Cardiovascular Research Advance Access first published online on August 4, 2008
This version [Corrected Proof] published online on August 24, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn205
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Nitric oxide inhibits Kv4.3 and human cardiac transient outward potassium current (Ito1)
1 Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain
2 Cardiovascular Research Unit, Hospital Clínico San Carlos, Madrid, Spain
3 Cardiac Surgery Department, Hospital Clínico San Carlos, Madrid, Spain
* Corresponding author. Tel: +34 34913941474; fax: +34 913941470. E-mail address: rcaballero{at}med.ucm.es
Aims: Chronic atrial fibrillation (CAF) is characterized by a shortening of the plateau phase of the action potentials (AP) and a decrease in the bioavailability of nitric oxide (NO). In this study, we analysed the effects of NO on Kv4.3 (IKv4.3) and on human transient outward K+ (Ito1) currents as well as the signalling pathways responsible for them. We also analysed the expression of NO synthase 3 (NOS3) in patients with CAF.
Methods and results: IKv4.3 and Ito1 currents were recorded in Chinese hamster ovary cells and in human atrial and mouse ventricular dissociated myocytes using the whole-cell patch clamp. The expression of NOS3 was analysed by western blotting. AP were recorded using conventional microelectrode techniques in mouse atrial preparations. NO and NO donors inhibited IKv4.3 and human Ito1 in a concentration- and voltage-dependent manner (IC50 for NO: 375.0 ± 48 nM) as a consequence of the activation of adenylate cyclase and the subsequent activation of the cAMP-dependent protein kinase and the serine–threonine phosphatase 2A. The density of the Ito1 recorded in ventricular myocytes from wild-type (WT) and NOS3-deficient mice (NOS3–/–) was not significantly different. Furthermore, the duration of atrial AP repolarization in WT and NOS3–/– mice was not different. The increase in NO levels to 200 nM prolonged the plateau phase of the mouse atrial AP and lengthened the AP duration measured at 20 and 50% of repolarization of the human atrial CAF-remodelled AP as determined using a mathematical model. However, the expression of NOS3 was not modified in left atrial appendages from CAF patients.
Conclusion: Our results suggested that the increase in the atrial NO bioavailability could partially restore the duration of the plateau phase of CAF-remodelled AP by inhibiting the Ito1 as a result of the activation of non-canonical enzymatic pathways.
KEYWORDS Atrial fibrillation; Nitric oxide; Human transient outward current; Patch clamp; Kv4.3 channels
Time for primary review: 27 days
These two authors contributed equally.