Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes
Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes
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DOI：
10.1016/s0735-1097(96)00377-4
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发表时间：
1996-12-01
影响因子：
24
通讯作者：
Yan, GX
中科院分区：
文献类型：
--
作者：
Antzelevitch, C;Sun, ZQ;Yan, GX
目标。本研究旨在阐明红霉素诱导的长QT综合征的细胞和离子基础。众所周知，红霉素可在心电图（ECG）上产生较长的QTU间隔，并与点扭转（TdP）的发生有关。这种广泛使用的抗生素产生不良反应的机制尚不清楚。本研究采用微电极和全细胞贴片湿润技术评估红霉素对心外膜、心内膜和M细胞的影响，这些细胞分别来自犬左心室的经壁条带、动脉灌注楔形和单个肌细胞。在分离条中，红霉素（10 ~ 100 μ g/ml）使M细胞的动作电位持续时间（APD）比心内膜细胞和心外膜细胞的动作电位持续时间（APD）明显延长，导致在缓慢刺激速率下复极在心室壁上大量分散。红霉素（50 ~ 100 μ g/ml）可诱导M区（20%）细胞早期后去极化（EADs），但对经壁心室游离壁条带心外膜或心内膜区无影响；红霉素（100 μ g/ml）也可引起犬左心室完整动脉灌注楔形APD延长和复极的经壁弥散，但未引起EADs，这些变化与经壁心电图QT间期延长有关。与TdP相似的多形性室性心动过速在红霉素作用后容易和可重复性地被诱导，而在红霉素作用前则不然。全细胞膜片钳技术用于检查红霉素对hf区分离的肌细胞的影响，显示药物对延迟整流钾电流（I-K）的快速激活成分（I-Kr）有抑制作用，但对缓慢激活成分（I-Ks）没有抑制作用。向内整流电流（I-KI）未受影响，结论。我们的数据表明M细胞对红霉素的III类作用有优先反应，这主要是由于红霉素在大量缺乏i - k的细胞群中抑制I-Kr的作用。我们的研究结果表明，红霉素因此产生较长的QT间期以及心室厅复极的显著分散，为tdp样速性心律失常的诱导奠定了基础，表现出典型的再入性特征。(C) 1996年由美国心脏病学会颁发
Objectives. This study sought to elucidate the cellular and ionic basis for erythromycin-induced long QT syndrome.Background. Erythromycin is known to produce long QTU intervals on the electrocardiogram (ECG) and to be associated with the development of torsade de pointes (TdP). The mechanisms responsible far the adverse effects of this widely used antibiotic are not well defined,Methods. The present study used microelectrode and whole-cell patch-damp techniques to assess the effects of erythromycin an epicardial, endocardial and M cells in transmural strips, arterially perfused wedges and single myocytes isolated from the canine left ventricle,Results. In isolated strips, erythromycin (10 to 100 mu g/ml) produced a much more pronounced prolongation of the action potential duration (APD) in M cells than in endocardial and epicardial cells, resulting in the development of a large dispersion of repolarization across the ventricular wall at slow stimulation rates, Erythromycin (50 to 100 mu g/ml) induced early afterdepolarizations (EADs) in cells in the M (20%) but not epicardial or endocardial regions in transmural strips of ventricular free wall, Erythromycin (100 mu g/ml) also caused APD prolongation and a transmural dispersion of repolarization, but not EADs, in intact arterially perfused wedges of canine left ventricle, These changes Here attended br the development of a long QT interval on the transmural ECG, A polymorphic ventricular tachycardia closely resembling TdP was readily and reproducibly induced after erythromycin but not before. Whole-cell patch-clamp techniques, used to examine the effects of erythromycin on myocytes isolated from the hf region, showed a potent effect of the drug to inhibit the rapidly activating component (I-Kr) but not the slowly activating component (I-Ks) of the delayed rectifier potassium current (I-K). The inward rectifier current (I-KI) Has unaffected,Conclusions. Our data demonstrate a preferential response of M cells to the class III actions of erythromycin, due principally to the effect of the drug to inhibit I-Kr in a population of cells largely devoid of I-Ks. Our findings indicate that erythromycin thus produces long QT intervals as well as a prominent dispersion of repolarization across the ventricular Hall, setting the stage for induction of TdP-like tachyarrhythmias displaying characteristics typical of reentry. (C) 1996 by the American College of Cardiology