Cardiovascular Research Advance Access [Accepted Manuscript] published online on August 4, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn205
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NO inhibits Kv4.3 and human cardiac transient outward potassium current (Ito1)
1 Department of Pharmacology, School of Medicine, Universidad Complutense. Madrid, Spain
2 Cardiovascular Research Unit
3 Cardiac Surgery Department. Hospital Clínico San Carlos. Madrid. Spain
Address for correspondence: Ricardo Caballero. Department of Pharmacology. School of Medicine. Universidad Complutense. 28040 Madrid, Spain. Phone: 34913941474; FAX: 34913941470. E-mail: 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 analyzed the effects of NO on Kv4.3 (IKv4.3) and on human transient outward K+ currents (Ito1) as well as the signaling pathways responsible for them. We also analyzed the expression of NO synthase 3 (NOS3) in patients with CAF.
Methods: 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 analyzed by Western blotting. AP were recorded using conventional microelectrode techniques in mouse atrial preparations.
Results: 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 of 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-remodeled AP as determined using a mathematical model. However, the expression of NOS3 was not modified in left atrial appendages from CAF patients.
Conclusions: Our results suggested that the increase in the atrial NO bioavailability could partially restore the duration of the plateau phase of CAF-remodeled AP by inhibiting the Ito1 as a result of the activation of noncanonical enzymatic pathways.
Time for primary review: 27 days
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