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.
Bibliographical noteFunding Information:
We thank the Réseau d’Animaleries de Montpellier (RAM) of Biocampus facility for the management of mouse lines. We thank all the personnel of the PCEA mouse breeding facility in Montpellier and of the iExplore platform for help in functional exploration of the mouse SND lines. The IGF research group is a member of the Laboratory of Excellence “Ion Channel Science and Therapeutics” supported by a grant from ANR (ANR-11-LABX-0015). Research has been supported by the Fondation pour la Recherche Medicale “Physiopathologie Cardiovasculaire” (DPC20171138970 to M.E.M.), by the Agence Nationale de Recherche (ANR-15-CE14-0004-01 to M.E.M and M.D.W.), the Fondation Genavie (to F.C.), the National Institutes of Health (HL105550 to K.W.) and the Fondation Leducq (TNE FANTASY 19CVD03 to M.E.M.).
© 2020, The Author(s).
- Bee Venoms/pharmacology
- Calcium Channels, L-Type/metabolism
- Disease Models, Animal
- GTP-Binding Proteins/metabolism
- Heart Conduction System/drug effects
- Heart Rate/drug effects
- NAV1.5 Voltage-Gated Sodium Channel/metabolism
- Potassium Channel Blockers/pharmacology
- Potassium Channels/metabolism
- Sinoatrial Node/drug effects
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural