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Properties of the transient outward, ultra-rapid delayed rectifier and acetylcholine-sensitive potassium currents in isolated atrial myocytes from dogs: sinus rhythm and tachypaced model of permanent atrial fibrillation
BMC Pharmacology volume 11, Article number: A60 (2011)
Atrial fibrillation (AF) is a common and severe arrhythmia, which largely affects quality of life. State-of-the-art treatment of AF still relies heavily on pharmacological modalities. Therefore, the aim of the present study was to investigate and compare the properties of three repolarizing currents which contribute to AF-induced remodeling, i.e. the transient outward (Ito), ultra-rapid delayed rectifier (IKur) and acetylcholine-sensitive potassium currents (IK,ACh) in isolated atrial myocytes obtained from normal (SR) and tachypaced model of permanent atrial fibrillation (ATR) dogs.
The tachypaced atrial fibrillation model was performed in dogs. Transmembrane ionic currents were investigated by applying the whole-cell patch clamp technique at 37°C, and ECG was recorded in conscious dogs.
In all atrial canine myocytes, we have identified an Ito current sensitive to 4-aminopyridine (4-AP; 3 mM). The current inactivation was best fitted by two exponentials. The Ito current was slightly downregulated in ATR cells when compared with that recorded in SR cells. The IKur current, measured as sustained current (Isus), was upregulated in ATR dogs. However, the selective IKur blocker 4-AP (50 µM) did not block either Isus or IKur „like tail” currents, which questions the reliability of these results. IK,ACh was activated by the cholinergic agonist carbachol (CCh; 2 µM). In SR, CCh activated a large current either at inward or outward directions. The selective IK,ACh blocker tertiapin (10 nM) blocked the CCh-induced current by 57%. In atrial myocytes from ATR dogs we could measure the presence of a constitutively active IK,ACh, which could be blocked by 26 % with 10 nM tertiapin. However, in ATR atrial myocytes, CCh in addition could also activate a significant ligand-dependent and tertiapine-sensitive IK,ACh current. Tertiapin effectively prevented burst-induced AF in conscious ATR dogs.
The presence of the constitutively activated IK,ACh in atrial myocytes from ATR dogs shows that electrical remodeling developed in our model; this was further supported by the inducibility of AF by rapid atrial bursts in these dogs. The IK,ACh current (both ligand-dependent and constitutively active currents) seems to play a significant role in the canine atrial electrical remodelling, and may be a promising drug target for suppressing AF.
This work was funded by grants from OTKA (CNK-77855, K-82079) and the National Development Agency (TÁMOP-4.2.1/B-09/1/KONV-2010-0005).
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Kohajda, Z., Kristóf, A., Kovács, P.P. et al. Properties of the transient outward, ultra-rapid delayed rectifier and acetylcholine-sensitive potassium currents in isolated atrial myocytes from dogs: sinus rhythm and tachypaced model of permanent atrial fibrillation. BMC Pharmacol 11, A60 (2011) doi:10.1186/1471-2210-11-S2-A60
- Atrial Fibrillation
- Atrial Myocytes
- Permanent Atrial Fibrillation
- Promising Drug Target