Antzelevitch C, Sun Z Q, Zhang Z Q, Yan G X
Masonic Medical Research Laboratory Utica, New York 13501, USA.
J Am Coll Cardiol. 1996 Dec;28(7):1836-48. doi: 10.1016/S0735-1097(96)00377-4.
This study sought to elucidate the cellular and ionic basts for erythromycin-induced long QT syndrome.
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 for the adverse effects of this widely used antibiotic are not well defined.
The present study used microelectrode and whole-cell patch-clamp techniques to assess the effects of erythromycin on epicardial, endocardial and M cells in transmural strips, arterially perfused wedges and single myocytes isolated from the canine left ventricle.
In isolated strips, erythromycin (10 to 100 micrograms/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 micrograms/ml) induced early after depolarizations (EADs) in cells in the M (20%) but not epicardial or endocardial regions in transmural strips of ventricular free wall. Erythromycin (100 micrograms/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 were attended by 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 M region, showed a potent effect of the drug to inhibit the rapidly activating component (IK(r)) but not the slowly activating component (IKs) of the delayed rectifier potassium current (IK). The inward rectifier current (IK1) was unaffected.
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 IK(r) in a population of cells largely devoid of IKs. Our findings indicate that erythromycin thus produces long QT intervals as well as a prominent dispersion of repolarization across the ventricular wall, setting the stage for induction of TdP-like tachyarrhythmias displaying characteristics typical of reentry.
本研究旨在阐明红霉素诱发长QT综合征的细胞和离子基础。
已知红霉素可使心电图（ECG）上的QT间期延长，并与尖端扭转型室速（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未明确。
本研究采用微电极和全细胞膜片钳技术，评估红霉素对犬左心室跨壁条带、动脉灌注楔形组织和分离的单个心肌细胞中的心外膜、心内膜和M细胞的影响。
在分离的条带中，红霉素（10至100微克/毫升）使M细胞动作电位时程（APD）的延长比心内膜和心外膜细胞更明显，在缓慢刺激频率下导致整个心室壁复极化离散度增大。红霉素（50至100微克/毫升）在心室游离壁跨壁条带的M区（20%）细胞中诱发早期后除极（EADs），但在心外膜或心内膜区域未诱发。红霉素（100微克/毫升）在犬左心室完整的动脉灌注楔形组织中也导致APD延长和复极化跨壁离散，但未诱发EADs。这些变化伴随着跨壁ECG上QT间期延长。在给予红霉素后而非之前，很容易且可重复地诱发一种酷似TdP的多形性室性心动过速。用于检测红霉素对从M区分离的心肌细胞影响的全细胞膜片钳技术显示，该药物对延迟整流钾电流（IK）的快速激活成分（IK(r)）有强效抑制作用，但对缓慢激活成分（IKs）无抑制作用。内向整流电流（IK1）未受影响。
我们的数据表明，M细胞对红霉素Ⅲ类作用存在优先反应，主要是因为该药物在很大程度上缺乏IKs的一群细胞中抑制IK(r)的作用。我们的研究结果表明，红霉素因此产生长QT间期以及整个心室壁复极化的显著离散，为诱发具有典型折返特征的TdP样快速性心律失常奠定了基础。
