BRONCHODILATOR AND ANTIINFLAMMATORY ACTIVITIES OF SCA40 - STUDIES IN HUMAN ISOLATED BRONCHUS, HUMAN EOSINOPHILS, AND IN THE GUINEA-PIG IN-VIVO

There is currently interest in the use of Inhibitors of cyclic nucleot ide phosphodiesterases (PDE) as potential anti-asthma agents. In this study we examined the effects of SCA40 (6-bromo-8-methylaminoimidazol[ 1.2-a] pyrazine-2-carbonitrile), a preferential inhibitor of PDE 3 als o endowed with PDE 4 and 5 inhibitory activities, on isolated bronchus and eosinophil functions and in an animal model of asthma. SCA4O (1 n M-0.1 mM) produced concentration-dependent inhibition of spontaneous a nd stimulated tone of human Isolated bronchus and reached a maximal re laxation similar to that of theophylline (3 mM). The potency (-log EC5 0 values) of SCA40 against spontaneous tone (6.52 +/- 0.10) was greate r than against tone raised by equieffective concentrations (similar to 70%) of histamine (5.76 +/- 0.06), leukotriene C-4 (5.44 +/- 0.11), a nd acetylcholine (4.98 +/- 0.09), In the presence of cytochalasin B, t he chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine ( FMLP; 0.5 mu M) induced leukotriene C-4 production in human eosinophil s isolated in discontinuous metrizamide gradients. The production of l eukotriene C-4 was inhibited by SCA40 in a concentration-related fashi on (-log IC50 = 6.04 +/- 0.20; n = 6). Rolipram, a selective PDE 4 inh ibitor, was also effective (-log IC50 = 7.29 +/- 0.32) bur the selecti ve PDE 3 inhibitor SKF94120 was scarcely effective (< 10% inhibition f or 10 mu M). In ovalbumin sensitized guinea-pigs, SCA4O (1 mg kg(-1), i.p.) given 30 min before antigen challenge significantly inhibited th e acute bronchoconstriction produced by aerosol antigen (5 mg ml(-1), 30 s) (antigen response was 185 +/- 13 and 91 +/- 21 cmH(2)O l(-1) s(- 1) in control and SCA40-treated animals, respectively, P < 0.05). Pre- treatment with SCA40 (1 mg kg(-1), i.p., 30 min pre- and 3 h post-anti gen exposure) prevented airway hyperreactivity to histamine which deve loped 24 h after exposure of conscious guinea-pigs to aerosol antigen. Eosinophil lung accumulation that accompanied airway hyperreactivity was also inhibited by SCAL40 (from 6.15 +/- 0.86 in control to 1.27 +/ - 0.27 in treated animals; expressed as eosinophils x 10(6); P < 0.05) . SCA40 (1 mg kg(-1), i.p.) also inhibited the microvascular leakage p roduced after inhaled antigen (5 mg ml(-1), 30 s) at all airway levels . The haemodynamic effects of SCA40 (1 mg kg(-1), i.p.) consisted of a rapid decrease (peak at 5 min) in mean arterial blood pressure (-39.4 +/- 2.4%) and tracheal mucosal blood flow (-13.5 +/- 2.0%) that slowl y recovered with time. These data support previous work showing that P DE inhibition results in antispasmodics and anti-inflammatory effects. SCA40 was effective in vitro and in vivo and these effects are probab ly related to its activity as a mixed PDE inhibitor.