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Targeted G-protein inhibition as a novel approach to decrease vagal atrial fibrillation by selective parasympathetic
Gary L Aistrup1, Roger Villuendas, Jason Ng
1Department 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.
Cardiovascular Research
|May 22, 2009
Summary
Targeted inhibition of G-protein interactions in the posterior left atrium using specific peptides significantly reduced vagal-induced atrial fibrillation (AF) by altering parasympathetic signaling.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Electrophysiology
Background:
- The parasympathetic nervous system significantly influences atrial fibrillation (AF) pathogenesis.
- Parasympathetic signaling is primarily mediated by the Gα(i)βγ heterotrimeric G-protein.
Purpose of the Study:
- To investigate if targeted inhibition of Gα(i) interactions in the posterior left atrium (PLA) could modify the substrate for vagal AF.
- To assess the potential of G-protein-coupled receptor signaling modulation for AF treatment.
Main Methods:
- Assessed cell-penetrating (cp)-Gα(i)1/2 and cp-Gα(i)3 peptides for their ability to attenuate cholinergic-parasympathetic signaling in feline atrial myocytes.
- Utilized high-density epicardial mapping in canine left atrium (LA), including PLA, pulmonary veins (PVs), and left atrial appendage (LAA).
Main Results:
- cp-Gα(i) peptides moderated carbachol attenuation of cellular Ca(2+) transients in atrial myocytes.
- Peptide delivery into the PLA prolonged effective refractory periods and diminished AF inducibility during vagal stimulation across the LA.
- Vagal responsiveness was altered in PLA, LAA, and PV regions following peptide administration.
Conclusions:
- Demonstrated the feasibility of using G(i)-protein inhibition for selective parasympathetic denervation in the PLA.
- Showcased a novel approach to modulate vagal responsiveness in the atria, potentially impacting AF treatment strategies.
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