Targeted G-protein inhibition as a novel approach to decrease vagal atrial fibrillation by selective parasympathetic attenuation

Gary L. Aistrup, Roger Villuendas, Jason Ng, Annette Gilchrist, Thomas W. Lynch, David Gordon, Ivan Cokic, Steven Mottl, Rui Zhou, David A. Dean, J. Andrew Wasserstrom, Jeffrey J. Goldberger, Alan H. Kadish, Rishi Arora

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

AimsThe 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, Gαiβγ, we hypothesized that targeted inhibition of Gαi interactions in the posterior left atrium (PLA) would modify the substrate for vagal AF.Methods and resultsCell-penetrating(cp) -Gαi1/2 and cp-Gαi3 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-Gαi1/2 and/or cp-Gαi3 peptides moderated carbachol attenuation of cellular Ca2+ 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-Gαi1/2 peptide or cp-Gαi3 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-Gαi peptides into the PLA, AF inducibility during vagal stimulation was significantly diminished.ConclusionThese results demonstrate the feasibility of using specific Gi-protein inhibition to achieve selective parasympathetic denervation in the PLA, with a resulting change in vagal responsiveness across the entire LA.

Original languageEnglish (US)
Pages (from-to)481-492
Number of pages12
JournalCardiovascular Research
Volume83
Issue number3
DOIs
StatePublished - Aug 2009

Keywords

  • Atrial fibrillation
  • Atrial refractoriness
  • Calcium transient
  • E-C coupling
  • G-proteins
  • Muscarinic
  • Parasympathetic
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Aistrup, G. L., Villuendas, R., Ng, J., Gilchrist, A., Lynch, T. W., Gordon, D., Cokic, I., Mottl, S., Zhou, R., Dean, D. A., Wasserstrom, J. A., Goldberger, J. J., Kadish, A. H., & Arora, R. (2009). Targeted G-protein inhibition as a novel approach to decrease vagal atrial fibrillation by selective parasympathetic attenuation. Cardiovascular Research, 83(3), 481-492. https://doi.org/10.1093/cvr/cvp148