Changes in I K, 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 (I K,ACh) that increases susceptibility to atrial fibrillation (AF), the underlying changes in I K,Ach channel function are unknown. This study aimed to establish how AT remodelling affects I K,ACh single-channel function.

METHODS AND RESULTS:

I K,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 I K,ACh conductance and rectification properties were sparse under control conditions. Atrial tachycardia induced prominent agonist-independent I K,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 I K,ACh activation (10 micromol/L carbachol), channel Po was enhanced much more in control cells ( approximately 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 I K,ACh. Atrial tachycardia had no significant effect on mRNA or protein expression of either of the subunits (Kir3.1, Kir3.4) underlying I K,ACh.

CONCLUSION:

Atrial tachycardia increases agonist-independent constitutive I K,ACh single-channel activity by enhancing spontaneous channel opening, providing a molecular basis for AT effects on macroscopic I K,ACh observed in previous studies, as well as associated refractoriness abbreviation and tertiapin-suppressible AF promotion. These results suggest an important role for constitutive I K,Ach channel opening in AT remodelling and support its interest as a potential target for AF therapy.

• Authors: Niels Voigt, Ange Maguy, Yung-Hsin Yeh, Xiaoyan Qi, Ursula Ravens, Dobromir Dobrev, Stanley Nattel
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 77 Issue 1 Pg. 35-43 (Jan 2008) ISSN: 0008-6363 [Print] England
• PMID: 18006448 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bee Venoms
• G Protein-Coupled Inwardly-Rectifying Potassium Channels
• Potassium Channels, Inwardly Rectifying
• tertiapin
• Carbachol
• Acetylcholine

Topics

• Acetylcholine (pharmacology)
• Animals
• Atrial Fibrillation (etiology)
• Bee Venoms (pharmacology)
• Carbachol (pharmacology)
• Dogs
• Female
• G Protein-Coupled Inwardly-Rectifying Potassium Channels (analysis, physiology)
• Heart Atria
• Male
• Myocytes, Cardiac (metabolism)
• Potassium Channels, Inwardly Rectifying (drug effects, physiology)
• Tachycardia (complications, metabolism)