title: Agonist-specific patterns of beta 2-adrenoceptor responses in human airway cells during prolonged exposure.
abstract: OBJECTIVE
  Beta(2)-adrenoceptor agonists (beta(2)-agonists) are important bronchodilators used in the treatment of asthma and chronic obstructive pulmonary disease. At the molecular level, beta(2)-adrenergic agonist stimulation induces desensitization of the beta(2)-adrenoceptor. In this study, we have examined the relationships between initial effect and subsequent reduction of responsiveness to restimulation for a panel of beta(2)-agonists in cellular and in vitro tissue models.
  
  
  METHODS
  Beta(2)-adrenoceptor-induced responses and subsequent loss of receptor responsiveness were studied in primary human airway smooth muscle cells and bronchial epithelial cells by measuring cAMP production. Receptor responsiveness was compared at equi-effective concentrations, either after continuous incubation for 24 h or after a 1 h pulse exposure followed by a 23 h washout. Key findings were confirmed in guinea pig tracheal preparations in vitro.
  
  
  RESULTS
  There were differences in the reduction of receptor responsiveness in human airway cells and in vitro guinea pig trachea by a panel of beta(2)-agonists. When restimulation occurred immediately after continuous incubation, loss of responsiveness correlated with initial effect for all agonists. After the 1 h pulse exposure, differences between agonists emerged, for example isoprenaline and formoterol induced the least reduction of responsiveness. High lipophilicity was, to some extent, predictive of loss of responsiveness, but other factors appeared to be involved in determining the relationships between effect and subsequent loss of responsiveness for individual agonists.
  
  
  CONCLUSIONS
  There were clear differences in the ability of different beta(2) agonists to induce loss of receptor responsiveness at equi-effective concentrations.
authors: Astra Zeneca Research & Development, Lund, Sweden. Caroline.Duringer@astrazeneca.com
authors: Caroline
authors: C
authors: Düringer
authors: Gunilla
authors: G
authors: Grundström
authors: Eylem
authors: E
authors: Gürcan
authors: Ian A
authors: IA
authors: Dainty
authors: Mandy
authors: M
authors: Lawson
authors: Solange H
authors: SH
authors: Korn
authors: Anders
authors: A
authors: Jerre
authors: Hanna Falk
authors: HF
authors: Håkansson
authors: Elisabet
authors: E
authors: Wieslander
authors: Karin
authors: K
authors: Fredriksson
authors: Carl Magnus
authors: CM
authors: Sköld
authors: Magnus
authors: M
authors: Löfdahl
authors: Claes-Göran
authors: CG
authors: Löfdahl
authors: David J
authors: DJ
authors: Nicholls
authors: David S
authors: DS
authors: Silberstein
mesh_terms: D000322:Adrenergic Agonists / Q000008:administration & dosage*; D058666:Adrenergic beta-2 Receptor Agonists; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D013997:Time Factors; D014132:Trachea / Q000166:cytology / Q000187:drug effects / Q000502:physiology
chemical_list: D000322:Adrenergic Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2