Vol. 280, Issue 1, 210-219, 1997

The Influence of Endogenous Catecholamines on the Inhibitory Effects of Rolipram Against Early- and Late-Phase Response to Antigen in the Guinea Pig

David C. Underwood, Jane K. Matthews, Ruth R. Osborn, Steven Bochnowicz and Theodore J. Torphy

Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania

Selective inhibitors of the low-K_m cAMP-specific phosphodiesterase (PDE4) inhibit inflammatory cell function and relax airway smooth muscle. Thus PDE4 inhibitors may be useful in the therapy of asthma. The present study was conducted to determine whether the in vivo activity of rolipram, a prototypical PDE4 inhibitor, is due to its ability to potentiate the anti-inflammatory effects of prostaglandins or catecholamines, endogenous activators of adenylyl cyclase, in models of the early- and late-phase response to antigen. Rolipram, administered i.v. to anesthetized, paralyzed and ventilated ovalbumin-sensitized guinea pigs, inhibited i.v. antigen-induced bronchoconstriction with an ID₅₀ value of 0.2 mg/kg. Pretreatment with either of the beta adrenoceptor antagonists propranolol and nadolol (0.5 mg/kg i.v.), enhanced the bronchial reactivity to antigen and abolished the inhibitory activity of rolipram (0.1-10 mg/kg i.v.). In addition, the inhibitory activity of three structurally dissimilar PDE4 inhibitors was nearly abolished by propranolol. Cyclooxygenase inhibition by indomethacin slightly enhanced the reactivity to antigen but did not affect the inhibitory activity of rolipram. Plasma catecholamine concentrations were not altered by rolipram (0.3 or 1 mg/kg i.v.), which indicates that there was no stimulation of catecholamine release. Bilateral adrenalectomy reduced plasma epinephrine concentrations (from 1700 pg/ml to 400 pg/ml), significantly enhanced airway reactivity to antigen and substantially reduced the inhibitory activity of rolipram (3 mg/kg i.v.). Pretreatment of conscious guinea pigs with the beta adrenoceptor antagonist nadolol, 2 mg/kg p.o., enhanced aerosol antigen-induced bronchoconstriction and pulmonary eosinophil influx measured by bronchoalveolar lavage. Nadolol reduced the inhibitory effect of rolipram against antigen-induced bronchoconstriction but not eosinophil influx. The inhibitory effect of rolipram was unaffected by indomethacin. The present data suggest that circulating catecholamines play an important protective role against antigen-induced bronchoconstriction in the guinea pig. Moreover, the inhibitory activity of PDE4 inhibitors against antigen-induced bronchoconstriction, but not eosinophil influx, is reduced by beta adrenergic blockade or adrenalectomy. Thus the inhibitory activity of PDE4 inhibitors against antigen-induced bronchoconstriction may be related to their synergism with endogenous catecholamines to supress mast cell degranulation.