Home > Publications Database > Inhibition of G protein-gated K+ channels by tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia. > print

001     153375
005     20240321221043.0
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041 _ _ |a English
082 _ _ |a 600
100 1 _ |a Bidaud, Isabelle
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245 _ _ |a Inhibition of G protein-gated K+ channels by tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia.
260 _ _ |a [London]
|c 2020
|b Macmillan Publishers Limited, part of Springer Nature
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520 _ _ |a 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.
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650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Bee Venoms: pharmacology
|2 MeSH
650 _ 2 |a Bradycardia: metabolism
|2 MeSH
650 _ 2 |a Bradycardia: physiopathology
|2 MeSH
650 _ 2 |a Calcium Channels, L-Type: metabolism
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a GTP-Binding Proteins: metabolism
|2 MeSH
650 _ 2 |a Heart Conduction System: drug effects
|2 MeSH
650 _ 2 |a Heart Rate: drug effects
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a NAV1.5 Voltage-Gated Sodium Channel: metabolism
|2 MeSH
650 _ 2 |a Potassium Channel Blockers: pharmacology
|2 MeSH
650 _ 2 |a Potassium Channels: metabolism
|2 MeSH
650 _ 2 |a Sinoatrial Node: drug effects
|2 MeSH
650 _ 2 |a Sinoatrial Node: physiopathology
|2 MeSH
700 1 _ |a Chong, Antony Chung You
|b 1
700 1 _ |a Carcouet, Agnes
|b 2
700 1 _ |a Waard, Stephan De
|b 3
700 1 _ |a Charpentier, Flavien
|b 4
700 1 _ |a Ronjat, Michel
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700 1 _ |a Waard, Michel De
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700 1 _ |a Isbrandt, Dirk
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700 1 _ |a Wickman, Kevin
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700 1 _ |a Vincent, Anne
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700 1 _ |a Mangoni, Matteo E
|b 10
700 1 _ |a Mesirca, Pietro
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|e Corresponding author
773 _ _ |a 10.1038/s41598-020-66673-8
|g Vol. 10, no. 1, p. 9835
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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