Bronchodilator and anti-inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes

1 Selective phosphodiesterase 4 (PDE4) inhibitors are of potential interest in the treatment of asthma. We examined the effects of the alkaloid S-(+)- glaucine, a PDE4 inhibitor, on human isolated bronchus and granulocyte func tion. 2 Glaucine selectively inhibited PDE4 from human bronchus and polymorphonuc lear leukocytes (PMN) in a non-competitive manner (K-i=3.4 mu M). Glaucine displaced [H-3]-rolipram from its high-affinity binding sites in rat brain cortex membranes (IC(50)similar to 100 mu M). 3 Glaucine inhibited the spontaneous and histamine-induced tone in human is olated bronchus (pD(2)similar to 4.5). Glaucine (10 mu M) did not potentiat e the isoprenaline-induced relaxation but augmented cyclic AMP accumulation by isoprenaline. The glaucine-induced relaxation was resistant to H-89, a protein kinase A inhibitor. Glaucine depressed the contractile responses to Ca2+ (pD'(2)similar to 3.62) and reduced the sustained rise of [Ca2+](i) p roduced by histamine in cultured human airway smooth muscle cells (-log IC( 50)similar to 4.3). 4 Glaucine augmented cyclic AMP levels in human polymorphonuclear leukocyte s challenged with N-formyl-Met-Leu-Phe (FMLP) or isoprenaline, and inhibite d FMLP-induced superoxide generation, elastase release, leukotriene B-4 pro duction, [Ca2+](i) signal and platelet aggregation as well as opsonized zym osan-, phorbol myristate acetate-, and A23187-induced superoxide release. T he inhibitory effect of glaucine on superoxide generation by FMLP was reduc ed by H-89. 5 In conclusion. Ca2+ channel antagonism by glaucine appears mainly respons ible for the relaxant effect of glaucine in human isolated bronchus while P DE4 inhibition contributes to the inhibitory effects of glaucine in human g ranulocytes. The very low PDE4/binding site ratio found for glaucine makes this compound attractive for further structure-activity studies.