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

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 I-KACh by the M-2, and two delayed rectifier K+ currents I-KM3 and I-K4AP by the M-3 and M-4 receptors, respectively. We studied the alterations of atrial mAChRs and their coupled K+ channels in the setting of AF in dogs with ventricular tachypacing-incluced CHF. Whole-patch-clamp recordings showed that the current densities of I-KACh (induced by 1 mM acetylcholine) and I-K4AP (induced by 1 mM 4-aminopyridine) were similar to45% and similar to55% lower, respectively, while that of I-KM3 (induced by 10 mM choline) was similar to75% higher, at a plateau voltage of 0 mV in atrial myocytes from CHF than those from healthy hearts. In healthy hearts, I-KACh comprised >60%, and I-KM3 and I-K4AP <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 I-KM3 increased to similar to 50%, exceeding those of I-KACh or I-K4AP. Western blot analyses with atrial membrane protein samples indicated that receptor densities of the M-2 and M-4 subtypes decreased by similar to 33% and similar to 22%, respectively, whereas that of the M-3 subtype increased by similar to 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. Copyright (C) 2004 S. Karger AG, Basel.