Abstract
AIMS: Atrial fibrillation (AF) is the most common chronic/recurrent arrhythmia, which significantly impairs quality of life and increases cardiovascular morbidity and mortality. Therefore, the aim of the present study was to investigate the properties of three repolarizing potassium currents which were shown to contribute to AF-induced electrical remodeling, i.e., the transient outward (I(to)), inward rectifier (I(K1)) and acetylcholine-sensitive (I(K,ACh)) potassium currents in isolated atrial myocytes obtained from dogs either with sinus rhythm (SR) or following chronic atrial tachypacing (400/min)-induced AF. METHODS: Atrial remodeling and AF were induced by chronic (4-6 weeks of) right atrial tachypacing (400/min) in dogs. Transmembrane ionic currents were measured by applying the whole-cell patch-clamp technique at 37 °C. RESULTS: The I(to) current was slightly downregulated in AF cells when compared with that recorded in SR cells. This downregulation was also associated with slowed inactivation kinetics. The I(K1) current was found to be larger in AF cells; however, this upregulation was not statistically significant in the voltage range corresponding with atrial action potential (-80 mV to 0 mV). I(K,ACh) was activated by the cholinergic agonist carbachol (CCh; 2 µM). In SR, CCh activated a large current either in inward or outward directions. The selective I(K,ACh) inhibitor tertiapin (10 nM) blocked the outward CCh-induced current by 61%. In atrial cardiomyocytes isolated from dogs with AF, the presence of a constitutively active I(K,ACh) was observed, blocked by 59% with 10 nM tertiapin. However, in "AF atrial myocytes", CCh activated an additional, significant ligand-dependent and tertiapin-sensitive I(K,ACh) current. CONCLUSIONS: In our dog AF model, I(to) unlike in humans was downregulated only in a slight manner. Due to its slow inactivation kinetics, it seems that I(to) may play a more significant role in atrial repolarization than in ventricular working muscle myocytes. The presence of the constitutively active I(K,ACh) in atrial myocytes from AF dogs shows that electrical remodeling truly developed in this model. The I(K,ACh) current (both ligand-dependent and constitutively active) seems to play a significant role in canine atrial electrical remodeling and may be a promising atrial selective drug target for suppressing AF.