Differential alterations of receptor densities of three muscarinic acetylcholine receptor subtypes and current densities of the corresponding K+ channels in canine atria with atrial fibrillation induced by experimental congestive heart failure

Cell Physiol Biochem. 2004;14(1-2):31-40. doi: 10.1159/000076924.

Abstract

Parasympathetic tone and congestive heart failure (CHF) are two of promoting factors in initiation and perpetuation of atrial fibrillation (AF). Recent studies indicate co-existence of multiple muscarinic acetylcholine receptor subtypes (mAChRs) that mediate several distinct K+ currents in the heart; inward rectifier K+ current IKACh by the M2, and two delayed rectifier K+ currents IKM3 and IK4AP by the M3 and M4 receptors, respectively. We studied the alterations of atrial mAChRs and their coupled K+ channels in the setting of AF in dogs with ventricular tachypacing-induced CHF. Whole-patch-clamp recordings showed that the current densities of IKACh (induced by 1 mM acetylcholine) and IK4AP (induced by 1 mM 4-aminopyridine) were ñ45% and ñ55% lower, respectively, while that of IKM3 (induced by 10 mM choline) was ñ75% higher, at a plateau voltage of 0 mV in atrial myocytes from CHF than those from healthy hearts. In healthy hearts, IKACh comprised >60%, and IKM3 and IK4AP <30%, of the total outward K+ currents mediated by mAChRs at depolarized potentials (between -20 mV and +50 mV). In AF atria of CHF dogs, however, the contribution of IKM3 increased to approximately 50%, exceeding those of IKACh or IK4AP. Western blot analyses with atrial membrane protein samples indicated that receptor densities of the M2 and M4 subtypes decreased by approximately 33% and approximately 22%, respectively, whereas that of the M3 subtype increased by approximately 2.3 folds, in parallel to the alterations of the corresponding K+ currents. We conclude that differential alterations of mAChR subtypes underlie differential alterations of their coupled K+ channels in AF atria and these differential alterations may contribute to atrial remodeling in AF induced in the setting of CHF.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrial Fibrillation / etiology*
  • Atrial Fibrillation / pathology
  • Atrial Fibrillation / physiopathology*
  • Disease Models, Animal
  • Dogs
  • Female
  • Heart Atria / cytology
  • Heart Atria / pathology
  • Heart Atria / physiopathology*
  • Heart Failure / complications*
  • Heart Failure / pathology
  • Male
  • Patch-Clamp Techniques
  • Potassium Channels / physiology*
  • Receptors, Muscarinic / classification
  • Receptors, Muscarinic / physiology*

Substances

  • Potassium Channels
  • Receptors, Muscarinic