Electrophysiological effects of brompheniramine on cardiac ion channels and action potential
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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2022, Toxicology LettersCitation Excerpt :To activate tail currents, the cells were held at −80 mV and hyperpolarized at −90 mV for 100 ms. The cells were then depolarized to +20 mV for 2 s followed by repolarization at −40 mV for 3 s. Voltage pulse was activated consecutively for 20 s and simulation frequency was set at 0.05 Hz. Drug concentration that inhibited ionic currents by 50 % was calculated via Hill equation: f = XH/(IC50H + XH), where H refers to Hill coefficient, IC50 refers to 50 % inhibitory concentration, X refers to concentration, and f refers to inhibition ratio (Kirsch et al., 2004; Redfern et al., 2003; Shin et al., 2006). The effects of 25I-NBOH on the isolated rat hearts were measured using a Langendorff apparatus (AD Instruments model: LE05200 and LE13206, PanLab, Spain).
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2020, Toxicology LettersCitation Excerpt :To assess hERG potassium channel inhibition caused by 4-AcO-DET and 4-HO-MET, the hERG assay was performed according to a previously described method (Yoon et al., 2019a,b). Briefly, the hERG assay was performed using Chinese hamster ovary (CHO) cells, and the drug concentration that inhibited the ionic currents by 50% was calculated using Hill equation: f = XH/(IC50H + XH); where, H = Hill coefficient, IC50 = 50% inhibitory concentration, X = concentration, f = inhibition ratio (Kirsch et al., 2004; Lee et al., 2016; Redfern et al., 2003; Shin et al., 2006). H9c2 cells were maintained in DMEM with 10% HI FBS and 1% antibiotics/antimycotics in an atmosphere of 95% air and 5% CO₂.
Subcutaneous brompheniramine for cutaneous analgesia in rats
2019, European Journal of PharmacologyCitation Excerpt :In in vitro experiments, brompheniramine has been shown to block muscarinic cholinergic receptors in human chinese hamster ovary (CHO) cells (Yasuda and Yasuda, 1999), sodium and calcium channels in CHO cells (Shin et al., 2006), as well as potassium channels in human embryonic kidney 293 (HEK-293) cells (Park et al., 2008). A previous electrophysiological study (Shin et al., 2006) showed that brompheniramine suppressed the transfected Nav1.5 channels from myocytes. Local anesthetic drugs blocked voltage-gated Na+ channels, and therefore induced the production of peripheral nerve block, spinal block, as well as skin infiltration anesthesia (Lirk et al., 2018).
Brugada syndrome after using cold medicine: Is there any relation?
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