Effects of cetirizine on the delayed K+ currents in cardiac cells:: comparison with terfenadine

1 The aim of the present experiments was to analyse the effect of the H-1-histamine antagonist, cetirizine, on the delayed K+ currents in cardiac cells and to compare its effects with another H-1-histamine antagonist terfenadine, known to possess proarrhythmic effects. 2 Whole cell currents were measured by use of the single electrode patch-clamp technique in rabbit and guinea-pig myocytes. 3 The activation relationship for the I(Kr )current in rabbit ventricular myocytes was depressed and its voltage-dependence shifted in the negative direction with a V-1/2 value -13.4+/-2.4 mV under control conditions which changed to -19.1+/-1.9 mV (n=4) in the presence of 0.1 mM cetirizine. 4 In rabbit ventricular myocytes the IC50 for block of I-Kr was 108+/-8 mu M (n = 5); in guinea-pig ventricular myocytes this concentration of cetirizine reduced the rapidly activating component I-Kr to 49+/-4.5% (n = 5), while the slowly activating I-Ks was less affected and only inhibited to 79+/-2.3% (n = 5). 5 The block of I-Kr did not show use-dependence and the time course of the tail current was not changed, suggesting rested-state block or fast activated-state block and no rapid recovery on deactivation. No important difference was found in the activity of the two enantiomers of cetirizine. 6 Terfenadine in comparison was more potent in blocking I-Kr, the IC50 being 96+/-15 nM (n = 6). 7 Based on the present results and information in the literature on binding, it was concluded that cetirizine is a relatively selective H-1-histamine receptor antagonist, with minor effects on K+ currents. The IC50 concentration for I-Kr block in heart cells was 1.000 times higher than the concentrations needed to block HI histamine receptors. The occurrence of cardiac arrhythmias due to K+ current blockade is therefore unlikely with this drug.