Universität zu Köln

Bidaud, Isabelle, Chong, Antony Chung You, Carcouet, Agnes, Waard, Stephan De, Charpentier, Flavien ORCID: 0000-0002-5057-0998, Ronjat, Michel ORCID: 0000-0002-9728-6425, Waard, Michel De, Isbrandt, Dirk, Wickman, Kevin, Vincent, Anne ORCID: 0000-0002-4743-2068, Mangoni, Matteo E. and Mesirca, Pietro (2020). Inhibition of G protein-gated K+ channels by tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia. Sci Rep, 10 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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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 Ca(v)1.3 (Ca(v)1.3(-/-)), T-type Ca(v)3.1 (Ca(v)3.1(-/-)), or both (Ca(v)1.3(-/-)/Ca(v)3.1(-/-)). We also studied mice haplo-insufficient for the Na+ channel Na(v)1.5 (Na(v)1.5(+/)) 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 (I-KACh) by the peptide tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Ca(v)1.3(-/-) (19%), Ca(v)1.3(-/-)/Ca(v)3.1(-/-) (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Na(v)1.5(+/-) mice by 24%. Our data suggest that the development of pharmacological I-KACh inhibitors for the management of SND and conduction disease is a viable approach.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bidaud, Isabelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Chong, Antony Chung You UNSPECIFIED UNSPECIFIED UNSPECIFIED Carcouet, Agnes UNSPECIFIED UNSPECIFIED UNSPECIFIED Waard, Stephan De UNSPECIFIED UNSPECIFIED UNSPECIFIED Charpentier, Flavien UNSPECIFIED orcid.org/0000-0002-5057-0998 UNSPECIFIED Ronjat, Michel UNSPECIFIED orcid.org/0000-0002-9728-6425 UNSPECIFIED Waard, Michel De UNSPECIFIED UNSPECIFIED UNSPECIFIED Isbrandt, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Wickman, Kevin UNSPECIFIED UNSPECIFIED UNSPECIFIED Vincent, Anne UNSPECIFIED orcid.org/0000-0002-4743-2068 UNSPECIFIED Mangoni, Matteo E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mesirca, Pietro UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-329741
DOI:	10.1038/s41598-020-66673-8
Journal or Publication Title:	Sci Rep
Volume:	10
Number:	1
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HIGH-AFFINITY INHIBITOR; HEART-RATE; FUNCTIONAL ROLES; I-KACH; TARGETED DISRUPTION; CAMP SENSITIVITY; TASK-FORCE; MUTATIONS; CA(V)1.3; RHYTHM Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32974