Inhibition of cardiac K v 4.3 (I to ) channel isoforms by class I antiarrhythmic drugs lidocaine and mexiletine.

Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE

Publication: 2005- : Amsterdam : Elsevier Science
Original Publication: Amsterdam, North Holland Pub. Co.

Anti-Arrhythmia Agents/*pharmacology ; Lidocaine/*pharmacology ; Mexiletine/*pharmacology ; Potassium Channel Blockers/*pharmacology ; Shal Potassium Channels/*antagonists & inhibitors; Animals ; Female ; Heart Ventricles/metabolism ; Humans ; Male ; Oocytes ; Protein Isoforms/antagonists & inhibitors ; Protein Isoforms/genetics ; Shal Potassium Channels/genetics ; Shal Potassium Channels/physiology ; Xenopus laevis

Transient outward K ⁺ current, I to , contributes to cardiac action potential generation and is primarily carried by K v 4.3 (KCND3) channels. Two K v 4.3 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 K v 4.3 channels and potential implications for remodeling-based antiarrhythmic management have not been assessed to date. We sought to test the hypotheses that K v 4.3 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 (K v 4.3-L) and short (K v 4.3-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 (IC 50 -K v 4.3-L: 0.8 mM; IC 50 -K v 4.3-S: 1.2 mM) and mexiletine (IC 50 -K v 4.3-L: 146 μM; IC 50 -K v 4.3-S: 160 μM) inhibited K v 4.3 with different sensitivity. Biophysical analyses identified accelerated and enhanced inactivation combined with delayed recovery from inactivation as primary biophysical mechanisms underlying K v 4.3 current reduction. In conclusion, differential effects on K v 4.3 isoforms extend the electropharmacological profile of lidocaine and mexiletine. Patient-specific remodeling of K v 4.3 isoforms may determine individual drug responses and requires consideration during clinical application of compounds targeting K v 4.3.
Competing Interests: Declaration of competing interest A.K.R. reports educational support from Boston Scientific and Medtronic. D.T. reports receiving lecture fees/honoraria from Bayer Vital, Boehringer Ingelheim Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Pfizer Pharma, Sanofi-Aventis, St. Jude Medical and ZOLL CMS. P.L. reports receiving lecture fees from Bayer Vital and Pfizer Pharma and educational support from Boston Scientific and Johnson & Johnson. B.S. reports personal fees for surgical proctoring services from Abbott. The remaining authors have reported that they have no relationships relevant to the content of this paper to disclose.
(Copyright © 2020 Elsevier B.V. All rights reserved.)

Keywords: Action potential; Heart failure; K(v)4.3 channel; Lidocaine; Mexiletine; Ventricular tachycardia

0 (Anti-Arrhythmia Agents)
0 (Potassium Channel Blockers)
0 (Protein Isoforms)
0 (Shal Potassium Channels)
1U511HHV4Z (Mexiletine)
98PI200987 (Lidocaine)

Date Created: 20200504 Date Completed: 20210324 Latest Revision: 20210324

20240829

10.1016/j.ejphar.2020.173159

32360350