title: The proarrhythmic antihistaminic drug terfenadine increases spontaneous calcium release in human atrial myocytes.
abstract: Spontaneous calcium release from the sarcoplasmic reticulum in cardiac myocytes plays a central role in cardiac arrhythmogenesis. Compounds intended for therapeutical use that interfere with intracellular calcium handling may therefore have an undesired proarrhythmic potential. Here we have used isolated human atrial myocytes to compare the effect of the proarrhythmic antihistaminic drug terfenadine with the non-proarrhythmic antihistaminic drugs fexofenadine and rupatadine on intracellular calcium homeostasis. Perforated patch-clamp technique was used to measure ionic currents and to detect spontaneous calcium release from the sarcoplasmic reticulum. Our results show that the compound terfenadine, with known arrhythmogenic effects, inhibits L-type calcium current (I(Ca)) with an IC(50) of 185 nM when cells are stimulated at 1.0 Hz. The inhibitory effect of 0.3 muM terfenadine increased from 19+/-4% at stimulation frequency of 0.2 Hz to 63+/-6% at 2.0 Hz. Moreover, terfenadine also increased spontaneous calcium release from the sarcoplasmic reticulum. At a concentration of 1 muM, terfenadine significantly increased the spontaneous Na-Ca exchange current (I(NCX)) frequency from 0.48+/-0.25 to 1.93+/-0.67 s(-1). In contrast, fexofenadine and rupatadine did not change I(Ca) or the frequency of spontaneous I(NCX). We conclude that the proarrhythmic antihistaminic drug terfenadine alters intracellular calcium handling in isolated human atrial myocytes. This experimental model may be suitable to screen for potential arrhythmogenic side-effects of compounds intended for therapeutical use.
authors.affiliation: Cell Physiology Laboratory, Cardiology Department, Institut Catalá de Ciencies Cardiovasculars, Hospital de la Santa Creu i Sant Pau, St Antoni M(a) Claret 167, 08025 Barcelona, Spain. lhove@santpau.es
authors.forename: Leif
authors.initials: L
authors.lastname: Hove-Madsen
authors.forename: Anna
authors.initials: A
authors.lastname: Llach
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Molina
authors.forename: Cristina
authors.initials: C
authors.lastname: Prat-Vidal
authors.forename: Jordi
authors.initials: J
authors.lastname: Farré
authors.forename: Santiago
authors.initials: S
authors.lastname: Roura
authors.forename: Juan
authors.initials: J
authors.lastname: Cinca
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D003533:Cyproheptadine / Q000031:analogs & derivatives / Q000494:pharmacology; D004594:Electrophysiology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D016593:Terfenadine / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D020746:Calcium Channels, L-Type; D006634:Histamine H1 Antagonists; C103639:rupatadine; D003533:Cyproheptadine; D016593:Terfenadine; C093230:fexofenadine; D002118:Calcium