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 H1-histamine antagonist, cetirizine, on the delayed K+ currents in cardiac cells and to compare its effects with another H1-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 IKr current in rabbit ventricular myocytes was depressed and its voltage-dependence shifted in the negative direction with a V1/2 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 IKr was 108+/-8 microM (n=5); in guinea-pig ventricular myocytes this concentration of cetirizine reduced the rapidly activating component IKr to 49+/-4.5% (n=5), while the slowly activating IKs was less affected and only inhibited to 79+/-2.3% (n=5). 5 The block of IKr 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 IKr, 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 H1-histamine receptor antagonist, with minor effects on K+ currents. The IC50 concentration for IKr block in heart cells was 1.000 times higher than the concentrations needed to block H1 histamine receptors. The occurrence of cardiac arrhythmias due to K+ current blockade is therefore unlikely with this drug.
Carmeliet
E
E
C.E.H.A., University Leuven, Gasthuisberg, Belgium.
D000818:Animals; D017332:Cetirizine / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D011817:Rabbits; D013237:Stereoisomerism; D016593:Terfenadine / Q000494:pharmacology*
D006634:Histamine H1 Antagonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D016593:Terfenadine; D017332:Cetirizine