Suppression of mammalian K+ channel family by ebastine.
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)) in Xenopus 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) (Kd = 0.14 microM, maximum block 74%) more effectively than the slowly delayed rectifier K+ current (I(Ks)) (Kd = 0.8 microM, maximum block 60%). Ebastine also suppressed I(Kr) in HERG-expressing X. laevis oocytes with the Kd value of 0.3 microM and a maximal block of 46% at 3 microM. The block of the rapidly activating delayed rectifier channel in rat myocytes (Iped) (Kd = 1.7 microM, maximum block 58%) had a small voltage dependence. Ebastine only minimally suppressed rat transient K+ current (Ito) (Kd = 1.1 microM, 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 microM). 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) > Iped. Ebastine-induced inhibition of all K+ current types was always weaker than that observed with similar concentrations of terfenadine.
Ko
C M
CM
Department of Pharmacology and Institute for Cardiovascular Sciences, Georgetown University Medical Center, Washington, D.C. 20007, USA.
Ducic
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Fan
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Shuba
Y M
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Morad
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M
D000818:Animals; D002090:Butyrophenones / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014982:Xenopus laevis
D002090:Butyrophenones; D006634:Histamine H1 Antagonists; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C058249:ebastine