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Cardiovascular Research 2007 74(3):406-415; doi:10.1016/j.cardiores.2007.01.020
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Copyright © 2007, European Society of Cardiology

Adrenergic control of a constitutively active acetylcholine-regulated potassium current in canine atrial cardiomyocytes

Yung-Hsin Yeha,b, Joachim R. Ehrlichc, Xiaoyan Qia, Terence E. Hébertd, Denis Chartiera and Stanley Nattela,d,*

aDepartment of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada
bFirst Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan, Taiwan
cDivision of Cardiology, J.W. Goethe University, Frankfurt, Germany
dDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada

* Corresponding author. 5000 Belanger Street, Montreal, Quebec, Canada H1T 1C8. Tel.: +1 514 376 3330x3990; fax: +1 514 376 1355. Email address: stanley.nattel{at}icm-mhi.org

Objectives: Canine atrial cardiomyocytes display a constitutively active, acetylcholine-regulated, time-dependent K+ current (IKH) that contributes to atrial repolarization and atrial tachycardia-induced atrial-fibrillation promotion. Adrenergic stimulation favors atrial arrhythmogenesis but its effects on IKH are poorly understood.

Methods and results: Adrenergic modulation of IKH was studied in isolated canine atrial cardiomyocytes with whole-cell patch-clamping, and action-potential consequences were assessed in multicellular preparations with fine-tipped microelectrodes. Isoproterenol increased IKH in a concentration-dependent manner (maximum 103±22% increase), an effect mimicked by forskolin and 8-bromo-cyclic AMP. Isoproterenol effects were prevented by propranolol and the selective β1-adrenoceptor blocker CGP-20712A, but not the β2-blocker ICI-118551. Isoproterenol enhancement was prevented by pipette-administered protein kinase A (PKA) inhibitor peptide or by superfusion of H89 (PKA blocker). Phenylephrine decreased IKH in a reversible, concentration-dependent way. This effect was blocked by the {alpha}-antagonist prazosin and the selective {alpha}1A-blocker niguldipine, but not the {alpha}1B-blocker chloroethylclonidine or the {alpha}1D inhibitor BMY-7378. Phenylephrine effects were prevented by the phospholipase C (PLC) inhibitor U73122 [GenBank] and the protein kinase C (PKC) inhibitor bisindolylmaleimide. The PKC-activating phorbol ester PDD (but not its inactive analogue {alpha}-PDD) mimicked phenylephrine effects. Action potential recordings in the presence and absence of the selective IKH blocker tertiapin indicated a functional role of {alpha}- and β-adrenergic actions on IKH. Adrenergic regulation of cholinergic agonist-induced K+ current paralleled that of IKH.

Conclusions: IKH is under dual regulation by the adrenergic system: β1-adrenergic stimulation enhances IKH via cAMP-dependent PKA pathways, whereas {alpha}1A-adrenergic stimulation inhibits IKH via PLC-mediated PKC activation. Modulation of constitutive acetylcholine-regulated K+ current is a novel potential mechanism for adrenergic control of atrial repolarization.

KEYWORDS Ion-channels; Second-messengers; Signal transduction

Time for primary review 37 days


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