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

Rui Hua, Sarah L. Macleod, Iuliia Polina, Motahareh Moghtadaei, Hailey J. Jansen, Oleg Bogachev, Stacy B. O'Blenes, John L. Sapp, Jean Francois Legare, Robert A. Rose

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 (I Ca,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 I Ca,L. ANP increased AP upstroke velocity (V max), AP duration, and I Ca,L similarly in wild-type and NPR-C -/- myocytes. In contrast, mANP decreased V max, AP duration, and I Ca,L, and these effects were completely absent in NPR-C -/- myocytes. ANP and mANP also had opposing effects on I Ca,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.

Original languageEnglish (US)
Pages (from-to)1240-1254
Number of pages15
JournalCirculation: Arrhythmia and Electrophysiology
Volume8
Issue number5
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

Keywords

  • action potentials
  • atrial fibrillation
  • atrial natriuretic peptides
  • calcium channels
  • electrophysiology

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