Different mechanisms of action of beta2-adrenergic receptor agonists: a comparison of reproterol, fenoterol and salbutamol on monocyte cyclic-AMP and leukotriene B4 production in vitro.
BACKGROUND
Beta2-adrenergic receptor agonists have several effects on airway function, most of which are mediated in a variety of cell types resulting in increased c-AMP-production and inhibition of inflammatory mediator production. However, their stimulating effects on cAMP-production became known to be inversed by increasing phosphodiesterase (PDE) activity and degradation of cAMP. Therefore, in this study we have evaluated the efficacy of reproterol, a dual acting beta2-adrenoceptor agonist and PDE-inhibitor, as compared to salbutamol and fenoterol with respect to production of cAMP and LTB4 in cultured monocytes.


METHODS
Isolated human monocytes (10(5)/ml) were incubated (n = 9) in suspension with beta2-adrenoceptor agonists (10(-10) -10(-4) M) for 30 minutes with and without IBMX. Then, cAMP production was determined following treatment with Triton-X100. Production of LTB4 was measured following incubation of beta2-adrenoceptor agonists for 4 hrs in the presence of LPS (10 mg/ml). cAMP and LTB subset 4 were measured in culture supernatants by enzyme immunoassay.


RESULTS
At 10(-5) M, production of cAMP was significantly stimulated by reproterol > fenoterol > salbutamol in a dose-dependent manner to an extent of *128%, *65%, 13% (*p<0.04) respectively. In contrast, LTB4-production was inhibited significantly to a similar degree by salbutamol and reproterol in a dose-dependent manner by 59% and 49% (10(-5) M, p<0.03), respectively, with decreasing inhibition (15%) after fenoterol. Following co-incubation with IBMX, cAMP production only increased significantly (p<0.002) after fenoterol (+110%) compared to salbutamol (+29%) and reproterol (+50%) (ANOVA, p<0.001).


CONCLUSIONS
These data suggest effects of the theophylline constituent of reproterol to inhibit adenylyl cyclase induced phosphodiesterase activity. The advantageous synergistic effects of reproterol on cAMP-production need to be further explored in trials.
Juergens
Uwe R
UR
Department of Pneumology, Allergology and Sleep Medicine, Medical Outpatient Clinic, Bonn University Hospital, Germany. uwejuergens@t-online.de
Stöber
M
M
Libertus
H
H
Darlath
W
W
Gillissen
A
A
Vetter
H
H
D015056:1-Methyl-3-isobutylxanthine / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D000420:Albuterol / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005280:Fenoterol / Q000494:pharmacology*; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism*; D009921:Metaproterenol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D004338:Drug Combinations; D010726:Phosphodiesterase Inhibitors; D018343:Receptors, Adrenergic, beta-2; C014792:reproterol; D007975:Leukotriene B4; D005280:Fenoterol; D009921:Metaproterenol; D013806:Theophylline; D000242:Cyclic AMP; D000420:Albuterol; D015056:1-Methyl-3-isobutylxanthine