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Suppression of mammalian K+ channel family by ebastine
1Department of Pharmacology and Institute for Cardiovascular Sciences, Georgetown University Medical Center, Washington, D.C. 20007, USA.
Insights
Ebastine, a novel H1-R antagonist, blocks cardiac potassium channels, particularly the rapidly delayed rectifier K+ current (I(Kr)). Its cardiotoxicity potential is less than terfenadine.
Area of Science:
- Cardiovascular Pharmacology
- Electrophysiology
- Drug Safety
Background:
- Nonsedating H1 receptor (H1-R) antagonists can affect cardiac QT intervals via K+ channel modulation.
- Variable cardiotoxicity exists among H1-R antagonists, necessitating investigation of novel agents like ebastine.
Purpose of the Study:
- To investigate the effects of ebastine on various cardiac K+ currents.
- To compare ebastine's K+ channel blocking effects with other H1-R antagonists, terfenadine and loratadine.
Main Methods:
- Electrophysiological recordings of K+ currents in isolated rat and guinea pig ventricular cardiomyocytes.
- Assessment of HERG-induced rapidly delayed rectifier K+ current (I(Kr)) in Xenopus laevis oocytes.
- Comparative analysis with terfenadine and loratadine at varying concentrations.
Main Results:
- Ebastine suppressed I(Kr) in guinea pig myocytes (Kd=0.14 µM) and HERG-expressing oocytes (Kd=0.3 µM).
- Ebastine also blocked I(Ks) and Iped, with varying potencies and voltage dependence.
- Inhibition of IKr, IKs, and Iped by ebastine was consistently weaker than that of terfenadine.
Conclusions:
- Ebastine exhibits differential blockade of cardiac K+ channels, with delayed rectifier currents being most susceptible.
- Ebastine's K+ channel inhibition is less potent than terfenadine, suggesting a potentially lower cardiotoxicity risk.
- At therapeutic concentrations (<100 nM), ebastine shows negligible effects on cardiac K+ currents.
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)) 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.