Division of Cardiology, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei City, Taiwan.
School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
Fundam Clin Pharmacol. 2024 Apr;38(2):262-275. doi: 10.1111/fcp.12953. Epub 2023 Sep 4.
Metabolic stress predisposes to ventricular arrhythmias and sudden cardiac death. Right ventricular outflow tract (RVOT) is the common origin of ventricular arrhythmias. Adenosine monophosphate-regulated protein kinase (AMPK) activation is an important compensatory mechanism for cardiac remodeling during metabolic stress.
The purpose of this study was to access whether AMPK inhibition would modulate RVOT electrophysiology, calcium (Ca ) regulation, and RVOT arrhythmogenesis or not.
Conventional microelectrodes were used to record electrical activity before and after compound C (10 µM, an AMPK inhibitor) in isoproterenol (1 µM)-treated rabbit RVOT tissue preparations under electrical pacing. Whole-cell patch-clamp and confocal microscopic examinations were performed in baseline and compound C-treated rabbit RVOT cardiomyocytes to investigate ionic currents and intracellular Ca transients in isolated rabbit RVOT cardiomyocytes.
Compound C decreased RVOT contractility, and reversed isoproterenol increased RVOT contractility. Compound C decreased the incidence, rate, and duration of isoproterenol-induced RVOT burst firing under rapid pacing. Compared to baseline, compound C-treated RVOT cardiomyocytes had a longer action potential duration, smaller intracellular Ca transients, late sodium (Na ), peak L-type Ca current density, Na -Ca exchanger, transient outward potassium (K ) current, and rapid and slow delayed rectifier K currents.
AMPK inhibition modulates RVOT electrophysiological characteristics and Ca homeostasis, contributing to lower RVOT arrhythmogenic activity. Accordingly, AMPK inhibition might potentially reduce ventricular tachyarrhythmias.
代谢应激使心室性心律失常和心脏性猝死的风险增加。右心室流出道（RVOT）是室性心律失常的常见起源部位。腺苷单磷酸调节蛋白激酶（AMPK）的激活是代谢应激时心脏重构的重要代偿机制。
本研究旨在探讨 AMPK 抑制是否会调节 RVOT 的电生理、钙（Ca）调节和 RVOT 心律失常发生。
使用常规微电极，在异丙肾上腺素（1 μM）处理的兔 RVOT 组织标本中，在电起搏前后记录化合物 C（10 μM，一种 AMPK 抑制剂）处理前后的电活动。在基础状态和化合物 C 处理的兔 RVOT 心肌细胞中进行全细胞膜片钳和共聚焦显微镜检查，以研究分离的兔 RVOT 心肌细胞中的离子电流和细胞内 Ca 瞬变。
化合物 C 降低了 RVOT 的收缩性，并逆转了异丙肾上腺素对 RVOT 收缩性的增强。与基础状态相比，化合物 C 降低了快速起搏下异丙肾上腺素诱导的 RVOT 爆发性放电的发生率、频率和持续时间。与基础状态相比，化合物 C 处理的 RVOT 心肌细胞的动作电位持续时间更长，细胞内 Ca 瞬变更小，晚期钠（Na）、峰值 L 型 Ca 电流密度、Na-Ca 交换体、瞬间外向钾（K）电流、快速和缓慢延迟整流钾电流更大。
AMPK 抑制调节 RVOT 的电生理特征和 Ca 稳态，降低 RVOT 的心律失常活性。因此，AMPK 抑制可能潜在地减少室性心动过速。
