Rosiglitazone reverses salbutamol-induced β(2) -adrenoceptor tolerance in airway smooth muscle.
OBJECTIVE
β₂-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)γ agonist rosiglitazone modulated salbutamol-induced β₂-adrenoceptor desensitization in vivo and in vitro.


METHODS
An in vivo model of homologous β₂-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent β₂-adrenoceptor tolerance. In vitro experiments on human bronchial smooth muscle cells were performed to increase the clinical relevance of the study.


RESULTS
In tracheal smooth muscle tissues from desensitized animals, we observed a decrease in the protective effect of salbutamol on carbachol-induced contraction, a hyperresponsiveness to cholinergic stimuli, a modest underexpression of β₂-adrenoceptor gene and a marked decrease in β-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored β₂-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPARγ agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitro β₂-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and β₂-adrenoceptor expression. Rosiglitazone and 15-deoxy-Δ¹²(,)¹⁴-prostaglandin J₂ restored salbutamol sensitivity in homologously desensitized cells.


CONCLUSIONS
These data suggest a potential pharmacodynamic interaction between PPARγ agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic potential of this combination in chronic airway disease.
Fogli
Stefano
S
Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Italy.
Pellegrini
Silvia
S
Adinolfi
Barbara
B
Mariotti
Veronica
V
Melissari
Erika
E
Betti
Laura
L
Fabbrini
Laura
L
Giannaccini
Gino
G
Lucacchini
Antonio
A
Bardelli
Claudio
C
Stefanelli
Fabio
F
Brunelleschi
Sandra
S
Breschi
Maria Cristina
MC
D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004361:Drug Tolerance; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists; D029424:Pulmonary Disease, Chronic Obstructive; D012333:RNA, Messenger / Q000032:analysis; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
D058666:Adrenergic beta-2 Receptor Agonists; D047495:PPAR gamma; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D003907:Dexamethasone; D002217:Carbachol; D000420:Albuterol