The proarrhythmic antihistaminic drug terfenadine increases spontaneous calcium release in human atrial myocytes
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The proarrhythmic antihistaminic drug terfenadine increases spontaneous calcium release in human atrial myocytes. / Hove-Madsen, Leif; Llach, Anna; Molina, Cristina E; Prat-Vidal, Cristina; Farré, Jordi; Roura, Santiago; Cinca, Juan.
in: EUR J PHARMACOL, Jahrgang 553, Nr. 1-3, 28.12.2006, S. 215-21.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - The proarrhythmic antihistaminic drug terfenadine increases spontaneous calcium release in human atrial myocytes
AU - Hove-Madsen, Leif
AU - Llach, Anna
AU - Molina, Cristina E
AU - Prat-Vidal, Cristina
AU - Farré, Jordi
AU - Roura, Santiago
AU - Cinca, Juan
PY - 2006/12/28
Y1 - 2006/12/28
N2 - 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.
AB - 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.
KW - Arrhythmias, Cardiac
KW - Calcium
KW - Calcium Channels, L-Type
KW - Cyproheptadine
KW - Electrophysiology
KW - Histamine H1 Antagonists
KW - Humans
KW - Image Processing, Computer-Assisted
KW - In Vitro Techniques
KW - Membrane Potentials
KW - Microscopy, Confocal
KW - Myocytes, Cardiac
KW - Patch-Clamp Techniques
KW - Sarcoplasmic Reticulum
KW - Terfenadine
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1016/j.ejphar.2006.09.023
DO - 10.1016/j.ejphar.2006.09.023
M3 - SCORING: Journal article
C2 - 17078945
VL - 553
SP - 215
EP - 221
JO - EUR J PHARMACOL
JF - EUR J PHARMACOL
SN - 0014-2999
IS - 1-3
ER -