Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 152, Issue 7, Pages 1021-1032Publisher
WILEY
DOI: 10.1038/sj.bjp.0707376
Keywords
muscarinic acetylcholine receptor (mAChR); M-2 receptor; M-3 receptor; M-4 receptor; ion channels; atrial fibrillation; ionic remodelling
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Background and purpose: Both parasympathetic tone and atrial tachycardia (AT) remodelling of ion channels play important roles in atrial fibrillation (AF) pathophysiology. Different muscarinic cholinergic receptor (mAChR) subtypes (M-2, M-3, M-4) in atrial cardiomyocytes are coupled to distinct K+ -currents (called I-KM2, I-KM3, I-KM4, respectively). Pulmonary veins (PVs) are important in AF and differential cholinergic current responses are a potential underlying mechanism. This study investigated AT-induced remodelling of mAChR subtypes and K+ -currents in left-atrial (LA) and PV cardiomyocytes. Experimental approach: Receptor expression was assayed by western blot. I-KM2, I-KM3 and I-KM4 were recorded with whole-cell patch-clamp in LA and PV cardiomyocytes of nonpaced control dogs and dogs after 7 days of AT-pacing (400 bpm). Key results: Current densities of I-KM2, I-KM3 and I-KM4 were significantly reduced by AT-pacing in LA and PV cardiomyocytes. PV cardiomyocyte current-voltage relations were similar to LA for all three cholinergic currents, both in control and AT remodelling. Membrane-protein expression levels corresponding to M-2, M-3 and M-4 subtypes were decreased significantly (by about 50%) after AT pacing. Agonist concentration-response relations for all three currents were unaffected by AT pacing. Conclusions and implications: AT downregulated all three mAChR-coupled K+ current subtypes, along with corresponding mAChR protein expression. These changes in cholinergic receptor-coupled function may play a role in AF pathophysiology. Cholinergic receptor-coupled K+ -currents in PV cardiomyocytes were similar to those in LA under control and AT-pacing conditions, suggesting that differential cholinergic current properties do not explain the role of PVs in AF.
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