The G Protein–Gated Potassium Current I K,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation

Abstract

The molecular mechanism of increased background inward rectifier current (IK1) 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). 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, IK1 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. Our results demonstrate that larger basal inward rectifier K+ current in cAF consists of increased IK1 activity and constitutively active I(K,ACh). Blockade of I(K,ACh) may represent a new therapeutic target in AF.