title: Inhibition of a TREK-like K+ channel current by noradrenaline requires both β1- and β2-adrenoceptors in rat atrial myocytes.
abstract: OBJECTIVE
  Noradrenaline plays an important role in the modulation of atrial electrophysiology. However, the identity of the modulated channels, their mechanisms of modulation, and their role in the action potential remain unclear. This study aimed to investigate the noradrenergic modulation of an atrial steady-state outward current (IKss).
  
  
  RESULTS
  Rat atrial myocyte whole-cell currents were recorded at 36°C. Noradrenaline potently inhibited IKss (IC50 = 0.90 nM, 42.1 ± 4.3% at 1 µM, n = 7) and potentiated the L-type Ca(2+) current (ICaL, EC50 = 136 nM, 205 ± 40% at 1 µM, n = 6). Noradrenaline-sensitive IKss was weakly voltage-dependent, time-independent, and potentiated by the arachidonic acid analogue, 5,8,11,14-eicosatetraynoic acid (EYTA; 10 µM), or by osmotically induced membrane stretch. Noise analysis revealed a unitary conductance of 8.4 ± 0.42 pS (n = 8). The biophysical/pharmacological properties of IKss indicate a TREK-like K(+) channel. The effect of noradrenaline on IKss was abolished by combined β1-/β2-adrenoceptor antagonism (1 µM propranolol or 10 µM β1-selective atenolol and 100 nM β2-selective ICI-118,551 in combination), but not by β1- or β2-antagonist alone. The action of noradrenaline could be mimicked by β2-agonists (zinterol and fenoterol) in the presence of β1-antagonist. The action of noradrenaline on IKss, but not on ICaL, was abolished by pertussis toxin (PTX) treatment. The action of noradrenaline on ICaL was mediated by β1-adrenoceptors via a PTX-insensitive pathway. Noradrenaline prolonged APD30 by 52 ± 19% (n = 5; P < 0.05), and this effect was abolished by combined β1-/β2-antagonism, but not by atenolol alone.
  
  
  CONCLUSIONS
  Noradrenaline inhibits a rat atrial TREK-like K(+) channel current via a PTX-sensitive mechanism involving co-operativity of β1-/β2-adrenoceptors that contributes to atrial APD prolongation.
authors.affiliation: Bristol Cardiovascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Bond
authors.affiliation: Bristol Cardiovascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK.
authors.forename: Stéphanie C M
authors.initials: SC
authors.lastname: Choisy
authors.affiliation: Bristol Cardiovascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Bryant
authors.affiliation: Bristol Cardiovascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK.
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.affiliation: Bristol Cardiovascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK a.james@bristol.ac.uk.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: James
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology*; D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017208:Rats, Wistar; D020239:Receptor Cross-Talk / Q000187:drug effects*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D020746:Calcium Channels, L-Type; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D009638:Norepinephrine
keywords: Arachidonic acid; Background K+ current; Beta-adrenoceptor; K2P channel; Osmotic stretch; Steady-state outward current; TREK-1