Abstract

Nonsedating H₁ receptor (H₁-R) antagonists exert variable effects on QT interval, most likely mediated through modulation of cardiac K⁺ channels. We examined the effects of a novel H₁-R antagonist, ebastine, on a family of K⁺ currents in isolated rat and guinea pig ventricular cardiomyocytes as well as on HERG-induced rapidly delayed rectifier K⁺ current (I_Kr) inXenopus laevis oocytes. The effect of ebastine was compared with that of two other H₁-R antagonists, terfenadine and loratadine, with and without reported cardiotoxicity, respectively. In guinea pig ventricular myocytes, ebastine at concentrations approximating those found in plasma under certain conditions suppressed in a voltage-independent manner the I_Kr (K _d = 0.14 μM, maximum block 74%) more effectively than the slowly delayed rectifier K⁺ current (I_Ks) (K _d= 0.8 μM, maximum block 60%). Ebastine also suppressed I_Kr in HERG-expressing X. laevis oocytes with the K _d value of 0.3 μM and a maximal block of 46% at 3 μM. The block of the rapidly activating delayed rectifier channel in rat myocytes (I_ped) (K _d = 1.7 μM, maximum block 58%) had a small voltage dependence. Ebastine only minimally suppressed rat transient K⁺ current (I_to) (K _d = 1.1 μM, maximum block 10%). The drug was also not a very potent blocker of the inwardly rectifier K⁺ current (I_K1) of rat and guinea pig (15 ± 3% block at 3 μM). At concentrations of <100 nM, ebastine produced negligible effect on all K⁺ currents. We conclude that ebastine blocks various cardiac K⁺ channels with different potencies. The group of delayed rectifier K⁺currents appeared to be most susceptible to ebastine with the order of sensitivity of I_Kr > I_Ks > I_ped. Ebastine-induced inhibition of all K⁺ current types was always weaker than that observed with similar concentrations of terfenadine.