钙调蛋白拮抗剂W-7抑制索他洛尔诱发离体兔心尖端扭转型室性心动过速  

Calmodulin antagonist inhibits torsade de pointes induced by d-sotalol in an isolated rabbit heart model

作　　者：卜军[1] 张存泰[1] 白融[1] 刘念[1] 李泱[1] 王琳[1] 

机构地区：[1]华中科技大学同济医学院附属同济医院心内科

出　　处：《中华心血管病杂志》2005年第4期364-368,共5页Chinese Journal of Cardiology

基　　金：国家自然科学基金资助项目(30470714);湖北省自然科学基金资助项目(2004ABA230)

摘　　要：目的　观察钙调蛋白拮抗剂W -7对离体兔心实验性尖端扭转型室性心动过速(TdP)的影响,并探讨其机制。方法　采用Langendorff灌流技术,在三度房室传导阻滞和低钾(1 .5mmol/L)、低镁(0 .35mmol/L)的条件下,用索他洛尔(30μmol/L)灌流离体雌兔心脏,建立TdP模型。36只雌兔心脏随机分为索他洛尔组和W 7低浓度( 20μmol/L)、中浓度( 50μmol/L)、高浓度( 100μmol/L)干预组,每组各9只兔。灌流全程同步记录不同起搏周长下的心电图和左室内、中、外三层心肌的单相动作电位复极时程,并观察各组QT间期、跨室壁心肌复极离散度(TDR)、早期后除极(EAD)和TdP的诱发率。结果　索他洛尔逆频率依赖性延长兔QT间期和增大左室三层心肌TDR,并有较高的EAD(100% )和TdP(78% )诱发率。W 7浓度依赖性地抑制EAD诱发率(20μmol/L为56%, 50μmol/L为44%, 100μmol/L为11% )和TdP诱发率(20μmol/L为44%, 50μmol/L为22%,100μmol/L为11% ),但对QT间期和TDR均无影响。结论　抑制钙调蛋白活性能够抑制离体兔心实验性TdP的发生,这种作用主要通过抑制EAD的机制而非通过影响跨室壁复极异质性的机制来发挥。Objective To evaluate the effects of W-7, a calmodulin inhibiter, on transmural dispersion of repolarization (TDR), early afterdepolarization (EAD) and torsade de pointes (TdP) induction after administration of d-sotalol in isolated rabbit heart.Methods TdP was induced by d-sotalol (30 μmol/L), bradycardia, and hypokalemic (1.5 mmol/L)/ hypomagnesaemic (0.35 mmol/L) solution in isolated female rabbit hearts. Thirty six rabbit hearts were divided into 4 groups (n= 9 each) : d-sotalol alone, d-sotalol + W-7(20 μmol/L), d-sotalol + W-7(50 μmol/L), and d-sotalol + W-7(100 μmol/L). Monophasic action potentials (MAPs) of the left ventricular epimyocardium (Epi), midmyocardium (M), and endomyocardium (Endo) were recorded simultaneously with ECG. The incidence of EAD and TdP were observed as well.Results Treatment with d-sotalol alone prolonged ventricular MAP duration and QT interval, increased TDR, and evoked high incidence of EAD (9/9) and spontaneous TdP (7/9) in hypokalemic /hypomagnesaemic solution in female rabbit heart. W-7 concentration -dependently decreased incidence of TdP (4/9 in 20 μmol/L; 2/9 in 50 μmol/L; 1/9 in 100 μmol/L). This effect of W-7 coincided with the decreased incidence of EAD(5/9 in 20 μmol/L ;4/9 in 50 μmol/L; 1/9 in 100 μmol/L). However, the d-sotalol-induced prolongation of QT interval and TDR was not significantly altered by W-7 at the three concentration used.Conclusions In isolated female rabbit hearts, calmodulin antagonist W-7 suppresses d-sotalol-induced TdP without altering TDR but does suppress EAD. The effects observed with W-7 also suggest a possible important role for calmodulin-activated enzymes in the induction of TdP.

关 键 词：尖端扭转型室性心动过速 钙调蛋白拮抗剂 索他洛尔 离体兔心 抑制 Langendorff mol/L 三度房室传导阻滞 心肌复极离散度 单相动作电位 QT间期 逆频率依赖性 早期后除极 浓度依赖性 复极异质性 TdP 诱发率 同步记录 复极时程 

分 类 号：R541.7[医药卫生—心血管疾病]