Background:
Although atrial tachycardia (AT) appears to promote agonist-independent constitutively active I
K,ACh
that increases susceptibility to AF, direct demonstration of dysregulated I
K,ACh
channel function is lacking. We studied AT effects on single I
K,ACh
channel activity in dog atria.
Methods:
I
K,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 I
K,ACh
conductance and rectification were observed in CTL and AT (Figure
). AT produced prominent agonist-independent I
K,ACh
activity due to 7-fold increased opening frequency (f
o
) and 10-fold increased open probability (P
o
) vs CTL (P<0.01 for each), but unaltered open time and single channel conductance. With maximum I
K,ACh
activation (10 μm carbachol, CCh), f
o
was 38% lower, open time constant 25% higher, and P
o
and unitary conductance unchanged for AT vs CTL. The selective Kir3 blocker tertiapin (100 nM) reduced f
o
and P
o
by 48% and 51% (P<0.05 each) without altering other channel properties, confirming the identity of
I
K,ACh.
Conclusions
: AT produces prominent agonist-independent constitutive single-channel I
K,ACh
activity, providing a molecular basis for previously-observed AT-enhanced macroscopic I
K,ACh
, as well as associated AP-shortening and tertiapin-suppressible AF promotion. These results suggest an important role for constitutively active I
K,ACh
channels in AT-remodeling and support their interest as a potential novel AF-therapy target.
Role of constitutively active acetylcholine-mediated potassium current in atrial contractile dysfunction caused by atrial tachycardia remodelling