The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation

Abstract

Background: 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).

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, 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.

Conclusions: 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.