新型抗心律失常药物Ro 22 - 9194对豚鼠心室细胞的电生理效应

Electrophysiological effects of Ro 22-9194, a new antiarrhythmic agent, on guinea-pig ventricular cells.

作者信息

Maruyama K, Kodama I, Anno T, Suzuki R, Toyama J

机构信息

Department of Circulation, Nagoya University, Japan.

出版信息

Br J Pharmacol. 1995 Jan;114(1):19-26. doi: 10.1111/j.1476-5381.1995.tb14900.x.

DOI:10.1111/j.1476-5381.1995.tb14900.x

PMID:7712017

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1510164/

Abstract

Cardiac effects of Ro 22-9194 were examined in papillary muscles and single ventricular myocytes isolated from guinea-pigs and compared with those of moricizine. 2. In papillary muscles, both Ro 22-9194 (> or = 10 microM) and moricizine (> or = 1 microM) caused a significant dose-dependent decrease in the maximum upstroke velocity (Vmax) and a shortening of the action potential duration. 3. In the presence of either drug, trains of stimuli at rates > or = 0.2 Hz led to an exponential decline in Vmax. This use-dependent block was enhanced at higher stimulation frequencies. A time constant (tau R) for Vmax recovery from the use-dependent block was 9.3 s for Ro 22-9194 and 26.4 s for moricizine. 4. The curves relating membrane potential and Vmax in single myocytes were shifted by Ro 22-9194 (30 microM) or by moricizine (3 microM) in a hyperpolarizing direction by 8.4 mV and 8.0 mV respectively. 5. In myocytes treated with Ro 22-9194 (30 microM), a 10 ms conditioning clamp to 0 mV caused a significant decrease in Vmax of the subsequent test action potential; further prolongation of the clamp pulse duration resulted in a modest enhancement of the Vmax inhibition. In the presence of moricizine (3 microM), a similar conditioning clamp > 200 ms caused a significant Vmax reduction; the longer the clamp pulse duration, the greater the Vmax reduction. 6. Ro 22-9194 > or = 30 microM caused a slight decrease of calcium inward current (ICa) of myocytes without affecting the delayed rectifier potassium current (IK). 7. These findings suggest that the primary electrophysiological effect of Ro 22-9194 as an antiarrhythmicagent is, like moricizine, a use- and voltage-dependent inhibition of sodium channels. From the onset and offset kinetics of the use-dependent block, Ro 22-9194 belongs to the intermediate kinetic Class I drugs, while moricizine is a slow kinetic drug. From the state-dependence of sodium channel block, Ro 22-9194 may belong to activated channel blockers, while moricizine belongs to inactivated channel blockers.

摘要

研究了Ro 22 - 9194对豚鼠分离的乳头肌和单个心室肌细胞的心脏效应，并与莫雷西嗪的效应进行了比较。2. 在乳头肌中，Ro 22 - 9194（≥10微摩尔）和莫雷西嗪（≥1微摩尔）均引起最大上升速度（Vmax）显著的剂量依赖性降低和动作电位时程缩短。3. 在任何一种药物存在下，频率≥0.2赫兹的刺激串导致Vmax呈指数下降。这种使用依赖性阻滞在更高刺激频率下增强。Ro 22 - 9194使Vmax从使用依赖性阻滞中恢复的时间常数（tau R）为9.3秒，莫雷西嗪为26.4秒。4. 单个肌细胞中膜电位与Vmax的关系曲线在Ro 22 - 9194（30微摩尔）或莫雷西嗪（3微摩尔）作用下分别向超极化方向移动8.4毫伏和8.0毫伏。5. 在用Ro 22 - 9194（30微摩尔）处理的肌细胞中，对0毫伏进行10毫秒的预处理钳制导致随后测试动作电位的Vmax显著降低；钳制脉冲持续时间进一步延长导致Vmax抑制略有增强。在莫雷西嗪（3微摩尔）存在下，类似的>200毫秒的预处理钳制导致Vmax显著降低；钳制脉冲持续时间越长，Vmax降低越大。6. Ro 22 - 9194≥30微摩尔使肌细胞的钙内向电流（ICa）略有降低，而不影响延迟整流钾电流（IK）。7. 这些发现表明，Ro 22 - 9194作为抗心律失常药物的主要电生理效应与莫雷西嗪一样，是对钠通道的使用和电压依赖性抑制。从使用依赖性阻滞的起始和消退动力学来看，Ro 22 - 9194属于中间动力学I类药物，而莫雷西嗪是慢动力学药物。从钠通道阻滞的状态依赖性来看，Ro 22 - 9194可能属于激活通道阻滞剂，而莫雷西嗪属于失活通道阻滞剂。