title: Inhibition by reproterol of cAMP PDE in intact mastocytoma P-815 cells.
abstract: In vitro studies in rat mastocytes and human monocytes suggested that reproterol (a selective beta(2)-adrenoceptor agonist with a theophylline moiety) exerts anti-inflammatory actions through inhibition of cyclic AMP (cAMP) PDE activity. Thus, reproterol was tested for its ability to inhibit cAMP PDE in cultured mouse mastocytoma P-815 cells. cAMP PDE activity was measured in intact cells by spectrofluorometry using the fluorescent substrate 2'-O-anthraniloyl cAMP. Reproterol was more potent than theophylline to inhibit cAMP PDE (pIC(50)=4.28+/-0.25 vs. 3.16+/-0.05). This contrasted with disrupted cells, where the PDE inhibitory potency of reproterol was low (pIC(50)=2.85+/-0.03) and similar to that of theophylline (pIC(50)=2.66+/-0.19). No cAMP PDE inhibition was found with other beta(2)-agonists tested (fenoterol, salbutamol, salmeterol and formoterol). Finally, the selective PDE inhibitors calmidazolium (100 nM), milrinone (5 microM) and rolipram (50 microM) inhibited cAMP PDE activity by approximately 20, 30 and 25% respectively. In conclusion, reproterol potently and non-specifically inhibited intracellular cAMP phosphodiesterases in intact mastocytoma cells. This can explain the previously reported beta(2)-adrenoceptor-independent anti-inflammatory actions of reproterol in vitro. Further studies are required to define the anti-inflammatory potential of reproterol in asthma.
authors.affiliation: INSERM U400, School of Medicine, 8 rue du Général Sarrail, 94010, Créteil Cédex, France.
authors.forename: M
authors.initials: M
authors.lastname: Alvarez-Guerra
authors.forename: H
authors.initials: H
authors.lastname: Libertus
authors.forename: R P
authors.initials: RP
authors.lastname: Garay
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D009921:Metaproterenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D013806:Theophylline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D004338:Drug Combinations; D010726:Phosphodiesterase Inhibitors; C014792:reproterol; D009921:Metaproterenol; D013806:Theophylline; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases