Laboratório de CardioBiologia, Departamento de Biofísica, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil.
Laboratory of Heart Biophysics, Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil.
Eur J Pharmacol. 2024 Nov 15;983:176980. doi: 10.1016/j.ejphar.2024.176980. Epub 2024 Sep 4.
Dronedarone (DRN) is a clinically used drug to mitigate arrhythmias with multichannel block properties, including the sodium channel Na1.5. Extracellular acidification is known to change the pharmacological properties of several antiarrhythmic drugs. Here, we explore how modification in extracellular pH (pHe) shapes the pharmacological profile of DRN upon Na1.5 sodium current (I) and in the ex vivo heart preparation. Embryonic human kidney cells (HEK293T/17) were used to transiently express the human isoform of Na1.5 α-subunit. Patch-Clamp technique was employed to study I. Neurotoxin-II (ATX-II) was used to induce the late sodium current (I). Additionally, ex vivo Wistar male rat preparations in the Langendorff system were utilized to study electrocardiogram (ECG) waves. DRN preferentially binds to the closed state inactivation mode of Na1.5 at pHe 7.0. The recovery from I inactivation was delayed in the presence of DRN in both pHe 7.0 and 7.4, and the use-dependent properties were distinct at pHe 7.0 and 7.4. However, the potency of DRN upon the peak I, the voltage dependence for activation, and the steady-state inactivation curves were not altered in both pHe tested. Also, the pHe did not change the ability of DRN to block I. Lastly, DRN in a concentration and pH dependent manner modulated the QRS complex, QT and RR interval in clinically relevant concentration. Thus, the pharmacological properties of DRN upon Na1.5 and ex vivo heart preparation partially depend on the pHe. The pHe changed the biological effect of DRN in the heart electrical function in relevant clinical concentration.
多非利特（DRN）是一种临床应用的抗心律失常药物，具有多通道阻滞特性，包括钠通道 Na1.5。已知细胞外酸化会改变几种抗心律失常药物的药理学特性。在这里，我们探讨细胞外 pH（pHe）的改变如何影响 DRN 对 Na1.5 钠电流（I）的药理学特性，并在离体心脏标本中产生影响。我们使用瞬时表达人源 Na1.5 α亚基的胚胎人肾细胞（HEK293T/17）来进行研究。我们采用膜片钳技术来研究 I。神经毒素-II（ATX-II）用于诱导晚期钠电流（I）。此外，我们还使用 Langendorff 系统中的离体 Wistar 雄性大鼠标本来研究心电图（ECG）波。DRN 优先与 Na1.5 的关闭状态失活模式结合，在 pHe 7.0 时。在 pHe 7.0 和 7.4 存在 DRN 时，I 失活的恢复均被延迟，而使用依赖性特性在 pHe 7.0 和 7.4 时有所不同。然而，在两种测试的 pHe 中，DRN 对峰值 I、激活的电压依赖性和稳态失活曲线的作用强度均未改变。此外，DRN 也不会改变其对 I 的阻断作用。最后，DRN 以浓度和 pH 依赖性的方式调节 QRS 复合波、QT 和 RR 间期，其浓度在临床相关范围内。因此，DRN 对 Na1.5 和离体心脏标本的药理学特性部分依赖于 pHe。在相关临床浓度下，pHe 改变了 DRN 对心脏电功能的生物学效应。
