Specific bradycardic agents block the hyperpolarization-activated cation current in central neurons

Abstract

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 ( I h ) 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 −3M resulted in a significant reduction in the amplitude of the I h current, in the amplitude of the I h activation curve, and in the slope of the fully activated I h I/V-relationship. The bradycardic agents did not affect the instantaneous currents with no contribution of I h , the time course of I h activation, the voltage range of I h activation, or the reversal potential of I h . The inhibitory effect was critically dependent upon I h activation with open I h 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 I h activation were not significantly affected. These data indicate a selective and use-dependent blockade exerted by specific bradycardic substances on the conductance underlying I h 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.