Suppression of human eosinophil respiratory burst and cyclic AMP hydrolysis by inhibitors of type IV phosphodiesterase: interaction with the beta adrenoceptor agonist albuterol.
The cyclic AMP phosphodiesterase (PDE) III/IV inhibitor, zardaverine, and the PDE IV-selective inhibitor, rolipram, both caused concentration-dependent inhibition of opsonized zymosan-stimulated superoxide anion generation by purified human peripheral blood eosinophils with approximate IC50 values of 30 and 40 microM, respectively. In contrast, the selective PDE III inhibitor, SK&F 94120, was ineffective in suppressing this functional response at concentrations below 100 microM. The inhibitory effects of rolipram and zardaverine on superoxide anion generation were increased in the presence of the beta-2 adrenoceptor agonist, albuterol, which itself was an inhibitor of eosinophil respiratory burst (IC50 = 20 microM). The effects of albuterol and the PDE inhibitors in combination were simply additive. Paradoxically, both rolipram and zardaverine significantly potentiated albuterol-induced cyclic AMP accumulation in a synergic fashion. Cyclic AMP PDE activity of eosinophil homogenates was inhibited by both zardaverine (IC50 = 515 nM) and rolipram (IC50 = 550 nM) as well as two other PDE IV-selective inhibitors, Ro 20-1724 (IC50 = 3.0 microM) and denbufylline (IC50 = 360 nM), whereas SK&F 94120 was ineffective. These data suggest that cyclic AMP levels in human eosinophils are regulated by the action of a type IV PDE isoenzyme and that elevation of the intracellular cyclic AMP concentration by PDE IV inhibition can suppress the functional activity of these cells. However, the suppressor effect of the PDE IV inhibitors appears to be independent of that of a beta-2 adrenoceptor agonist, implying a possible adenylyl cyclase-independent mechanism of action for beta agonists in eosinophils.
Dent
G
G
Department of Thoracic Medicine, Royal Brompton, National Heart and Lung Institute, London, United Kingdom.
Giembycz
M A
MA
Evans
P M
PM
Rabe
K F
KF
Barnes
P J
PJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D004357:Drug Synergism; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D016897:Respiratory Burst / Q000187:drug effects*; D020889:Rolipram
D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011760:Pyrrolidinones; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D020889:Rolipram; D000420:Albuterol; C066436:zardaverine