Adenosine monophosphate-regulated protein kinase inhibition modulates electrophysiological characteristics and calcium homeostasis of rabbit right ventricular outflow tract

Yen Yu Lu, Chen Chuan Cheng, Yao Chang Chen, Yung Kuo Lin, Satoshi Higa, Yu Hsun Kao, Yi Jen Chen

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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. Objectives: The purpose of this study was to access whether AMPK inhibition would modulate RVOT electrophysiology, calcium (Ca2+) regulation, and RVOT arrhythmogenesis or not. Methods: 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 Ca2+ transients in isolated rabbit RVOT cardiomyocytes. Results: 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 Ca2+ transients, late sodium (Na+), peak L-type Ca2+ current density, Na+-Ca2+ exchanger, transient outward potassium (K+) current, and rapid and slow delayed rectifier K+ currents. Conclusion: AMPK inhibition modulates RVOT electrophysiological characteristics and Ca2+ homeostasis, contributing to lower RVOT arrhythmogenic activity. Accordingly, AMPK inhibition might potentially reduce ventricular tachyarrhythmias.
Original languageEnglish
Pages (from-to)e12953
Number of pages14
JournalFundamental and Clinical Pharmacology
Volume38
Issue number2
DOIs
Publication statusPublished - Sept 2023

Keywords

  • AMPK
  • calcium homeostasis
  • electrophysiological characteristics
  • right ventricular outflow tract
  • ventricular arrhythmia

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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