Effect of descarboethoxyloratadine, the major metabolite of loratadine, on the human cardiac potassium channel Kv1.5.
The effects of descarboethoxyloratadine (DCL), the major metabolite of loratadine, were studied on a human cardiac K+ channel (hKv1.5) cloned from human ventricle and stably expressed in a mouse cell line by means of the patch-clamp technique. DCL (1-100 microM) inhibited hKv1.5 current in a concentration-dependent manner with an apparent affinity constant of 12.5+/-1.2 microM. The blockade increased steeply over the voltage range of channel opening, which indicated that DCL binds preferentially to the open state of the channel. At more depolarized potentials a weaker voltage-dependence was observed consistent with a binding reaction sensing approximately 20% of the transmembrane electrical field. DCL, 20 microM, increased the time constant of deactivation of tail currents, thus inducing a 'crossover' phenomenon. The present results demonstrated that DCL blocked hKv1.5 channels in a concentration-, voltage-, and time-dependent manner.
Caballero
R
R
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Delpón
E
E
Valenzuela
C
C
Longobardo
M
M
Franqueza
L
L
Tamargo
J
J
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles; D006801:Humans; D015640:Ion Channel Gating; D051666:Kv1.5 Potassium Channel; D017336:Loratadine / Q000378:metabolism* / Q000031:analogs & derivatives; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000494:pharmacology*
C496981:KCNA5 protein, human; C496982:Kcna5 protein, mouse; D051666:Kv1.5 Potassium Channel; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D017336:Loratadine; C121345:desloratadine