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000153375 041__ $$aEnglish
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000153375 1001_ $$aBidaud, Isabelle$$b0
000153375 245__ $$aInhibition of G protein-gated K+ channels by tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia.
000153375 260__ $$a[London]$$bMacmillan Publishers Limited, part of Springer Nature$$c2020
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000153375 520__ $$aSinus 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.
000153375 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
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000153375 650_2 $$2MeSH$$aAnimals
000153375 650_2 $$2MeSH$$aBee Venoms: pharmacology
000153375 650_2 $$2MeSH$$aBradycardia: metabolism
000153375 650_2 $$2MeSH$$aBradycardia: physiopathology
000153375 650_2 $$2MeSH$$aCalcium Channels, L-Type: metabolism
000153375 650_2 $$2MeSH$$aDisease Models, Animal
000153375 650_2 $$2MeSH$$aGTP-Binding Proteins: metabolism
000153375 650_2 $$2MeSH$$aHeart Conduction System: drug effects
000153375 650_2 $$2MeSH$$aHeart Rate: drug effects
000153375 650_2 $$2MeSH$$aMice
000153375 650_2 $$2MeSH$$aNAV1.5 Voltage-Gated Sodium Channel: metabolism
000153375 650_2 $$2MeSH$$aPotassium Channel Blockers: pharmacology
000153375 650_2 $$2MeSH$$aPotassium Channels: metabolism
000153375 650_2 $$2MeSH$$aSinoatrial Node: drug effects
000153375 650_2 $$2MeSH$$aSinoatrial Node: physiopathology
000153375 7001_ $$aChong, Antony Chung You$$b1
000153375 7001_ $$aCarcouet, Agnes$$b2
000153375 7001_ $$aWaard, Stephan De$$b3
000153375 7001_ $$aCharpentier, Flavien$$b4
000153375 7001_ $$aRonjat, Michel$$b5
000153375 7001_ $$aWaard, Michel De$$b6
000153375 7001_ $$0P:(DE-2719)2810976$$aIsbrandt, Dirk$$b7$$udzne
000153375 7001_ $$aWickman, Kevin$$b8
000153375 7001_ $$aVincent, Anne$$b9
000153375 7001_ $$aMangoni, Matteo E$$b10
000153375 7001_ $$0P:(DE-HGF)0$$aMesirca, Pietro$$b11$$eCorresponding author
000153375 773__ $$0PERI:(DE-600)2615211-3$$a10.1038/s41598-020-66673-8$$gVol. 10, no. 1, p. 9835$$n1$$p9835$$tScientific reports$$v10$$x2045-2322$$y2020
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