title: Targeted G-protein inhibition as a novel approach to decrease vagal atrial fibrillation by selective parasympathetic attenuation.
abstract: OBJECTIVE
  The parasympathetic nervous system is thought to play a key role in atrial fibrillation (AF). Since parasympathetic signalling is primarily mediated by the heterotrimeric G-protein, Galpha(i)betagamma, we hypothesized that targeted inhibition of Galpha(i) interactions in the posterior left atrium (PLA) would modify the substrate for vagal AF.
  
  
  RESULTS
  Cell-penetrating(cp)-Galpha(i)1/2 and cp-Galpha(i)3 C-terminal peptides were assessed for their ability to attenuate cholinergic-parasympathetic signalling in isolated feline atrial myocytes and in canine left atrium (LA). Confocal fluorescence microscopy indicated that cp-Galpha(i)1/2 and/or cp-Galpha(i)3 peptides moderated carbachol attenuation of cellular Ca(2+) transients in isolated atrial myocytes. High-density epicardial mapping of dog PLA, left atrial pulmonary veins (PVs), and left atrial appendage (LAA) indicated that the delivery of cp-Galpha(i)1/2 peptide or cp-Galpha(i)3 peptide into the PLA prolonged effective refractory periods at baseline and during vagal stimulation in the PLA and to varying extents also in the LAA and PV regions. After delivery of cp-Galpha(i) peptides into the PLA, AF inducibility during vagal stimulation was significantly diminished.
  
  
  CONCLUSIONS
  These results demonstrate the feasibility of using specific G(i)-protein inhibition to achieve selective parasympathetic denervation in the PLA, with a resulting change in vagal responsiveness across the entire LA.
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University-Feinberg School of Medicine, Northwestern Memorial Hospital, 251 East Huron, Galter 10-240, Chicago, IL 60611, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Aistrup
authors.forename: Roger
authors.initials: R
authors.lastname: Villuendas
authors.forename: Jason
authors.initials: J
authors.lastname: Ng
authors.forename: Annette
authors.initials: A
authors.lastname: Gilchrist
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Lynch
authors.forename: David
authors.initials: D
authors.lastname: Gordon
authors.forename: Ivan
authors.initials: I
authors.lastname: Cokic
authors.forename: Steven
authors.initials: S
authors.lastname: Mottl
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.forename: David A
authors.initials: DA
authors.lastname: Dean
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Wasserstrom
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Goldberger
authors.forename: Alan H
authors.initials: AH
authors.lastname: Kadish
authors.forename: Rishi
authors.initials: R
authors.lastname: Arora
mesh_terms: D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002415:Cats; D018679:Cholinergic Agonists / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D017764:Parasympathectomy / Q000379:methods*; D010455:Peptides / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D012032:Refractory Period, Electrophysiological; D013997:Time Factors; D014630:Vagus Nerve / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D002317:Cardiovascular Agents; D018679:Cholinergic Agonists; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D010455:Peptides; D043585:Receptor, Muscarinic M2; D002217:Carbachol; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D011188:Potassium