Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Current

Tamura, Atsushi; Ogura, Takehiko; Uemura, Hiroko; Reien, Yoshie; Kishimoto, Takashi; Nagai, Toshio; Komuro, Issei; Miyazaki, Masaru; Nakaya, Haruaki

doi:10.1254/jphs.08312fp

Cited by 41 publications

(28 citation statements)

References 30 publications

(21 reference statements)

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“…We also found that lidocaine modulated cloned HCN2 and HCN4 homomeric channel currents via a decrease in tonic and maximal current amplitude, but with no change in voltage dependence of activation. Our observations regarding the effects of lidocaine on mouse HCN4 currents are generally consistent with an earlier report of rabbit HCN4 current modulation by lidocaine (Tamura et al, 2009). HCN channel inhibition was observed at concentrations that can be readily achieved during systemic administration of lidocaine (Ed- Fig.…”

Section: Discussionsupporting

confidence: 91%

“…The current study extends previous work on HCN4 (Tamura et al, 2009) and demonstrates that HCN channel inhibition by lidocaine includes HCN1 and HCN2, the two other HCN subunits expressed in cardiomyocytes. These results could thus be relevant for both classic antiarrhythmic actions and cardiotoxic effects of systemic lidocaine (Trujillo and Nolan, 2000;Pinter and Dorian, 2001).…”

Section: Discussionsupporting

confidence: 88%

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Local Anesthetic Inhibits Hyperpolarization-Activated Cationic Currents

Meng

Liu²,

Bayliss³

et al. 2011

Mol Pharmacol

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Systemic administration of local anesthetics has beneficial perioperative properties and an anesthetic-sparing and antiarrhythmic effect, although the detailed mechanisms of these actions remain unclear. In the present study, we investigated the effects of a local anesthetic, lidocaine, on hyperpolarizationactivated and cyclic nucleotide-gated (HCN) channels that contribute to the pacemaker currents in rhythmically oscillating cells of the heart and brain. Voltage-clamp recordings were used to examine the properties of cloned HCN subunit currents expressed in Xenopus laevis oocytes and human embryonic kidney (HEK) 293 cells under control condition and lidocaine administration. Lidocaine inhibited HCN1, HCN2, HCN1-HCN2, and HCN4 channel currents at 100 M in both oocytes and/or HEK 293 cells; it caused a decrease in both tonic and maximal current (ϳ30 -50% inhibition) and slowed current activation kinetics for all subunits. In addition, lidocaine evoked a hyperpolarizing shift in half-activation voltage (⌬V 1/2 of ϳϪ10 to Ϫ14 mV), but only for HCN1 and HCN1-HCN2 channels. By fitting concentration-response data to logistic functions, we estimated half-maximal (EC 50 ) concentrations of lidocaine of ϳ30 to 40 M for the shift in V 1/2 observed with HCN1 and HCN1-HCN2; for inhibition of current amplitude, calculated EC 50 values were ϳ50 to 70 M for HCN1, HCN2, and HCN1-HCN2 channels. A lidocaine metabolite, monoethylglycinexylidide (100 M), had similar inhibitory actions on HCN channels. These results indicate that lidocaine potently inhibits HCN channel subunits in dose-dependent manner over a concentration range relevant for systemic application. The ability of local anesthetics to modulate I h in central neurons may contribute to central nervous system depression, whereas effects on I f in cardiac pacemaker cells may contribute to the antiarrhythmic and/or cardiovascular toxic action.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 88%

Local Anesthetic Inhibits Hyperpolarization-Activated Cationic Currents

Meng

Liu²,

Bayliss³

et al. 2011

Mol Pharmacol

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“…4C). Although a small inhibitory effect on HCN channels explaining the nonsignificant decrease of the phase 4 slope (to 584.16 Ϯ 79.55 FU/s) could not be ruled out (20), lidocaine rather prolonged phase 4 of the cardiomyocyte electrical activity, whereas ivabradine slowed it down dose dependently. Additionally, these results strongly suggest that HCN channels are functionally involved in the generation of phase 4 of the action potential of the Cor.4U cells and participate in the regulation of their spontaneous beating rate.…”

Section: Waveform Recording: Microscope Vs Plate Reader Signalsmentioning

confidence: 91%

High-throughput drug profiling with voltage- and calcium-sensitive fluorescent probes in human iPSC-derived cardiomyocytes

