title: Effects of Wild-Type and Mutant Forms of Atrial Natriuretic Peptide on Atrial Electrophysiology and Arrhythmogenesis.
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.
  
  
  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.
authors.affiliation: From the Department of Physiology and Biophysics (R.H., S.L.M., I.P., M.M., H.J.J., O.B., S.B.O., J.L.S., R.A.R.), IWK Health Centre (S.B.O.), Department of Surgery (S.B.O., J.-F.L.), Division of Cardiology (J.L.S.), School of Biomedical Engineering (R.A.R.), Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Hua
authors.affiliation: From the Department of Physiology and Biophysics (R.H., S.L.M., I.P., M.M., H.J.J., O.B., S.B.O., J.L.S., R.A.R.), IWK Health Centre (S.B.O.), Department of Surgery (S.B.O., J.-F.L.), Division of Cardiology (J.L.S.), School of Biomedical Engineering (R.A.R.), Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: MacLeod
authors.affiliation: From the Department of Physiology and Biophysics (R.H., S.L.M., I.P., M.M., H.J.J., O.B., S.B.O., J.L.S., R.A.R.), IWK Health Centre (S.B.O.), Department of Surgery (S.B.O., J.-F.L.), Division of Cardiology (J.L.S.), School of Biomedical Engineering (R.A.R.), Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Iuliia
authors.initials: I
authors.lastname: Polina
authors.affiliation: From the Department of Physiology and Biophysics (R.H., S.L.M., I.P., M.M., H.J.J., O.B., S.B.O., J.L.S., R.A.R.), IWK Health Centre (S.B.O.), Department of Surgery (S.B.O., J.-F.L.), Division of Cardiology (J.L.S.), School of Biomedical Engineering (R.A.R.), Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Motahareh
authors.initials: M
authors.lastname: Moghtadaei
authors.affiliation: From the Department of Physiology and Biophysics (R.H., S.L.M., I.P., M.M., H.J.J., O.B., S.B.O., J.L.S., R.A.R.), IWK Health Centre (S.B.O.), Department of Surgery (S.B.O., J.-F.L.), Division of Cardiology (J.L.S.), School of Biomedical Engineering (R.A.R.), Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Hailey J
authors.initials: HJ
authors.lastname: Jansen
authors.affiliation: From the Department of Physiology and Biophysics (R.H., S.L.M., I.P., M.M., H.J.J., O.B., S.B.O., J.L.S., R.A.R.), IWK Health Centre (S.B.O.), Department of Surgery (S.B.O., J.-F.L.), Division of Cardiology (J.L.S.), School of Biomedical Engineering (R.A.R.), Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Oleg
authors.initials: O
authors.lastname: Bogachev
authors.affiliation: From the Department of Physiology and Biophysics (R.H., S.L.M., I.P., M.M., H.J.J., O.B., S.B.O., J.L.S., R.A.R.), IWK Health Centre (S.B.O.), Department of Surgery (S.B.O., J.-F.L.), Division of Cardiology (J.L.S.), School of Biomedical Engineering (R.A.R.), Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Stacy B
authors.initials: SB
authors.lastname: O'Blenes
authors.affiliation: From the Department of Physiology and Biophysics (R.H., S.L.M., I.P., M.M., H.J.J., O.B., S.B.O., J.L.S., R.A.R.), IWK Health Centre (S.B.O.), Department of Surgery (S.B.O., J.-F.L.), Division of Cardiology (J.L.S.), School of Biomedical Engineering (R.A.R.), Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: John L
authors.initials: JL
authors.lastname: Sapp
authors.affiliation: From the Department of Physiology and Biophysics (R.H., S.L.M., I.P., M.M., H.J.J., O.B., S.B.O., J.L.S., R.A.R.), IWK Health Centre (S.B.O.), Department of Surgery (S.B.O., J.-F.L.), Division of Cardiology (J.L.S.), School of Biomedical Engineering (R.A.R.), Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Legare
authors.affiliation: From the Department of Physiology and Biophysics (R.H., S.L.M., I.P., M.M., H.J.J., O.B., S.B.O., J.L.S., R.A.R.), IWK Health Centre (S.B.O.), Department of Surgery (S.B.O., J.-F.L.), Division of Cardiology (J.L.S.), School of Biomedical Engineering (R.A.R.), Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. robert.rose@dal.ca.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rose
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology*; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects*
chemical_list: D009320:Atrial Natriuretic Factor
keywords: action potentials; atrial fibrillation; atrial natriuretic peptides; calcium channels; electrophysiology