Changes in IK,ACh single-channel activity with atrial tachycardia remodelling in canine atrial cardiomyocytes

Abstract

Aims: Although atrial tachycardia (AT) remodelling promotes agonist-independent, constitutively active, acetylcholine-regulated K +-current (IK,ACh) that increases susceptibility to atrial fibrillation (AF), the underlying changes in IK,Ach channel function are unknown. This study aimed to establish how AT remodelling affects I K,ACh single-channel function. Methods and results: IK,ACh single-channel activity was studied via cell-attached patch-clamp in isolated left atrial cardiomyocytes of control and AT (7 days, 400 min-1) dogs. Atrial tachycardia prolonged the mean duration of induced AF from 44 ± 22 to 413 ± 167 s, and reduced atrial effective refractory period at a 360 ms cycle length from 126 ± 3 to 74 ± 5 ms (n = 9/group, P < 0.001). In the absence of cholinergic stimulation, single-channel openings with typical IK,ACh conductance and rectification properties were sparse under control conditions. Atrial tachycardia induced prominent agonist-independent IK,ACh activity because of increased opening frequency (fo) and open probability (Po: approximately seven- and 10-fold, respectively, vs. control), but did not alter open time-constant, single-channel conductance, and membrane density. With maximum IK,ACh activation (10 μmol/L carbachol), channel Po was enhanced much more in control cells (∼42-fold) than in AT-remodelled myocytes (approximately five-fold). The selective Kir3 current blocker tertiapin-Q (100 nmol/L) reduced fo and Po at -100 mV by 48 and 51%, respectively (P < 0.05 for each), without altering other channel properties, confirming the identity of IK,ACh. Atrial tachycardia had no significant effect on mRNA or protein expression of either of the subunits (Kir3.1, Kir3.4) underlying IK,ACh. Conclusion: Atrial tachycardia increases agonist-independent constitutive IK,ACh single-channel activity by enhancing spontaneous channel opening, providing a molecular basis for AT effects on macroscopic IK,ACh observed in previous studies, as well as associated refractoriness abbreviation and tertiapin-suppressible AF promotion. These results suggest an important role for constitutive IK,Ach channel opening in AT remodelling and support its interest as a potential target for AF therapy. © The Author 2007.