The G protein-gated potassium current IK,ACh is constitutively active in patients with chronic atrial fibrillation

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,I-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 IK, ACh blocker tertiapin was used for inhibition of I-K,I-ACh. Whole-cell basal current was larger in cAF than in SR, whereas carbachol (CCh)-activated IK, ACh was lower in cAF than in SR. Tertiapin (0.1 to 100 nmol/L) reduced IK, ACh in a concentration-dependent manner with greater potency in cAF than in SR (-logIC(50): 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,I-ACh to basal current. In single-channel recordings, constitutively active I-K,I-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,I-ACh. Blockade of I-K,I-ACh may represent a new therapeutic target in AF.