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 beta1-adrenoceptor blocker CGP-20712A, but not the beta2-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 alpha1A-blocker niguldipine, but not the alpha1B-blocker chloroethylclonidine or the alpha1D inhibitor BMY-7378. Phenylephrine effects were prevented by the phospholipase C (PLC) inhibitor U73122 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 beta-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: beta1-adrenergic stimulation enhances IKH via cAMP-dependent PKA pathways, whereas alpha1A-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.
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 beta1-adrenoceptor blocker CGP-20712A, but not the beta2-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 alpha1A-blocker niguldipine, but not the alpha1B-blocker chloroethylclonidine or the alpha1D inhibitor BMY-7378. Phenylephrine effects were prevented by the phospholipase C (PLC) inhibitor U73122 and the protein kinase C (PKC) inhibitor bisindolylmaleimide. The PKC-activating phorbol esterPDD (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 beta-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: beta1-adrenergic stimulation enhances IKH via cAMP-dependent PKA pathways, whereas alpha1A-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.