摘要
目的探讨维拉帕米治疗2型长QT综合征(LQT2)的作用机制。方法制备兔左心室楔形心肌块,稳定1 h后灌注E-4031 0.5μmol·L-1建立LQT2心肌块模型;同时按照分组分别灌注维拉帕米0.5,1.0和2.5μmol·L-1,30 min后开始采集数据,采集时间持续30 min。以2000 ms基础步长连续起搏(S1S1刺激),同步记录心内、外膜下心肌的跨膜动作电位和跨壁心电图,测量动作电位复极达90%的时程(APD90)、跨壁复极离散度(TDR)和心电图QT间期,并观察各组自发和程序刺激(S1S2刺激)诱发的早期后除极(EAD)和尖端扭转型室速(TdP)的发生率。结果灌注E-4031 0.5μmol·L-1后,左心室楔形心肌块心内、外膜下APD90和QT间期均显著延长(P<0.01),TDR显著增加(P<0.01),并观察到自发或程序刺激诱发的EAD及TdP发作。同时灌注维拉帕米0.5,1.0和2.5μmol·L-1,LQT2模型内、外膜下心肌APD90和QT间期呈浓度依赖性地缩短(P<0.01),TDR显著减小(P<0.01),自发或程序刺激诱发的EAD和TdP明显受到抑制。硝苯地平1.0μmol·L-1有类似作用,且强度更大。结论维拉帕米可通过缩小心肌TDR和抑制EAD减少LQT2患者TdP的发生。
OBJECTlVE To investigate the mechanism of verapamil in the treatment of type 2 Iong QT syndrome（LQT2）using a rabbit Ieft ventricuIar myocardial wedge preparation. METHODS E-4031 （0.5 μmol·L-1 ）was used to induce the LQT2 model after rabbit Ieft ventricuIar wedge preparations were equilibrated for 1 h,and verapamil（0.5,1.0 and 2.5 μmol·L-1 ,respectively）was perfused in different groups. Data were colIected for a period of 30 min starting 30 min after adding the respective drug. Transmembrane action potentials of endocardial and epicardial myocardium were recorded simuItaneously at a basic cycIe Iength of 2000 ms（S1S1）together with a transmural ECG. The effect of verapamil （0.5,1.0 and 2.5 μmol·L-1 ）on action potential duration at 90% repolarization（APD90 ）,QT interval, transmural dispersion of repolarization（TDR）and the development of earIy afterdepolarization（EAD） and torsades de pointes（TdP）were evaluated in the LQT2 myocardial wedge model. RESULTS E-4031 （0.5 μmol·L-1 ）markedIy prolonged endocardial and epicardial APD90 and QT interval（ P﹤0.01）,and dramaticalIy increased TDR（P﹤0.01）. Spontaneous or programmed electrical stimuIation-induced EAD and TdP were also observed in the model. Verapamil（0.5,1.0 and 2.5 μmol·L-1 ）dose-dependentIy abbreviated endocardial and epicardial APD90 and QT interval（P﹤0.01）,significantIy decreased TDR（P﹤0.01）,and suppressed EAD and TdP in the LQT2 model. Concordant but stronger effects on the electro-physiological properties of the LQT2 model were noticed when nifedipine was perfused. CONCLUSlON Verapamil inhibits TdP in the LQT2 model by reducing TDR and suppressing EAD.
出处
《中国药理学与毒理学杂志》
CAS
CSCD
北大核心
2014年第4期503-509,共7页
Chinese Journal of Pharmacology and Toxicology
基金
国家自然科学基金项目(81370290)~~
关键词
维拉帕米
2
型长
QT
综合征
跨壁复极离散度
尖端扭转型室速
verapamiI
type 2 Iong QT syndrome
transmuraI dispersion of repoIarization
torsades de pointes
