Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 26, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm051
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Changes in IK,ACh single channel activity with atrial tachycardia remodeling in canine atrial cardiomyocytes
Department of Pharmacology and Toxicology, Dresden University of Technology, Germany(N.V., U.R., D.D.) and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada (N.V., A.M., Y.Y., X.Q.,S.N.)
Address for correspondence: Stanley Nattel, Research Center, Montreal Heart Institute, 5000 Belanger Street E, Montreal, Quebec, H1T 1C8, Canada E-mail: stanley.nattel{at}icm-mhi.org
Changes in IK,ACh single channel activity with atrial tachycardia remodeling in canine atrial cardiomyocytes. Niels Voigt, Ange Maguy, Yung-Hsin Yeh, Xiaoyan Qi, Ursula Ravens, Dobromir Dobrev, Stanley Nattel
Aims: Although atrial tachycardia (AT) remodeling 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 remodeling affects IK,ACh single channel function.
Methods: 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.
Results: AT 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. AT induced prominent agonist-independent IK,ACh activity due to increased opening frequency (fo) and open probability (Po: 
7- and 10-fold respectively versus 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-remodeled myocytes (5-fold). The selective Kir3 current blocker tertiapin (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. AT had no significant effect on mRNA or protein expression of either of the subunits (Kir3.1, Kir3.4) underlying IK,ACh.
Conclusions: AT 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 remodeling and support its interest as a potential target for AF therapy.
KEYWORDS acetylcholine; antiarrhythmic agents; arrhythmia (mechanisms); ion channels; remodeling
Time for primary review: 10 days
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