title: Phosphodiesterase 4 inhibitors modulate beta2-adrenoceptor agonist-induced human airway hyperresponsiveness.
abstract: Chronic exposure of human isolated bronchi to beta2-adrenergic agonists, especially fenoterol, potentiates smooth muscle contraction in response to endothelin-1 (ET-1), a peptide implicated in chronic inflammatory airway diseases. 5'-Cyclic adenosine monophosphate (cAMP) pathways are involved in fenoterol-induced hyperresponsiveness. The present study investigated whether chronic elevation of intracellular cAMP by other pathways than beta2-adrenoceptor stimulation provokes bronchial hyperresponsiveness. Samples from eighteen human bronchi were sensitized to ET-1 by prolonged incubation with 0.1 microM fenoterol (15 h, 21 degrees C), or, under similar conditions, were incubated with a selective type-3 phosphodiesterase inhibitor (1 microM siguazodan), two selective type-4 phosphodiesterase inhibitors (0.1 microM rolipram and 0.1 microM cilomilast), a combination of fenoterol and rolipram (0.1 microM each) or of fenoterol and cilomilast (0.1 microM each). Rolipram and cilomilast, but not siguazodan, induced hyperresponsiveness (p < 0.01 and p < 0.05 vs. paired controls, respectively) similar to the fenoterol effect. Fenoterol-induced bronchial hyperresponsiveness was significantly enhanced by coincubation with cilomilast (p < 0.05 vs. fenoterol alone) but not with rolipram. Our results suggest that prolonged activation of intracellular cAMP through phosphodiesterase 4 inhibition induces hyperresponsiveness to ET-1 in human isolated bronchi. However, differences in subcellular localization of phosphodiesterase 4 may provoke divergent responsiveness patterns when human bronchi are continuously exposed to selective phosphodiesterase inhibitors with or without beta2-adrenergic agonists.
authors.affiliation: UPRES EA220, Faculté de Médecine Paris-Ouest and UFR Biomédicale des Saints-Pères, 45 rue des Saints-Pères, 75006 Paris, France. christophe.faisy@wanadoo.fr
authors.forename: Christophe
authors.initials: C
authors.lastname: Faisy
authors.forename: Paul-André
authors.initials: PA
authors.lastname: Risse
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Naline
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guerot
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Fagon
authors.forename: Phillipe
authors.initials: P
authors.lastname: Devillier
authors.forename: Charles
authors.initials: C
authors.lastname: Advenier
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000032:analysis / Q000037:antagonists & inhibitors*; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000201:enzymology; D002264:Carboxylic Acids / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D019332:Endothelin-1 / Q000494:pharmacology; D005280:Fenoterol / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D019332:Endothelin-1; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D005280:Fenoterol; C433247:Cilomilast; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram