Sunami A, Kanno T, Kanda A
Pharmacology Research Laboratory, Taiho Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima, Japan.
Arch Int Pharmacodyn Ther. 1995 Sep-Oct;330(2):151-64.
The electrophysiological effects of MPC-1304, a novel calcium antagonist, were examined using the conventional microelectrode and whole-cell patch-clamp techniques in guinea-pig hearts. MPC-1304, at 100 nM or higher concentrations, produced a dose-dependent reduction in the action potential duration of guinea-pig papillary muscles, without changes in resting membrane potentials and maximum rate of rise of action potentials. In guinea-pig ventricular myocytes, MPC-1304 (1-100 nM) dose-dependently depressed the initial inward currents induced by depolarizing pulses from a holding potential of -30 mV in the external Tyrode solution, as did nifedipine, whereas the late outward current was not changed by MPC-1304. In the presence of 100 nM of MPC-1304 or 100 nM of nifedipine, the first depolarizing pulse from a holding potential of -80 mV caused a depression of the isolated L-type Ca2+ current (I(Ca)) by 29.5 % and 29.4 % of the control, respectively (tonic block), and successive pulses further suppressed I(Ca) in a use-dependent manner (use-dependent block). The degree of steady state use-dependent block of I(Ca) by 100 nM of MPC-1304 was 25.5 % at the stimulus frequency of 1 Hz and further increased to 34.0 % at 2 Hz (frequency-dependent block), which were significantly larger than those by 100 nM of nifedipine at both frequencies. The onset rate of use-dependent block by 100 nM MPC-1304 was significantly smaller than that by 100 nM nifedipine. MPC-1304 (100 nM) and nifedipine (100 nM) shifted the steady state inactivation curve of I(Ca) toward the negative potential by 3.3 mV and 9.1 mV in the mid-potential of the curve, respectively. The estimated dissociation constants of MPC-1304 were 137.7 and 49.9 nM for the resting and inactivated states of the L-type Ca2+ channel, respectively, and those of nifedipine were 113.9 and 18.1 nM, respectively. We conclude that MPC-1304 suppress the L-type Ca2+ channel with slow kinetics in a voltage- and frequency-dependent manner, which might be caused by its high affinity to the activated as well as to the inactivated state of the channel.
使用传统微电极和全细胞膜片钳技术，在豚鼠心脏中研究了新型钙拮抗剂MPC - 1304的电生理效应。MPC - 1304在浓度为100 nM或更高时，可使豚鼠乳头肌动作电位时程呈剂量依赖性缩短，而静息膜电位和动作电位最大上升速率无变化。在豚鼠心室肌细胞中，MPC - 1304（1 - 100 nM）可使在外部Tyrode溶液中从 - 30 mV的钳制电位去极化脉冲诱发的初始内向电流呈剂量依赖性降低，硝苯地平也有同样作用，而MPC - 1304对晚期外向电流无影响。在存在100 nM的MPC - 1304或100 nM的硝苯地平时，从 - 80 mV的钳制电位发出的第一个去极化脉冲分别使分离的L型Ca2 +电流（I(Ca)）降低至对照的29.5%和29.4%（强直阻滞），随后的脉冲以使用依赖性方式进一步抑制I(Ca)（使用依赖性阻滞）。100 nM的MPC - 1304在1 Hz刺激频率下对I(Ca)的稳态使用依赖性阻滞程度为25.5%，在2 Hz时进一步增加至34.0%（频率依赖性阻滞），在这两个频率下均显著大于100 nM硝苯地平的阻滞程度。100 nM MPC - 1304的使用依赖性阻滞起始速率显著小于100 nM硝苯地平。MPC - 1304（100 nM）和硝苯地平（100 nM）分别使I(Ca)的稳态失活曲线在曲线中点电位处向负电位移动3.3 mV和9.1 mV。MPC - 1304对L型Ca2 +通道静息态和失活态的估计解离常数分别为137.7 nM和49.9 nM，硝苯地平的分别为113.9 nM和18.1 nM。我们得出结论，MPC - 1304以电压和频率依赖性方式，通过缓慢的动力学抑制L型Ca2 +通道，这可能是由于其对通道的激活态和失活态具有高亲和力所致。
