Laboratory of Cardiobiology, Department of Biophysics, Paulista School of Medicina, Federal University of Sao Paulo, Botucatu Street, 862, Biological Science Building, 7th floor, São Paulo, São Paulo, Brazil.
Post-Graduate Program in Health Sciences, Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2023 Dec;396(12):3775-3788. doi: 10.1007/s00210-023-02569-4. Epub 2023 Jun 20.
The TASK-1 channel belongs to the two-pore domain potassium channel family. It is expressed in several cells of the heart, including the right atrial (RA) cardiomyocytes and the sinus node, and TASK-1 channel has been implicated in the pathogenesis of atrial arrhythmias (AA). Thus, using the rat model of monocrotaline-induced pulmonary hypertension (MCT-PH), we explored the involvement of TASK-1 in AA. Four-week-old male Wistar rats were injected with 50 mg/kg of MCT to induce MCT-PH and isolated RA function was studied 14 days later. Additionally, isolated RA from six-week-old male Wistar rats were used to explore the ability of ML365, a selective blocker of TASK-1, to modulate RA function. The hearts developed right atrial and ventricular hypertrophy, inflammatory infiltrate and the surface ECG demonstrated increased P wave duration and QT interval, which are markers of MCT-PH. The isolated RA from the MCT animals showed enhanced chronotropism, faster contraction and relaxation kinetics, and a higher sensibility to extracellular acidification. However, the addition of ML365 to extracellular media was not able to restore the phenotype. Using a burst pacing protocol, the RA from MCT animals were more susceptible to develop AA, and simultaneous administration of carbachol and ML365 enhanced AA, suggesting the involvement of TASK-1 in AA induced by MCT. TASK-1 does not play a key role in the chronotropism and inotropism of healthy and diseased RA; however, it may play a role in AA in the MCT-PH model.
TASK-1 通道属于双孔钾通道家族。它在心脏的几种细胞中表达，包括右心房（RA）心肌细胞和窦房结，并且 TASK-1 通道已被牵连到房性心律失常（AA）的发病机制中。因此，我们使用野百合碱诱导的肺动脉高压（MCT-PH）大鼠模型，探讨了 TASK-1 在 AA 中的作用。将 50mg/kg 的 MCT 注射到 4 周龄雄性 Wistar 大鼠中，以诱导 MCT-PH，并在 14 天后研究 RA 功能。此外，还使用 6 周龄雄性 Wistar 大鼠的 RA 来探讨 TASK-1 的选择性阻断剂 ML365 调节 RA 功能的能力。心脏发生右心房和心室肥大、炎症浸润，体表心电图显示 P 波持续时间和 QT 间期增加，这是 MCT-PH 的标志物。MCT 动物的分离 RA 显示出增强的变时性、更快的收缩和舒张动力学，以及对外周酸化的更高敏感性。然而，将 ML365 添加到细胞外介质中不能恢复表型。使用突发起搏方案，MCT 动物的 RA 更容易发生 AA，同时给予卡巴胆碱和 ML365 增强 AA，提示 TASK-1 参与了 MCT 诱导的 AA。TASK-1 在健康和患病 RA 的变时性和变力性中不起关键作用；然而，它可能在 MCT-PH 模型中的 AA 中发挥作用。
