Effects of Wild-Type and Mutant Forms of Atrial Natriuretic Peptide on Atrial Electrophysiology and Arrhythmogenesis

Circ Arrhythm Electrophysiol. 2015 Oct;8(5):1240-54. doi: 10.1161/CIRCEP.115.002896. Epub 2015 Jul 30.

Abstract

Background: Atrial natriuretic peptide (ANP) is a hormone with numerous beneficial cardiovascular effects. Recently, a mutation in the ANP gene, which results in the generation of a mutant form of ANP (mANP), was identified and shown to cause atrial fibrillation in people. The mechanism(s) through which mANP causes atrial fibrillation is unknown. Our objective was to compare the effects of wild-type ANP and mANP on atrial electrophysiology in mice and humans.

Methods and results: Action potentials (APs), L-type Ca(2+) currents (ICa,L), and Na(+) current were recorded in atrial myocytes from wild-type or natriuretic peptide receptor C knockout (NPR-C(-/-)) mice. In mice, ANP and mANP (10-100 nmol/L) had opposing effects on atrial myocyte AP morphology and ICa,L. ANP increased AP upstroke velocity (Vmax), AP duration, and ICa,L similarly in wild-type and NPR-C(-/-) myocytes. In contrast, mANP decreased Vmax, AP duration, and ICa,L, and these effects were completely absent in NPR-C(-/-) myocytes. ANP and mANP also had opposing effects on ICa,L in human atrial myocytes. In contrast, neither ANP nor mANP had any effect on Na(+) current in mouse atrial myocytes. Optical mapping studies in mice demonstrate that ANP sped electric conduction in the atria, whereas mANP did the opposite and slowed atrial conduction. Atrial pacing in the presence of mANP induced arrhythmias in 62.5% of hearts, whereas treatment with ANP completely prevented the occurrence of arrhythmias.

Conclusions: These findings provide mechanistic insight into how mANP causes atrial fibrillation and demonstrate that wild-type ANP is antiarrhythmic.

Keywords: action potentials; atrial fibrillation; atrial natriuretic peptides; calcium channels; electrophysiology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects*
  • Action Potentials / physiology
  • Animals
  • Atrial Fibrillation / drug therapy*
  • Atrial Fibrillation / physiopathology*
  • Atrial Natriuretic Factor / pharmacology*
  • Cardiac Pacing, Artificial
  • Electrophysiological Phenomena / drug effects*
  • Heart Atria / drug effects*
  • Heart Atria / physiopathology
  • Humans
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / drug effects*

Substances

  • Atrial Natriuretic Factor