非抗心律失常药物诱发LQT及室性心律失常电生理学机制的系列研究
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摘要
实验背景及目的 QT间期延长综合征(LQT)患者可因严重的室性心律失常，如尖端扭转型室速(torsade de pointes)、室颤而出现晕厥、抽搐，甚至心源性猝死。LQT根据发病机制可分为遗传性和继发性两种。继发性LQT主要是由药物的副作用引发，特别是抗心律失常药，如奎尼丁，但也有非抗心律失常药，如抗精神病药、大环内酯类抗生素或其它药物诱发LQT、甚至猝死的报道。
本实验通过酚噻嗪(抗精神病药)、bepridil(抗心绞痛药)和红霉素(大环内酯类抗生素)对豚鼠单心室肌细胞动作电位时程(APD)及动作电位形成过程中主要离子通道作用的研究，探讨此三类非抗心律失常药物诱发LQT及多形性室性心动过速的电生理学机制。
方法与结果 本实验采用斑片钳(patch-clamp)技术中的Nystatin-破膜法研究了上述三种药物对豚鼠单心室肌细胞APD的作用。我们发现，在5Hz频率刺激的情况下，100μmol／L酚噻嗪使10个实验细胞的APD均明显延长，APD_(90)平均延长25.8％(P＜0.01)，这一延长作用为可逆性的。100μmol／L红霉素不能使APD延长，但300μmol／L的红霉素却使APD_(90)平均延长11.89％(P＜0.05)。0.1μmol／L bepridil使APD明显延长(APD_(90)平均延长18.01％，P＜0.05)，当bepridil在
Background Long QT syndrome (LQT) is a cardiovascular disease that
causes syncope, seizure, and sudden death from cardiac arrhythmias, such
as torsade de pointes, and ventricular fibrillation. LQT can be inherited or
acquired.
Acquired LQT most frequently results from medications, often
antiarrhythmic drugs, such as quinidine. There were also reports of LQT,
even unexpected sudden cardiac death after the administrations of
psychoactive drugs, macrolide antibiotics, or other no-antiarrhythmic
agents.
In order to understand the mechanisms of LQT induced by these no-
antiarrhythmics drugs, we studied the effects of phenothiazine
(psychoactive drug), bepridil (antianginal drug), erythromycin (antibiotics)
on action potential duration (APD) and main currents involved in the
depolarization and repolarization of isolated guinea pig ventricular
myocytes.
Methods and results Effects of the three drugs on APD of single guinea pig ventricular myocytes were studied by using Nystatin-perfortated configuration of the patch-clamp techniques. At a stimulation frequency of 5 Hz, phenothiazine (100 μmol/L) prolonged APD_(90) by % (p<0.01), and the effect was reversible. Erythromycin also prolonged APD, but only at concentration of 300 μmol/L (APD_(90) prolonged 11.89%, p<0.05), 100 μmol/L of erythromycin did not prolong the APD. 0.1 μmol/L bepridil prolonged APD_(90) by 18.01% (p<0.05), but 1 μmol/L and 3 μmol/L bepridil did not change APD compared with that of control, while 10 μmol/L and 30 μmol/L
本实验通过酚噻嗪(抗精神病药)、bepridil(抗心绞痛药)和红霉素(大环内酯类抗生素)对豚鼠单心室肌细胞动作电位时程(APD)及动作电位形成过程中主要离子通道作用的研究，探讨此三类非抗心律失常药物诱发LQT及多形性室性心动过速的电生理学机制。
方法与结果 本实验采用斑片钳(patch-clamp)技术中的Nystatin-破膜法研究了上述三种药物对豚鼠单心室肌细胞APD的作用。我们发现，在5Hz频率刺激的情况下，100μmol／L酚噻嗪使10个实验细胞的APD均明显延长，APD_(90)平均延长25.8％(P＜0.01)，这一延长作用为可逆性的。100μmol／L红霉素不能使APD延长，但300μmol／L的红霉素却使APD_(90)平均延长11.89％(P＜0.05)。0.1μmol／L bepridil使APD明显延长(APD_(90)平均延长18.01％，P＜0.05)，当bepridil在
Background Long QT syndrome (LQT) is a cardiovascular disease that
causes syncope, seizure, and sudden death from cardiac arrhythmias, such
as torsade de pointes, and ventricular fibrillation. LQT can be inherited or
acquired.
Acquired LQT most frequently results from medications, often
antiarrhythmic drugs, such as quinidine. There were also reports of LQT,
even unexpected sudden cardiac death after the administrations of
psychoactive drugs, macrolide antibiotics, or other no-antiarrhythmic
agents.
In order to understand the mechanisms of LQT induced by these no-
antiarrhythmics drugs, we studied the effects of phenothiazine
(psychoactive drug), bepridil (antianginal drug), erythromycin (antibiotics)
on action potential duration (APD) and main currents involved in the
depolarization and repolarization of isolated guinea pig ventricular
myocytes.
Methods and results Effects of the three drugs on APD of single guinea pig ventricular myocytes were studied by using Nystatin-perfortated configuration of the patch-clamp techniques. At a stimulation frequency of 5 Hz, phenothiazine (100 μmol/L) prolonged APD_(90) by % (p<0.01), and the effect was reversible. Erythromycin also prolonged APD, but only at concentration of 300 μmol/L (APD_(90) prolonged 11.89%, p<0.05), 100 μmol/L of erythromycin did not prolong the APD. 0.1 μmol/L bepridil prolonged APD_(90) by 18.01% (p<0.05), but 1 μmol/L and 3 μmol/L bepridil did not change APD compared with that of control, while 10 μmol/L and 30 μmol/L
引文
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