Abstract

The cardiac tissue contains not only beta-type adrenergic receptors (ARs) but also alpha-type ARs (α-ARs). Both types of ARs play a significant role in the regulation of the electrophysiology of cardiomyocytes in different parts of the heart, including the atrioventricular node (AVN). An augmentation of the α₁‑AR mediated component of adrenergic signaling causes an impaired conduction of excitation in the heart and the onset of different rhythm disturbances, including AVN-associated arrhythmias. The activation of α₁‑AR facilitates anionic transmembrane transport causing electrophysiological changes in myocytes. The purpose of this research is to study the effects of anion/chlorine blockade on the α₁-AR-mediated proarrhythmic alteration of AVN functioning. The functional characteristics of AVN, including AVN conduction time, AVN refractoriness, and AVN conduction alterations, were examined via recording of surface electrograms in the Langendorff-perfused isolated rat heart (Wistar, 250 ± 30 g). Phenylephrine (PE, 10 µM) was used as an α₁-AR agonist. Probenecid (100 µM) was used as the anion/chlorine transmembrane conductance blocker. The activation of α₁-AR by the PE agonist results in a statistically significant increase in atrioventricular delay (AVD, N = 10, p < 0.001) and the effective refractory period (ERP) in the AVN (by 9.8 ± 1.2%, n = 10, p < 0.001). Also, PE induces AV-blocks and oscillations in AVD (N = 10) at stimulation rates close to ERP. Probenecid significantly reduces the range of AVD oscillations during nonstationary conduction in the AVN. In addition, the probenecid attenuates the ERP prolongation caused by PE (107 ± 4 ms, N = 6 and 114.2 ± 5.35 ms, N = 10 in the presence of PE alone and PE with probenecid, respectively), thereby returning its values to the typical level for normal conditions. As a result, probenecid maintains the physiological mode of AVN conduction when α₁-ARs are stimulated. This also suggests that chloride channels and anion carriers may contribute to α₁-AR-mediated AVN arrhythmias.

中文翻译：

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丙磺舒对大鼠心脏房室结α-1-肾上腺素受体激活致心律失常作用的影响

摘要

心脏组织不仅含有β型肾上腺素受体（AR），还含有α型肾上腺素受体（α-AR）。两种类型的 AR 在心脏不同部位（包括房室结（AVN））心肌细胞电生理的调节中发挥着重要作用。 α ₁ -AR 介导的肾上腺素信号传导成分的增强会导致心脏兴奋传导受损，并引发不同的节律紊乱，包括 AVN 相关的心律失常。 α ₁ -AR的激活促进阴离子跨膜转运，导致肌细胞发生电生理变化。本研究的目的是研究阴离子/氯阻断对 α ₁ -AR 介导的 AVN 功能致心律失常改变的影响。通过记录 Langendorff 灌注的离体大鼠心脏（Wistar，250 ± 30 g）的表面电图来检查 AVN 的功能特征，包括 AVN 传导时间、AVN 不应性和 AVN 传导改变。去氧肾上腺素 (PE, 10 µM) 用作 α ₁ -AR 激动剂。使用丙磺舒 (100 µM) 作为阴离子/氯跨膜电导阻滞剂。 PE 激动剂激活 α _{1 -AR 导致房室延迟 (AVD,} N = 10, p < 0.001) 和 AVN 有效不应期 (ERP)显着增加（增加 9.8 ± 1.2%， n ）。 = 10，p < 0.001）。此外，PE在接近 ERP 的刺激速率下会引起 AV 阻滞和 AVD 振荡 ( N = 10)。丙磺舒显着降低 AVN 非稳态传导期间 AVD 振荡的范围。此外，丙磺舒减弱了 PE 引起的 ERP 延长（单独使用 PE 和使用丙磺舒的 PE 时分别为107 ± 4 ms， N = 6 和 114.2 ± 5.35 ms，N = 10），从而将其值恢复到正常条件下的典型水平。因此，当 α ₁ -AR 受到刺激时，丙磺舒可维持 AVN 传导的生理模式。这也表明氯离子通道和阴离子载体可能导致α1 _- AR介导的AVN心律失常。