Masumiya H, Tanaka H, Shigenobu K
Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
Eur J Pharmacol. 1997 Sep 17;335(1):15-21. doi: 10.1016/s0014-2999(97)01150-3.
Effects of various Ca2+ channel antagonists on the action potential configuration of rabbit sino-atrial node tissue were examined with standard microelectrode techniques. All Ca2+ channel antagonists decreased the maximum rate of phase 0 depolarization (Vmax) and increased the cycle length. The potency order to increase the cycle length was nisoldipine = verapamil > nifedipine = clentiazem > efonidipine > diltiazem. The potency order to decrease Vmax and to shift the threshold potential to a positive direction was the same as that to increase the cycle length, indicating that the major mechanism of negative chronotropism was inhibition of the L-type Ca2+ current. All Ca2+ channel antagonists except efonidipine shifted the maximum diastolic potential to the positive direction, decreased the action potential amplitude and prolonged the action potential duration. The effects of nifedipine were slightly weaker than those of other drugs when compared at equally bradycardiac concentrations. These differences may reflect differences in drug effects on currents other than the L-type Ca2+ current. A characteristic feature of efonidipine was selective suppression of the later phase of pacemaker depolarization with no effect on action potential amplitude and duration. Similar suppression of the later phase was observed with 50 microM Ni2+, which is reported to inhibit the T-type, but not L-type, Ca2+ current. Thus, efonidipine appears to suppress selectively the later phase of pacemaker depolarization through inhibition of both L- and T-type Ca2+ currents, which may be the underlying mechanism for its reported potent negative chronotropic but weak inotropic activity.
采用标准微电极技术研究了各种钙通道拮抗剂对兔窦房结组织动作电位形态的影响。所有钙通道拮抗剂均降低0期去极化最大速率（Vmax）并延长周期长度。延长周期长度的效价顺序为尼索地平 = 维拉帕米 > 硝苯地平 = 克仑硫卓 > 依福地平 > 地尔硫卓。降低Vmax并使阈电位向正向移动的效价顺序与延长周期长度的顺序相同，表明负性变时性的主要机制是抑制L型钙电流。除依福地平外，所有钙通道拮抗剂均使最大舒张电位向正向移动，降低动作电位幅度并延长动作电位时程。在同等心动过缓浓度下比较时，硝苯地平的作用略弱于其他药物。这些差异可能反映了药物对L型钙电流以外的电流的作用差异。依福地平的一个特征是选择性抑制起搏去极化的后期阶段，而对动作电位幅度和时程无影响。用50微摩尔镍离子也观察到了类似的后期抑制作用，据报道镍离子可抑制T型而非L型钙电流。因此，依福地平似乎通过抑制L型和T型钙电流来选择性抑制起搏去极化的后期阶段，这可能是其报道的强效负性变时作用但弱的变力作用的潜在机制。
