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

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.