Inhibition of cardiac Kv4.3 (Ito) channel isoforms by class I antiarrhythmic drugs lidocaine and mexiletine.
Eur J Pharmacol
; 880: 173159, 2020 Aug 05.
Article
em En
| MEDLINE
| ID: mdl-32360350
ABSTRACT
Transient outward K+ current, Ito, contributes to cardiac action potential generation and is primarily carried by Kv4.3 (KCND3) channels. Two Kv4.3 isoforms are expressed in human ventricle and show differential remodeling in heart failure (HF). Lidocaine and mexiletine may be applied in selected patients to suppress ventricular arrhythmias, without effects on sudden cardiac death or mortality. Isoform-dependent effects of antiarrhythmic drugs on Kv4.3 channels and potential implications for remodeling-based antiarrhythmic management have not been assessed to date. We sought to test the hypotheses that Kv4.3 channels are targeted by lidocaine and mexiletine, and that drug sensitivity is determined in isoform-specific manner. Expression of KCND3 isoforms was quantified using qRT-PCR in left ventricular samples of patients with HF due to either ischemic or dilated cardiomyopathies (ICM or DCM). Long (Kv4.3-L) and short (Kv4.3-S) isoforms were heterologously expressed in Xenopus laevis oocytes to study drug sensitivity and effects on biophysical characteristics activation, deactivation, inactivation, and recovery from inactivation. In the present HF patient cohort KCND3 isoform expression did not differ between ICM and DCM. In vitro, lidocaine (IC50-Kv4.3-L 0.8 mM; IC50-Kv4.3-S 1.2 mM) and mexiletine (IC50-Kv4.3-L 146 µM; IC50-Kv4.3-S 160 µM) inhibited Kv4.3 with different sensitivity. Biophysical analyses identified accelerated and enhanced inactivation combined with delayed recovery from inactivation as primary biophysical mechanisms underlying Kv4.3 current reduction. In conclusion, differential effects on Kv4.3 isoforms extend the electropharmacological profile of lidocaine and mexiletine. Patient-specific remodeling of Kv4.3 isoforms may determine individual drug responses and requires consideration during clinical application of compounds targeting Kv4.3.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Bloqueadores dos Canais de Potássio
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Canais de Potássio Shal
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Lidocaína
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Mexiletina
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Antiarrítmicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Eur J Pharmacol
Ano de publicação:
2020
Tipo de documento:
Article