Agonist-specific patterns of beta 2-adrenoceptor responses in human airway cells during prolonged exposure.
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.
Düringer
Caroline
C
Astra Zeneca Research & Development, Lund, Sweden. Caroline.Duringer@astrazeneca.com
Grundström
Gunilla
G
Gürcan
Eylem
E
Dainty
Ian A
IA
Lawson
Mandy
M
Korn
Solange H
SH
Jerre
Anders
A
Håkansson
Hanna Falk
HF
Wieslander
Elisabet
E
Fredriksson
Karin
K
Sköld
Carl Magnus
CM
Löfdahl
Magnus
M
Löfdahl
Claes-Göran
CG
Nicholls
David J
DJ
Silberstein
David S
DS
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
D000322:Adrenergic Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2