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

PMID 7516499


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.

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DK-AH 269, ≥98% (HPLC), solid
C28H38N2O5 · HCl