and reversal potential ofI_(to)had no change.CA shifted the activation curve ofI_(to)to the depolarized direction,with significantly decreased half activation voltage(V_(1/2⁃a))(P<0.01).CA shifted the inactivation curve ofI_(to)to the hyperpolarized direc⁃tion,with significantly decreased half inactivation voltage(V_(1/2⁃in))(P<0.01).In addition,CA significantly prolonged the recovery con⁃stant time(τ)afterI_(to)inactivation(P<0.05).These results indicated that CA could alleviate experimental atrial fibrillation in rats and inhibit the current density,activation,inactivation,and recovery processes ofI_(to).CONCLUSION CA has an antagonism effect on drug⁃induced atrial fibrillation by inhibitingI_(to)and regulating gating kinetic ofI_(to).
作者
王洁如
顾有为
许正新
WANG Jie-ru;GU You-wei;XU Zheng-xin(Department of Pharmacology,School of Medicine,Yangzhou University,Yangzhou225000,China;Key Laboratory of Integrative Medicine in Geriatrics Control of Jiangsu Province,Yangzhou225001,China;Jiangsu Key Laboratory of Non-coding RNA Basic and Clinical Transformation,Yangzhou225009,China)
出处
《中国药学杂志》
CAS
CSCD
北大核心
2023年第9期792-798,共7页
Chinese Pharmaceutical Journal
基金
国家自然科学基金项目资助(82174129)
扬州大学大学生科技创新基金重点项目资助(X20210726)。
