title: Alpha 1-adrenergic inhibition of the beta-adrenergically activated Cl- current in guinea pig ventricular myocytes.
abstract: alpha-Adrenergic receptor stimulation regulates the activity of a number of different cardiac ion channels, including those underlying one or more distinct Cl- conductances. The whole-cell patch-clamp technique was used in the present study to investigate the effects of alpha-adrenergic stimulation on the beta-adrenergically regulated Cl- current in guinea pig ventricular myocytes. Neither alpha 1-adrenergic receptor stimulation with methoxamine (25 to 500 mumol/L) nor direct activation of endogenous protein kinase C (PKC) with phorbol 12,13-dibutyrate (PDBu, 100 nmol/L) evoked a Cl- current. On the contrary, the Cl- current activated by 30 nmol/L isoproterenol was inhibited by methoxamine, with an EC50 of 6.7 +/- 2.6 mumol/L, and this response was blocked by prazosin, an alpha 1-adrenergic receptor antagonist. Prazosin also decreased the EC50 for current activation by norepinephrine from 53 +/- 7.1 to 18 +/- 3.8 nmol/L, demonstrating that the ability of this endogenous neurotransmitter to activate the Cl- current through beta-adrenergic receptor stimulation is limited by its intrinsic ability to also activate alpha-adrenergic receptors. Methoxamine did not inhibit the Cl- current evoked by either direct activation of adenylate cyclase with forskolin or inhibition of phosphodiesterase activity with 3-isobutyl-1-methylxanthine, indicating that alpha-adrenergic stimulation inhibits beta-adrenergic responses at a point upstream of adenylate cyclase activation. Methoxamine also did not inhibit the Cl- current activated by histamine, suggesting that alpha-adrenergic stimulation specifically inhibits beta-adrenergic receptor-mediated responses. The inhibitory effect of methoxamine was not mimicked by PDBu, and it persisted in the presence of bisindolylmaleimide, a selective PKC inhibitor. However, methoxamine inhibition of the isoproterenol-activated Cl- current was sensitive to pertussis toxin. These results suggest that alpha-adrenergic receptor stimulation inhibits the beta-adrenergically activated Cl- current, demonstrating a novel mechanism by which alpha-adrenergic receptors may regulate ion channel activity in the heart.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-4970, USA. rdh3@po.cwru.edu
authors.forename: L M
authors.initials: LM
authors.lastname: Oleksa
authors.forename: L C
authors.initials: LC
authors.lastname: Hool
authors.forename: R D
authors.initials: RD
authors.lastname: Harvey
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
chemical_list: D018118:Chloride Channels; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D011493:Protein Kinase C; D008729:Methoxamine; D009638:Norepinephrine