The role of stretch-activated channels in atrial fibrillation and the impact of intracellular acidosis.
The incidence of atrial fibrillation correlates with increasing atrial size. The electrical consequences of atrial stretch contribute to both the initiation and maintenance of atrial fibrillation. It is suggested that altered calcium handling and stretch-activated channel activity could explain the experimental findings of stretch-induced depolarisation, shortened refractoriness, slowed conduction and increased heterogeneity of refractoriness and conduction. Stretch-activated channel blocking agents protect against these pro-arrhythmic effects. Gadolinium, GsMTx-4 toxin and streptomycin prevent the stretch-related vulnerability to atrial fibrillation without altering the drop in refractory period associated with stretch. Changes the activity of two-pore K+ channels, which are sensitive to stretch and pH but not gadolinium, could underlie the drop in refractoriness. Intracellular acidosis induced with propionate amplified the change in refractoriness with stretch in the isolated rabbit heart model in keeping with the clinical observation of increased propensity to atrial fibrillation with acidosis. We propose that activation of non-specific cation stretch-activated channels provides the triggers for acute atrial fibrillation with high atrial pressure while activation of atrial two-pore K+ channels shortens atrial refractory period and increases heterogeneity of refractoriness, providing the substrate for atrial fibrillation to be sustained. Stretch-activated channel blockade represents an exciting target for future antiarrhythmic drugs.
Ninio
Daniel M
DM
Discipline of Physiology, School of Molecular & Biomedical Science, University of Adelaide, SA 5005, Australia.
Saint
David A
DA
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000503:physiopathology*; D016275:Atrial Function / Q000187:drug effects / Q000502:physiology*; D005682:Gadolinium / Q000627:therapeutic use; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology*; D006863:Hydrogen-Ion Concentration; D036341:Intercellular Signaling Peptides and Proteins; D042541:Intracellular Space / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000627:therapeutic use; D015221:Potassium Channels / Q000502:physiology*; D011422:Propionates / Q000494:pharmacology; D011817:Rabbits; D013111:Spider Venoms / Q000627:therapeutic use; D013307:Streptomycin / Q000627:therapeutic use
D036341:Intercellular Signaling Peptides and Proteins; C411249:MTx4 protein, Grammostola spatulata; D010455:Peptides; D015221:Potassium Channels; D011422:Propionates; D013111:Spider Venoms; D005682:Gadolinium; D013307:Streptomycin