BLOCK OF INACTIVATED SODIUM-CHANNELS AND OF DEPOLARIZATION-INDUCED AUTOMATICITY IN GUINEA-PIG PAPILLARY-MUSCLE BY AMIODARONE
BLOCK OF INACTIVATED SODIUM-CHANNELS AND OF DEPOLARIZATION-INDUCED AUTOMATICITY IN GUINEA-PIG PAPILLARY-MUSCLE BY AMIODARONE
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DOI：
10.1161/01.res.55.3.278
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发表时间：
1984-01-01
影响因子：
20.1
通讯作者：
KATZUNG, BG
中科院分区：
文献类型：
--
作者：
MASON, JW;HONDEGHEM, LM;KATZUNG, BG
应用单蔗糖间隙电压钳技术研究了胺碘酮对豚鼠心室乳头肌的电生理作用。测量动作电位上行的一阶时间导数作为Na电流的指标。在动作电位上升过程中，制剂未进行电压钳位。胺碘酮的急性作用（4.4x. 10-5 M和8.8x. 10-5 M;各6个实验）和单剂量水平长期给药的影响（9只实验动物vs. 8只对照动物）。所有实验条件下的结果在定性上相同，并且在急性研究中具有浓度依赖性。胺碘酮引起明显的使用依赖性抑制，即刺激序列期间动作电位上升的一阶导数。例如，在正常的静息电位下，慢性胺碘酮治疗将周期长度为300毫秒的系列的第16次搏动的动作电位的上行程的第一时间导数减少到70 ± 100毫秒。15%（平均值±）SD）的初始值。这种阻断作用在去极化保持电位时增强，在超极化保持电位时减弱。动作电位上升的一阶导数的减少依赖于Na通道失活。对于所有实验，在-20至+20 mV范围内的1-s钳位后，动作电位上行的平均标准化一阶时间导数为0.92 ± 0.95。0.08在对照条件下和0.66 ±. 0.20在胺碘酮存在下（< 0.01）。胺碘酮引起的动作电位上行程的一阶导数降低可通过缩短动作电位平台来最小化，并通过使用电压钳延长平台至所有通道失活的电位来放大。在静息电位下从胺碘酮阻断中恢复（约-85mV）的时间常数为1.63 ± 1.5mV。0.24 S.在-100至-65 mV范围内，超极化使该时间常数适度缩短，去极化使其延长。在药物与心脏Na通道的状态依赖性相互作用的计算机模型中分析数据，得到以下解离常数：静止状态> 0.1M，活化状态. simeq。10-3 M，和失活状态。2倍。10-5 M.胺碘酮还延长动作电位时程，并在所有实验条件下持续抑制去极化诱导的自律性。显然，胺碘酮是一种有效的Na通道阻滞剂，其主要作用机制是在失活状态下对Na通道的选择性亲和力。
The electrophysiological effects of amiodarone were studied in guinea pig papillary muscle by means of the single sucrose gap voltage clamp technique. The 1st time derivative of the upstroke of the action potential was measured as an indicator of the Na current. The preparations were not voltage clamped during the action potential upstroke. Acute effects of amiodarone (4.4 .times. 10-5 M and 8.8 .times. 10-5 M; 6 experiments each) and effects of chronic administration at a single dose level (9 experimental vs. 8 control animals) were studied. Results were qualitatively the same for all experimental conditions, and concentration dependent in the acute studies. Amiodarone caused marked use-dependent depression the 1st time derivative of the upstroke of the action potential during stimulus trains. For example, at normal resting potential, chronic amiodarone treatment reduced the 1st time derivative of the upstroke of the action potential of the 16th beat of trains of cycle length 300 msec to 70 .+-. 15% (mean .+-. SD) of the initial value. This blocking effect was accentuated at more depolarized holding potentials and reduced at hyperpolarized holding potentials. Reduction of the 1st time derivative of the upstroke of the action potential depended upon Na channel inactivation. For all experiments, the mean normalized 1st time derivative of the upstroke of the action potential following a 1-s clamp in the -20 to +20 mV range was 0.92 .+-. 0.08 in the control condition and 0.66 .+-. 0.20 in the presence of amiodarone (< 0.01). The reduction of the 1st time derivative of the upstroke of the action potential by amiodarone could be minimized by shortening the action potential plateau, and exaggerated by lengthening the plateau with a voltage clamp to potentials at which all channels are inactivated. Recovery from block by amiodarone at the resting potential (.apprx. -85 mV) had a time constant of 1.63 .+-. 0.24 s. Over the -100 to -65 mV range, this time constant was moderately shortened by hyperpolarization and lengthened by depolarization. Analysis of the data in a computer model of the state-dependent interaction of drugs with the cardiac Na channel yielded the following dissociation constants: rested state > 0.1 M, activated state .simeq. 10-3 M, and inactivated state .simeq. 2 .times. 10-5 M. Amiodarone also prolonged action potential duration and consistently inhibited depolarization-induced automaticity in all experimental conditions. Evidently, amiodarone is a potent Na channel blocker and a major mechanism of its action is selective affinity for Na channels in the inactivated state.