Abstract 950: Direct Evidence for an Important Role of Agonist-independent Constitutive IK,ACh Channel Activity in Atrial Tachycardia Remodeling
Background: Although atrial tachycardia (AT) appears to promote agonist-independent constitutively active IK,ACh that increases susceptibility to AF, direct demonstration of dysregulated IK,ACh channel function is lacking. We studied AT effects on single IK,ACh channel activity in dog atria.
Methods: IK,ACh channel activity was recorded with cell-attached patch clamp in isolated atrial myocytes of control (CTL) and AT (7 days, 400 min−1) dogs.
Results: AT prolonged inducible AF duration from 44±22 to 413±167 s; N=9 dogs/gp, P<0.001. In the absence of cholinergic stimulation, single-channel openings with typical IK,ACh conductance and rectification were observed in CTL and AT (Figure⇓). AT produced prominent agonist-independent IK,ACh activity due to 7-fold increased opening frequency (fo) and 10-fold increased open probability (Po) vs CTL (P<0.01 for each), but unaltered open time and single channel conductance. With maximum IK,ACh activation (10 μm carbachol, CCh), fo was 38% lower, open time constant 25% higher, and Po and unitary conductance unchanged for AT vs CTL. The selective Kir3 blocker tertiapin (100 nM) reduced fo and Po by 48% and 51% (P<0.05 each) without altering other channel properties, confirming the identity of IK,ACh.
Conclusions: AT produces prominent agonist-independent constitutive single-channel IK,ACh activity, providing a molecular basis for previously-observed AT-enhanced macroscopic IK,ACh, as well as associated AP-shortening and tertiapin-suppressible AF promotion. These results suggest an important role for constitutively active IK,ACh channels in AT-remodeling and support their interest as a potential novel AF-therapy target.