title: Adrenergic control of a constitutively active acetylcholine-regulated potassium current in canine atrial cardiomyocytes.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada, and First Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Ehrlich
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qi
authors.forename: Terence E
authors.initials: TE
authors.lastname: Hébert
authors.forename: Denis
authors.initials: D
authors.lastname: Chartier
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D018663:Adrenergic Agents / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001514:Bee Venoms / Q000494:pharmacology; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004095:Dihydropyridines / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004963:Estrenes / Q000494:pharmacology; D006325:Heart Atria; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010656:Phenylephrine / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011224:Prazosin / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011760:Pyrrolidinones / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
chemical_list: D018663:Adrenergic Agents; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D001514:Bee Venoms; D004095:Dihydropyridines; D004963:Estrenes; D007093:Imidazoles; D007211:Indoles; D007546:Isoquinolines; D008301:Maleimides; D010879:Piperazines; D015221:Potassium Channels; D011412:Propanolamines; D011760:Pyrrolidinones; D018340:Receptors, Adrenergic, alpha-1; D018342:Receptors, Adrenergic, beta-1; D013449:Sulfonamides; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D010656:Phenylephrine; D015240:Phorbol 12,13-Dibutyrate; C029738:tertiapin; C051731:chlorethylclonidine; C026777:ICI 118551; D011433:Propranolol; C049763:CGP 20712A; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases; C053428:BMY 7378; D007545:Isoproterenol; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C088060:bisindolylmaleimide; D003000:Clonidine; D000109:Acetylcholine; D011224:Prazosin; C054074:niguldipine