Abstract
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.
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This work was supported by the São Paulo Research Foundation (FAPESP) (through grants # 2019/21304-4, 2021/05584-7 and 2020/14635-1 to DRC, grant #2019/18918-0 to DSS, and grant #2021/15122-0 to LPM) and the National Council for Scientific and Technological Development [CNPq] # 304257/2020-6.
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Jorge Lucas Teixeira-Fonseca and Danilo Roman-Campos contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Jorge Lucas Teixeira-Fonseca, Julliane V. Joviano-Santos, Samuel Santos Bezerra, Michael Ramon de Lima Conceição, Polyana Leal-Silva, Leisiane Pereira Marques, and Diego Santos Souza. The first draft of the manuscript was written by Jorge Lucas Teixeira-Fonseca and Danilo Roman-Campos and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Teixeira-Fonseca, J.L., Joviano-Santos, J.V., Beserra, S.S. et al. Exploring the involvement of TASK-1 in the control of isolated rat right atrium function from healthy animals and an experimental model of monocrotaline-induced pulmonary hypertension. Naunyn-Schmiedeberg's Arch Pharmacol 396, 3775–3788 (2023). https://doi.org/10.1007/s00210-023-02569-4
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DOI: https://doi.org/10.1007/s00210-023-02569-4