Keevil V L, Huang C L, Chau P L, Sayeed R A, Vandenberg J I
Department of Biochemistry, University of Cambridge, UK.
Pflugers Arch. 2000 Jun;440(2):275-82. doi: 10.1007/s004240000264.
Changes in cardiac gap junction expression, such as those following myocardial infarction and produced in connexin knockout mice, are associated with a predisposition to arrhythmias. The present experiments investigated the effects of heptanol, a reversible gap junction inhibitor, on isolated Langendorff-perfused rabbit hearts. The introduction and withdrawal of heptanol inhibited both pressure generation and electrical conduction. These effects were completely reversible. Possible mechanisms for these findings were investigated through measurement of the concentration dependence of heptanol's effects upon conduction velocity and repolarization duration. Low concentrations of heptanol (less than 0.3 mM) caused small but significant increases in the delay between the stimulus (delivered to the basal septum) artefact and local activation of the left ventricle, as measured from bipolar electrogram (BEG) recordings. There was a steep increase in the latency between stimulus and left-ventricular activation at concentrations of heptanol above 0.3 mM. These findings are explicable by earlier reports of heptanol actions on gap junctions in vitro and modelling studies of the effects of reduced gap junction conductance on conduction velocity. Heptanol decreased repolarization duration, measured from the activation recovery interval (ARI) of BEGs, and monophasic action potential duration at 70% repolarization (MAPD70). Heptanol also reduced left-ventricular developed pressure (LVDP), and the maximum rates of contraction and relaxation of the left ventricle; these effects were concentration dependent and reversible. However, changes in ARIs, LVDP and the maximum rates of change of pressure lacked the steep response to 0.3-1.0 mM heptanol shown by the latency. These other effects are therefore likely to be mediated by cellular targets other than gap junctions. Perfusion of hearts with heptanol was also associated with a high incidence of arrhythmias. During premature stimulation protocols arrhythmias could be induced in hearts perfused with 0.1-0.3 mM heptanol but not at higher concentrations. This suggests that there is a critical range of slowed conduction that permits the development of re-entrant arrhythmias in the normal heart, although the effects of heptanol on repolarization duration may also contribute to its pro-arrhythmic activity.
心脏缝隙连接表达的变化，例如心肌梗死后以及连接蛋白基因敲除小鼠所产生的变化，与心律失常易感性相关。本实验研究了一种可逆性缝隙连接抑制剂庚醇对离体Langendorff灌注兔心脏的影响。庚醇的加入和撤除均抑制了压力产生和电传导。这些效应完全可逆。通过测量庚醇效应的浓度依赖性对传导速度和复极持续时间的影响，研究了这些发现的可能机制。低浓度庚醇（小于0.3 mM）导致刺激（施加于基底间隔）伪迹与左心室局部激活之间的延迟有小但显著的增加，这是通过双极电图（BEG）记录测量的。在庚醇浓度高于0.3 mM时，刺激与左心室激活之间的潜伏期急剧增加。这些发现可以用早期关于庚醇在体外对缝隙连接作用的报道以及缝隙连接电导降低对传导速度影响的建模研究来解释。庚醇缩短了复极持续时间，这是从BEG的激活恢复间期（ARI）和70%复极时的单相动作电位持续时间（MAPD70）测量的。庚醇还降低了左心室舒张末压（LVDP）以及左心室的最大收缩和舒张速率；这些效应具有浓度依赖性且可逆。然而，ARI、LVDP和压力变化最大速率的改变对0.3 - 1.0 mM庚醇缺乏潜伏期所显示的陡峭反应。因此，这些其他效应可能由缝隙连接以外的细胞靶点介导。用庚醇灌注心脏也与心律失常的高发生率相关。在早搏刺激方案期间，在灌注0.1 - 0.3 mM庚醇的心脏中可诱发心律失常，但在更高浓度时则不能。这表明存在一个关键的传导减慢范围，使得正常心脏中能够发生折返性心律失常，尽管庚醇对复极持续时间的影响也可能导致其促心律失常活性。
