Circulation. 2001;104:2551-2557
doi: 10.1161/hc4601.099466
doi: 10.1161/hc4601.099466
(Circulation. 2001;104:2551.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Molecular Basis of Downregulation of G-Protein–Coupled Inward Rectifying K+ Current (IK,ACh) in Chronic Human Atrial Fibrillation
Decrease in GIRK4 mRNA Correlates With Reduced IK,ACh and Muscarinic Receptor–Mediated Shortening of Action Potentials
From the Department of Pharmacology and Toxicology, (D.D., E.G., E.W., H.M.H., O.H., C.D., T.C., U.R.) and Cardiovascular Centre Dresden (S.S.), Medical Faculty, University of Technology, Dresden, Germany.
Correspondence to Dr Dobromir Dobrev, Institut für Pharmakologie, TU Dresden, Fetscherstr 74, D-01307 Dresden, Germany. E-mail dobrev{at}rcs.urz.tu-dresden.de
Background Clinical and experimental evidence suggest that the parasympathetic nervous system is involved in the pathogenesis of atrial fibrillation (AF). However, it is unclear whether changes in G-protein-coupled inward rectifying K+ current (IK,ACh) contribute to chronic AF.
Methods and Results In the present study, we used electrophysiological recordings and competitive reverse-transcription polymerase chain reaction to study changes in IK,ACh and the level of the IK,ACh GIRK4 subunit in isolated human atrial myocytes and the atrial tissue of 39 patients with sinus rhythm and 24 patients with chronic AF. The density of IK,ACh was 
50% smaller in myocytes from patients with AF compared with those in sinus rhythm, and this was accompanied by decreased levels of GIRK4 mRNA. The current density of the inward rectifying K+ current (IK1) was 2-fold larger during AF than in sinus rhythm, in correspondence with an increase in Kir2.1 mRNA. The larger IK1 in AF is consistent with more negative membrane potentials in right atrial trabeculae from AF patients. Moreover, action potential duration was reduced in AF, and the action potential shortening produced by muscarinic receptor stimulation was attenuated, indicating that the changes of IK1 and IK,ACh were functionally relevant.
Conclusions Chronic human AF induces transcriptionally mediated upregulation of IK1 but downregulation of IK,ACh and attenuates the muscarinic receptor–mediated shortening of atrial action potentials. This suggests that atrial myocytes adapt to a chronically high rate by downregulating IK,ACh to counteract the shortening of the atrial effective refractory period due to electrical remodeling.
Key Words: remodeling • fibrillation • ion channels • action potentials
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