Inhibition of G protein-gated K+ channels by tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia
Inhibition of G protein-gated K+ channels by tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia
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DOI：
10.1038/s41598-020-66673-8
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发表时间：
2020-06-17
影响因子：
4.6
通讯作者：
Mesirca, Pietro
中科院分区：
文献类型：
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作者：
Bidaud, Isabelle;Chong, Antony Chung You;Mesirca, Pietro
窦房结（SAN）功能障碍（SND）表现为低心率（HR），常伴有房性心动过速或房室（AV）传导阻滞。目前治疗慢性 SND 的唯一方法是植入电子起搏器。由于 SND 在人群中的负担日益增加，因此需要针对慢性 SND 和心脏传导阻滞的新药物疗法。我们开发了一系列转基因小鼠品系，概括了与不同程度的房室传导阻滞相关的人类原发性 SND。这些小鼠是通过 L 型 Ca(v)1.3 (Ca(v)1.3(-/-))、T 型 Ca(v)3.1 (Ca(v)3.1(-/-)) 或两者 (Ca(v)1.3(-/-)/Ca(v)3.1(-/-)) 基因消融而产生的。我们还研究了 Na+ 通道 Na(v)1.5 (Na(v)1.5(+/)) 单倍体不足的小鼠和超极化激活 f-(HCN4) 通道的 cAMP 依赖性调节已被废除的小鼠 (HCN4-CNBD)。我们通过遥测心电图记录分析了肽特硫平-Q 对 G 蛋白激活的 K+ 电流 (I-KACh) 的药理学抑制是否可以改善这些小鼠品系的 HR 和 AV 传导。 Tertiapin-Q 显着改善 Ca(v)1.3(-/-) (19%)、Ca(v)1.3(-/-)/Ca(v)3.1(-/-) (23%) 和 HCN4-CNBD (14%) 小鼠的 HR。 Tertiapin-Q 还将 Na(v)1.5(+/-) 小鼠的心脏传导改善了 24%。我们的数据表明，开发药理学 I-KACh 抑制剂来治疗 SND 和传导疾病是一种可行的方法。
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.