Elsevier

Pharmacological Research

Volume 54, Issue 6, December 2006, Pages 414-420
Pharmacological Research

Electrophysiological effects of brompheniramine on cardiac ion channels and action potential

https://doi.org/10.1016/j.phrs.2006.08.004Get rights and content

Abstract

Some antihistamines (mainly terfenadine and astemizole) have been demonstrated to cause QT interval prolongation and, in some cases, torsade-de-pointes. We investigated the cardiac electrophysiological effects of brompheniramine, a conventional antihistamine. Brompheniramine was reported to prolong QT interval in isolated hearts. To evaluate the electrophysiological effects of brompheniramine, we used whole-cell patch clamp techniques in human ether-a-go-go related gene (hERG)-stably transfected CHO cells, the SCN5A sodium channel transiently transfected CHO cells, and rat myocytes and conventional microelectrode recording techniques in isolated guinea pig papillary muscles. As for the IhERG, the IC50 value of brompheniramine was found to be 0.90 ± 0.14 μM with a Hill coefficient (nH) of 1.75 ± 0.42. Action potential duration at 90% repolarization (APD90) was slightly prolonged by brompheniramine at 10 and 100 μM, but APD50 was shortened by 100 μM. Moreover, despite the potent hERG current block, reductions of the Vmax and total amplitude of action potential were observed at high concentrations of brompheniramine. The change in action potential parameters and poor correlations between hERG and APD assay indicated additional effects of brompheniramine on non-hERG channels. In agreement with this hypothesis, the inhibition of INa (IC50 values: 21.26 ± 2.52 μM) and ICa (IC50 values: 16.12 ± 9.43 μM) by brompheniramine was observed. The results of this study suggest that brompheniramine may possess classes III, Ib and IV properties, especially at high concentrations and that additional studies on non-hERG channels will be necessary to elucidate the complex electrophysiological effects of brompheniramine on the heart.

Introduction

Antihistamines are widely used to relieve allergic rhinitis and conjunctivitis, motion sickness, chronic urticaria, and histamine-induced pruritis. Terfenadiene and astemizole, histamine H1-receptor antagonists, have been linked to the clinical syndrome of torsades-de-pointes [1], [2], [3], [4]. Notably, drug-induced prolongation of the QT interval is often associated with the onset of torsade-de-pointes, resulting in a life-threatening ventricular arrhythmia [5]. Block of voltage-dependent potassium (K+) channels in the human heart is one means by which drugs can prolong cardiac repolarization and precipitate ventricular arrhythmia. In particular, the blockade of the human ether-a-go-go-related gene (hERG) K+ channels can induce QT interval prolongation [6], [7]. Both of these antihistamine drugs appear to interfere with the repolarization process by blocking hERG channels [8], [9]. Brompheniramine is a member of the alkylamine class of H1-histamine antagonist with demonstrated potencies with respect to QT interval prolongation [10]. However, the effects of the brompheniramine on action potential generated by various cardiac ion channels including the hERG are poorly understood. A drug may interact with more than one channel target to produce either offsetting or synergistic effects on the action potential [11]. In the present study, we investigated the effects of brompheniramine on the cardiac action potential duration (APD), hERG, sodium (Na+) channels and calcium (Ca2+) currents to determine their relative potency for inhibiting each channel.

Section snippets

Recording of action potentials

This study was conducted in facilities approved by the AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care) International. All procedures were approved by our Institutional Animal Care and Use Committee (IACUC). Male Hartley guinea pigs (280–300 g) were used in this study. Their hearts were rapidly removed and placed in Normal Tyrode (NT) solution (mM): 143 NaCl; 5.4 KCl; 5.0 HEPES; 0.33 H2PO4; 0.5 MgCl2; 16.6 glucose; 1.8 CaCl2; pH 7.4. Papillary muscles were excised

Recording of hERG currents

Brompheniramine tested in these experiments blocked hERG K+ channels expressed in CHO cells in a concentration-dependent manner as displayed in Fig. 1. In these experiments, cells were depolarized for 2 s to +20 mV from a holding potential of −80 mV followed by a 3 s repolarization back to −60 mV. Tail currents were recorded at 100 ms after repolarization to −60 mV. Brompheniramine reduced peak tail current amplitude measured at −60 mV in a concentration-dependent manner. The IC50 value of 0.90 ± 0.14 μM

Discussion

Brompheniramine is a first generation propylamine-derivative antihistamine and H1-histamine antagonist. It is widely used for the relief of upper respiratory symptoms, including nasal and/or sinus congestion, associated with allergy or the common cold [12]. QT interval prolongation, arrhythmias and sudden death are well-known adverse effects of the histamine H1-receptor antagonists such as terfenadiene and astemizole.

The present study is the first attempt to evaluate the electrophysiological

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