Published Online
on December 5, 2005

A more recent version of this article appeared on December 13, 2005

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Submitted on July 14, 2005
Revised on September 22, 2005
Accepted on October 7, 2005

The G Protein-Gated Potassium Current I_K,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation

D. Dobrev MD^*, A. Friedrich CandMed, N. Voigt CandMed, N. Jost PhD, E. Wettwer PhD, T. Christ MD, M. Knaut MD, and U. Ravens MD

From the Department of Pharmacology and Toxicology (D.D., A.F., N.V., E.W., T.C., U.R.) and Cardiovascular Center (M.K.), Medical Faculty, Dresden University of Technology, Dresden, Germany; and Department of Pharmacology and Pharmacotherapy (N.J.), Medical University of Szeged, Szeged, Hungary.

^* To whom correspondence should be addressed. E-mail: dobrev{at}rcs.urz.tu-dresden.de.

Background--The molecular mechanism of increased background inward rectifier current (I_K1) in atrial fibrillation (AF) is not fully understood. We tested whether constitutively active acetylcholine (ACh)-activated I_K,ACh contributes to enhanced basal conductance in chronic AF (cAF).

Methods and Results--Whole-cell and single-channel currents were measured with standard voltage-clamp techniques in atrial myocytes from patients with sinus rhythm (SR) and cAF. The selective I_K,ACh blocker tertiapin was used for inhibition of I_K,ACh. Whole-cell basal current was larger in cAF than in SR, whereas carbachol (CCh)-activated I_K,ACh was lower in cAF than in SR. Tertiapin (0.1 to 100 nmol/L) reduced I_K,ACh in a concentration-dependent manner with greater potency in cAF than in SR (-logIC₅₀: 9.1 versus 8.2; P<0.05). Basal current contained a tertiapin-sensitive component that was larger in cAF than in SR (tertiapin [10 nmol/L]-sensitive current at -100 mV: cAF, -6.7±1.2 pA/pF, n=16/5 [myocytes/patients] versus SR, -1.7±0.5 pA/pF, n=24/8), suggesting contribution of constitutively active I_K,ACh to basal current. In single-channel recordings, constitutively active I_K,ACh was prominent in cAF but not in SR (channel open probability: cAF, 5.4±0.7%, n=19/9 versus SR, 0.1±0.05%, n=16/9; P<0.05). Moreover, I_K1 channel open probability was higher in cAF than in SR (13.4±0.4%, n=19/9 versus 11.4±0.7%, n=16/9; P<0.05) without changes in other channel characteristics.

Conclusions--Our results demonstrate that larger basal inward rectifier K⁺ current in cAF consists of increased I_K1 activity and constitutively active I_K,ACh. Blockade of I_K,ACh may represent a new therapeutic target in AF.

Key words: arrhythmia • fibrillation • ion channels • remodeling • signal transduction

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