BLOCK OF HUMAN CARDIAC KV1.5 CHANNELS BY LORATADINE - VOLTAGE-DEPENDENT, TIME-DEPENDENT AND USE-DEPENDENT BLOCK AT CONCENTRATIONS ABOVE THERAPEUTIC LEVELS

Objective: The aim of this study was to analyze the effects of loratad ine on a human cardiac K+ channel (hKv1.5) cloned from human ventricle and stably expressed in a mouse cell line. Methods: Currents were stu died using the whole-cell configuration of the patch - clamp technique in Ltk(-) cells transfected with the gene encoding hKv1.5 channels. R esults: Loratadine inhibited in a concentration-dependent manner the h Kv1.5 current, the apparent affinity being 1.2 +/- 0.2 mu M. The block ade increased steeply between -30 and 0 mV which corresponded with the voltage range for channel opening, thus suggesting that the drug bind s preferentially to the open state of the channel. The apparent associ ation and dissociation rate constants were (3.6 +/- 0.5) x 10(6).M-1.s (-1) and 3.7 +/- 1.6.s(-1) respectively. Loratadine, 1 mu M, increased the time constant of deactivation of tail currents elicited on return to -40 mV after 500 ms depolarizing pulses to +60 mV from 36.2 +/- 3. 4 to 64.9 +/- 3.6 ms (n = 6, P < 0.01), thus inducing a 'crossover' ph enomenon. Application of trains of pulses at 1 Hz lead to a progressiv e increase in the blockade reaching a final value of 48.6 +/- 4.3%. Re covery from loratadine-induced block at -80 mV exhibited a time consta nt of 743.0 +/- 78.0 ms. Finally, the results of a mathematical simula tion of the effects of loratadine, based on an open-channel block mode l, reproduced fairly well the main effects of the drug. Conclusions: T he present results demonstrated that loratadine blocked hKv1.5 channel s in a concentration-, voltage-, time- and use-dependent manner but on ly at concentrations much higher than therapeutic plasma levels in man . (C) 1997 Elsevier Science B.V.