RT Journal Article SR Electronic T1 Suppression of Mammalian K+ Channel Family by Ebastine JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 233 OP 244 VO 281 IS 1 A1 Ko, Chang Mann A1 Ducic, Ivan A1 Fan, Jing A1 Shuba, Yaroslav M. A1 Morad, Martin YR 1997 UL http://jpet.aspetjournals.org/content/281/1/233.abstract AB 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 (IKr) 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 IKr (K d = 0.14 μM, maximum block 74%) more effectively than the slowly delayed rectifier K+ current (IKs) (K d= 0.8 μM, maximum block 60%). Ebastine also suppressed IKr 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 (Iped) (K d = 1.7 μM, maximum block 58%) had a small voltage dependence. Ebastine only minimally suppressed rat transient K+ current (Ito) (K d = 1.1 μM, maximum block 10%). The drug was also not a very potent blocker of the inwardly rectifier K+ current (IK1) 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 IKr > IKs > Iped. Ebastine-induced inhibition of all K+ current types was always weaker than that observed with similar concentrations of terfenadine. The American Society for Pharmacology and Experimental Therapeutics