Remodelling of human atrial K+ currents but not ion channel expression by chronic beta-blockade

Access to files

Full-text and supplementary files are not available from Manchester eScholar. Full-text is available externally using the following links:

Abstract

Chronic beta-adrenoceptor antagonist (beta-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K(+) currents. The aim of this study was to investigate the effects of chronic beta-blockade on transient outward, sustained and inward rectifier K(+) currents (I(TO), I(KSUS) and I(K1)) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic beta-blockade was associated with a 41% reduction in I(TO) density: 9.3 +/- 0.8 (30 myocytes, 15 patients) vs 15.7 +/- 1.1 pA/pF (32, 14), p < 0.05; without affecting its voltage-, time- or rate dependence. I(K1) was reduced by 34% at -120 mV (p < 0.05). Neither I(KSUS), nor its increase by acute beta-stimulation with isoprenaline, was affected by chronic beta-blockade. Mathematical modelling suggested that the combination of I(TO)- and I(K1)-decrease could result in a 28% increase in APD(90). Chronic beta-blockade did not alter mRNA or protein expression of the I(TO) pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvbeta1, Kvbeta2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in I(K1). A reduction in atrial I(TO) and I(K1) associated with chronic beta-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits.

Keyword(s)

Action Potentials/drug effects; Adrenergic beta-Antagonists/*pharmacology; Aged; Anti-Arrhythmia Agents/pharmacology; Atrial Fibrillation/drug therapy/metabolism; Female; Heart Atria/drug effects/*metabolism; Humans; Ion Channels/*drug effects/metabolism; Male; Middle Aged; Myocytes, Cardiac/*drug effects/*metabolism/physiology; Patch-Clamp Techniques; Potassium Channels/*drug effects/genetics/*metabolism; Receptors, Adrenergic, beta/drug effects/physiology

Bibliographic metadata

Institutional metadata

Record metadata