Agonist-specific patterns of beta(2)-adrenoceptor responses in human airway cells during prolonged exposure.

Research output: Contribution to journalArticle

Abstract

Background and purpose: 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. Experimental approach: 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. Key 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 and implications: There were clear differences in the ability of different beta(2) agonists to induce loss of receptor responsiveness at equi-effective concentrations.

Details

Authors
  • Caroline Düringer
  • Gunilla Grundström
  • Eylem Gürcan
  • Ian A Dainty
  • Mandy Lawson
  • Solange H Korn
  • Anders Jerre
  • Hanna Falk Håkansson
  • Elisabet Wieslander
  • Karin Hägerbrand
  • Carl Magnus Sköld
  • Magnus Löfdahl
  • Claes-Göran Löfdahl
  • David J Nicholls
  • David S Silberstein
Organisations
External organisations
  • AstraZeneca, UK
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmacology and Toxicology
Original languageEnglish
Pages (from-to)169-179
JournalBritish Journal of Pharmacology
Volume158
Publication statusPublished - 2009
Publication categoryResearch
Peer-reviewedYes