Journal Article

DZNE-2020-01372

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Inhibition of G protein-gated K+ channels by tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia.

Bidaud, I. ; Chong, A. C. Y. ; Carcouet, A. ; Waard, S. D. ; Charpentier, F. ; Ronjat, M. ; Waard, M. D. ; Isbrandt, D.DZNE* ; Wickman, K. ; Vincent, A. ; Mangoni, M. E. ; Mesirca, P. (Corresponding author)

2020
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41598-020-66673-8

Abstract: Sinus node (SAN) dysfunction (SND) manifests as low heart rate (HR) and is often accompanied by atrial tachycardia or atrioventricular (AV) block. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Because of the growing burden of SND in the population, new pharmacological therapies of chronic SND and heart block are desirable. We developed a collection of genetically modified mouse strains recapitulating human primary SND associated with different degrees of AV block. These mice were generated with genetic ablation of L-type Cav1.3 (Cav1.3-/-), T-type Cav3.1 (Cav3.1-/-), or both (Cav1.3-/-/Cav3.1-/-). We also studied mice haplo-insufficient for the Na+ channel Nav1.5 (Nav1.5+/) and mice in which the cAMP-dependent regulation of hyperpolarization-activated f-(HCN4) channels has been abolished (HCN4-CNBD). We analysed, by telemetric ECG recording, whether pharmacological inhibition of the G-protein-activated K+ current (IKACh) by the peptide tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Cav1.3-/- (19%), Cav1.3-/-/Cav3.1-/- (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Nav1.5+/- mice by 24%. Our data suggest that the development of pharmacological IKACh inhibitors for the management of SND and conduction disease is a viable approach.

Keyword(s): Animals (MeSH) ; Bee Venoms: pharmacology (MeSH) ; Bradycardia: metabolism (MeSH) ; Bradycardia: physiopathology (MeSH) ; Calcium Channels, L-Type: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; GTP-Binding Proteins: metabolism (MeSH) ; Heart Conduction System: drug effects (MeSH) ; Heart Rate: drug effects (MeSH) ; Mice (MeSH) ; NAV1.5 Voltage-Gated Sodium Channel: metabolism (MeSH) ; Potassium Channel Blockers: pharmacology (MeSH) ; Potassium Channels: metabolism (MeSH) ; Sinoatrial Node: drug effects (MeSH) ; Sinoatrial Node: physiopathology (MeSH)

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Contributing Institute(s):

1. Experimental Neurophysiology (AG Isbrandt)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2020

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