Pape H C
Abteilung für Neurophysiologie, Medizinische Fakultät, Ruhr-Universität, Bochum, Germany.
Neuroscience. 1994 Mar;59(2):363-73. doi: 10.1016/0306-4522(94)90602-5.
A class of pharmacologically active substances, known as "specific bradycardic agents", exerts a negative chronotropic influence on cardiac activity, which heavily relies upon a potent blockade of the hyperpolarization-activated cation current in Purkinje fibers. Since the cation conductance activated by hyperpolarization seems to represent an ubiquitous class of membrane channel in mammals, the present study was undertaken to evaluate the influence of specific bradycardic agents [UL-FS 49 (zatebradine) and its derivative DK-AH 268] on excitable cells of the central nervous system. Thalamocortical relay neurons of the dorsolateral geniculate nucleus, prepared from the guinea-pig thalamus as in vitro slices, were taken as model cells, because the significance of the hyperpolarization-activated cation current (Ih) for electrogenic activity is well documented in these neurons. Local application to relay neurons of the bradycardic agents at concentrations in the range 10(-5) to 10(-3) M resulted in a significant reduction in the amplitude of the Ih current, in the amplitude of the Ih activation curve, and in the slope of the fully activated Ih I/V-relationship. The bradycardic agents did not affect the instantaneous currents with no contribution of Ih, the time course of Ih activation, the voltage range of Ih activation, or the reversal potential of Ih. The inhibitory effect was critically dependent upon Ih activation with open Ih channels probably representing a sufficient condition for blockade. Significant recovery from block did not occur. Under current-clamp conditions, slow anomalous inward rectification of the membrane in the hyperpolarizing direction was blocked, and the resting input resistance increased by 30% associated with a negative shift (average 10 mV) of the membrane potential into a region of Ca(2+)-mediated burst activity. Parameters of electrophysiological activity outside the range of Ih activation were not significantly affected. These data indicate a selective and use-dependent blockade exerted by specific bradycardic substances on the conductance underlying Ih with no alteration in the gating properties. In view of the existence of hyperpolarization-activated cation conductances in neurons from various regions of the mammalian peripheral and central nervous systems, the results of the present study remind us of possible neuronal side-effects of bradycardia-producing agents.
一类被称为“特异性心动过缓药物”的药理活性物质，对心脏活动产生负性变时作用，这在很大程度上依赖于对浦肯野纤维中超极化激活阳离子电流的强效阻断。由于超极化激活的阳离子电导似乎代表了哺乳动物中一类普遍存在的膜通道，因此开展了本研究，以评估特异性心动过缓药物[UL-FS 49（扎替雷定）及其衍生物DK-AH 268]对中枢神经系统可兴奋细胞的影响。以豚鼠丘脑制成的体外切片中的背外侧膝状核丘脑皮质中继神经元作为模型细胞，因为在这些神经元中超极化激活阳离子电流（Ih）对电活动的重要性已有充分记录。将心动过缓药物以10⁻⁵至10⁻³ M的浓度局部应用于中继神经元，导致Ih电流幅度、Ih激活曲线幅度以及完全激活的Ih电流-电压关系斜率显著降低。心动过缓药物不影响无Ih贡献的瞬时电流、Ih激活的时间进程、Ih激活的电压范围或Ih的反转电位。抑制作用严重依赖于Ih激活，开放的Ih通道可能是阻断的充分条件。未出现明显的阻断恢复。在电流钳制条件下，膜在超极化方向的缓慢异常内向整流被阻断，静息输入电阻增加30%，同时膜电位负向偏移（平均10 mV）进入钙介导的爆发活动区域。Ih激活范围之外的电生理活动参数未受到显著影响。这些数据表明，特异性心动过缓物质对Ih所依赖的电导产生选择性和使用依赖性阻断，而门控特性无改变。鉴于哺乳动物外周和中枢神经系统不同区域的神经元中存在超极化激活阳离子电导，本研究结果提醒我们产生心动过缓药物可能存在神经元副作用。
