Kawamura T, Kodama I, Toyama J, Hayashi H, Saito H, Yamada K
Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Cardiovasc Res. 1990 Nov;24(11):925-31. doi: 10.1093/cvr/24.11.925.
The aim was to study the differences in cardiac sodium channel block among combinations of class I antiarrhythmic drugs.
Conventional glass microelectrode techniques were used to record transmembrane action potentials and their maximum upstroke velocity (dV/dtmax) reflecting the sodium channel availability, during treatment of the preparations with mexiletine (20, 40 microM) in combination with aprindine (5 microM), disopyramide (40 microM), and flecainide (5 microM).
Guinea pig papillary muscles (n = 6.8 per experiment) were used for the study.
In preparations constantly stimulated at 1 Hz, a shortening of action potential duration by aprindine was further enhanced, while prolongation by disopyramide or flecainide was reduced, after additional application of mexiletine. Trains of stimuli (0.5-2.0 Hz) were applied following a long quiescent period to evaluate "tonic" and "use dependent" decrease (block) of dV/dtmax. Additional application of mexiletine to the other three drugs resulted in an enhancement of tonic block. Use dependent block by aprindine at 0.5-1.0 Hz was reduced by 8-9% after admixture of mexiletine, reflected in net increase in dV/dtmax at steady states (reductive effect). Dual exponential components of dV/dtmax recovery from use dependent block in presence of both drugs suggest their competitive interaction on a common receptor site associated with sodium channels. Use dependent block by flecainide at 0.5-2.0 Hz was increased (p less than 0.01) after admixture of mexiletine. Steady state dV/dtmax was therefore largely inhibited by the drug combination (synergistic effect). Use dependent block in the presence of both disopyramide and mexiletine was similar to that predicted from the algebraic sum of each treatment.
Combined application of class I antiarrhythmic drugs causes not only additive but also reductive or synergistic effects on dV/dtmax through modulation of use dependent block.
旨在研究I类抗心律失常药物联合应用时心脏钠通道阻滞的差异。
采用传统玻璃微电极技术记录跨膜动作电位及其反映钠通道可用性的最大除极速度（dV/dtmax），在豚鼠乳头肌标本用美西律（20、40微摩尔）分别与阿普林定（5微摩尔）、丙吡胺（40微摩尔）和氟卡尼（5微摩尔）联合处理期间进行记录。
豚鼠乳头肌（每次实验n = 6 - 8）用于本研究。
在以1Hz持续刺激的标本中，额外应用美西律后，阿普林定引起的动作电位时程缩短进一步增强，而丙吡胺或氟卡尼引起的动作电位时程延长则减弱。在长时间静息期后施加串刺激（0.5 - 2.0Hz）以评估dV/dtmax的“强直”和“使用依赖性”降低（阻滞）。美西律与其他三种药物联合应用导致强直阻滞增强。美西律与阿普林定混合后，阿普林定在0.5 - 1.0Hz时的使用依赖性阻滞降低了8 - 9%，表现为稳态时dV/dtmax的净增加（还原效应）。两种药物存在时dV/dtmax从使用依赖性阻滞恢复的双指数成分提示它们在与钠通道相关的共同受体位点上存在竞争性相互作用。美西律与氟卡尼混合后，氟卡尼在0.5 - 2.0Hz时的使用依赖性阻滞增加（p < 0.01）。因此，药物组合对稳态dV/dtmax有很大抑制作用（协同效应）。丙吡胺和美西律同时存在时的使用依赖性阻滞与每种处理的代数和预测结果相似。
I类抗心律失常药物联合应用不仅通过调节使用依赖性阻滞对dV/dtmax产生相加作用，还产生还原或协同作用。
