TY  - JOUR
AU  - Bidaud, Isabelle
AU  - Chong, Antony Chung You
AU  - Carcouet, Agnes
AU  - Waard, Stephan De
AU  - Charpentier, Flavien
AU  - Ronjat, Michel
AU  - Waard, Michel De
AU  - Isbrandt, Dirk
AU  - Wickman, Kevin
AU  - Vincent, Anne
AU  - Mangoni, Matteo E
AU  - Mesirca, Pietro
TI  - Inhibition of G protein-gated K+ channels by tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia.
JO  - Scientific reports
VL  - 10
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DZNE-2020-01372
SP  - 9835
PY  - 2020
AB  - 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
KW  - Animals
KW  - Bee Venoms: pharmacology
KW  - Bradycardia: metabolism
KW  - Bradycardia: physiopathology
KW  - Calcium Channels, L-Type: metabolism
KW  - Disease Models, Animal
KW  - GTP-Binding Proteins: metabolism
KW  - Heart Conduction System: drug effects
KW  - Heart Rate: drug effects
KW  - Mice
KW  - NAV1.5 Voltage-Gated Sodium Channel: metabolism
KW  - Potassium Channel Blockers: pharmacology
KW  - Potassium Channels: metabolism
KW  - Sinoatrial Node: drug effects
KW  - Sinoatrial Node: physiopathology
LB  - PUB:(DE-HGF)16
C6  - pmid:32555258
C2  - pmc:PMC7300035
DO  - DOI:10.1038/s41598-020-66673-8
UR  - https://pub.dzne.de/record/153375
ER  -