Bedut

Seminatore-Nole

Lamamy

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Bedut S, Seminatore-Nole C, Lamamy V, Caignard S, Boutin JA, Nosjean O, Stephan JP, Coge F. High-throughput drug profiling with voltage-and calcium-sensitive fluorescent probes in human iPSC-derived cardiomyocytes. Am J Physiol Heart Circ Physiol 311: H44 -H53, 2016. First published May 3, 2016 doi:10.1152/ajpheart.00793.2015.-Cardiomyocytes derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (hiPSCs) are increasingly used for in vitro assays and represent an interesting opportunity to increase the data throughput for drug development. In this work, we describe a 96-well recording of synchronous electrical activities from spontaneously beating hiPSC-derived cardiomyocyte monolayers. The signal was obtained with a fast-imaging plate reader using a submillisecond-responding membrane potential recording assay, FluoVolt, based on a newly derived voltagesensitive fluorescent dye. In our conditions, the toxicity of the dye was moderate and compatible with episodic recordings for Ͼ3 h. We show that the waveforms recorded from a whole well or from a single cell-sized zone are equivalent and make available critical functional parameters that are usually accessible only with gold standard techniques like intracellular microelectrode recording. This approach allows accurate identification of the electrophysiological effects of reference drugs on the different phases of the cardiac action potential as follows: fast depolarization (lidocaine), early repolarization (nifedipine, Bay K8644, and veratridine), late repolarization (dofetilide), and diastolic slow depolarization (ivabradine). Furthermore, the data generated with the FluoVolt dye can be pertinently complemented with a calcium-sensitive dye for deeper characterization of the pharmacological responses. In a semiautomated plate reader, the two probes used simultaneously in 96-well plates provide an easy and powerful multiparametric assay to rapidly and precisely evaluate the cardiotropic profile of compounds for drug discovery or cardiac safety.

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“…Whole-cell membrane current recording was performed in MIN6 cells at room temperature, as described previously (17 1 mM MgCl 2 , 20 mM CsCl, 5 mM ATP-K 2 , 10 mM EGTA, and 5 mM HEPES, and was adjusted to pH 7.4. The patch pipettes, made from glass capillaries with a diameter of 1.5 mm using a vertical microelectrode puller, were filled with the internal solution, and their resistance was 5 -10 MΩ.…”

Section: Patch Clamp Studymentioning

confidence: 99%

Inhibition of ATP-Sensitive K+ Channels and L-Type Ca2+ Channels by Amiodarone Elicits Contradictory Effect on Insulin Secretion in MIN6 Cells

et al. 2011

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Abstract. Some class I antiarrhythmic drugs induce a sporadic hypoglycemia by producing insulin secretion via inhibition of ATP-sensitive K + (K ATP ) channels of pancreatic β-cells. It remains undetermined whether amiodarone produces insulin secretion by inhibiting K ATP channels. In this study, effects of amiodarone on K ATP channels, L-type Ca 2+ channel, membrane potential, and insulin secretion were examined and compared with those of quinidine in a β-cell line (MIN6). Amiodarone as well as quinidine inhibited the openings of the K ATP channel in a concentration-dependent manner without affecting its unitary amplitude in inside-out membrane patches of single MIN6 cells, and the IC 50 values were 0.24 and 4.9 μM, respectively. The L-type Ca 2+ current was also inhibited by amiodarone as well as quinidine in a concentration-dependent manner. Although glibenclamide (0.1 μM) or quinidine (10 μM) significantly potentiated the insulin secretion from MIN6 cells, amiodarone (1 -30 μM) failed to increase insulin secretion. Amiodarone (30 μM) and nifedipine (10 μM) significantly inhibited the increase in insulin secretion produced by 0.1 μM glibenclamide. Amiodarone (30 μM) produced a gradual decrease of the membrane potential, but did not produce repetitive electrical activity in MIN6 cells. Glibenclamide (1 μM) produced a slow depolarization, followed by spiking activity which was inhibited by 30 μM amiodarone. Thus, amiodarone is unlikely to produce hypoglycemia in spite of potent inhibitory action on K ATP channels in insulin-secreting cells, possibly due to its Ca 2+ channel-blocking action.

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Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Current

Cited by 41 publications

References 30 publications

Local Anesthetic Inhibits Hyperpolarization-Activated Cationic Currents

Local Anesthetic Inhibits Hyperpolarization-Activated Cationic Currents

High-throughput drug profiling with voltage- and calcium-sensitive fluorescent probes in human iPSC-derived cardiomyocytes

Inhibition of ATP-Sensitive K+ Channels and L-Type Ca2+ Channels by Amiodarone Elicits Contradictory Effect on Insulin Secretion in MIN6 Cells

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