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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, Vol. 553, No. 1-3, 28.12.2006, p. 215-21.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Hove-Madsen, L, Llach, A, Molina, CE, Prat-Vidal, C, Farré, J, Roura, S & Cinca, J 2006, 'The proarrhythmic antihistaminic drug terfenadine increases spontaneous calcium release in human atrial myocytes', EUR J PHARMACOL, vol. 553, no. 1-3, pp. 215-21. https://doi.org/10.1016/j.ejphar.2006.09.023

APA

Hove-Madsen, L., Llach, A., Molina, C. E., Prat-Vidal, C., Farré, J., Roura, S., & Cinca, J. (2006). The proarrhythmic antihistaminic drug terfenadine increases spontaneous calcium release in human atrial myocytes. EUR J PHARMACOL, 553(1-3), 215-21. https://doi.org/10.1016/j.ejphar.2006.09.023

Vancouver

Hove-Madsen L, Llach A, Molina CE, Prat-Vidal C, Farré J, Roura S et al. The proarrhythmic antihistaminic drug terfenadine increases spontaneous calcium release in human atrial myocytes. EUR J PHARMACOL. 2006 Dec 28;553(1-3):215-21. https://doi.org/10.1016/j.ejphar.2006.09.023

Bibtex

@article{dc82becc43a04078b57d401ad91131a3,
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.",
keywords = "Arrhythmias, Cardiac, Calcium, Calcium Channels, L-Type, Cyproheptadine, Electrophysiology, Histamine H1 Antagonists, Humans, Image Processing, Computer-Assisted, In Vitro Techniques, Membrane Potentials, Microscopy, Confocal, Myocytes, Cardiac, Patch-Clamp Techniques, Sarcoplasmic Reticulum, Terfenadine, Journal Article, Research Support, Non-U.S. Gov't",
author = "Leif Hove-Madsen and Anna Llach and Molina, {Cristina E} and Cristina Prat-Vidal and Jordi Farr{\'e} and Santiago Roura and Juan Cinca",
year = "2006",
month = dec,
day = "28",
doi = "10.1016/j.ejphar.2006.09.023",
language = "English",
volume = "553",
pages = "215--21",
journal = "EUR J PHARMACOL",
issn = "0014-2999",
publisher = "Elsevier",
number = "1-3",

}

RIS

TY - JOUR

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 -