There is currently interest in the use of inhibitors of
cyclic nucleotide 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 also endowed with PDE 4 and 5 inhibitory activities, on isolated bronchus and eosinophil functions and in an animal model of
asthma.
SCA40 (1 nM-0.1 mM) produced concentration-dependent inhibition of spontaneous and stimulated tone of human isolated bronchus and reached a maximal relaxation similar to that of
theophylline (3 mM). The potency (-log EC50 values) of
SCA40 against spontaneous tone (6.52 +/- 0.10) was greater than against tone raised by equieffective concentrations (approximately 70%) of
histamine (5.76 +/- 0.06),
leukotriene C4 (5.44 +/- 0.11), and
acetylcholine (4.98 +/- 0.09). In the presence of
cytochalasin B, the chemotactic
peptide N-formyl-L-methionyl-L-leucyl-
L-phenylalanine (FMLP; 0.5 microM) induced
leukotriene C4 production in human eosinophils isolated in discontinuous
metrizamide gradients. The production of
leukotriene C4 was inhibited by
SCA40 in a concentration-related fashion (-log IC50 = 6.04 +/- 0.20; n = 6).
Rolipram, a selective
PDE 4 inhibitor, was also effective (-log IC50 = 7.29 +/- 0.32) but the selective PDE 3 inhibitor SKF94120 was scarcely effective (< 10% inhibition for 10 microM). In
ovalbumin sensitized guinea-pigs,
SCA40 (1 mg kg(-1), i.p.) given 30 min before
antigen challenge significantly inhibited the acute bronchoconstriction produced by
aerosol antigen (5 mg ml(-1), 30 s) (
antigen response was 185 +/- 13 and 91 +/- 21 cmH2O l(-1) s(-1) in control and
SCA40-treated animals, respectively, P < 0.05). Pretreatment with
SCA40 (1 mg kg(-1), i.
p., 30 min pre- and 3 h post-
antigen exposure) prevented airway hyperreactivity to
histamine which developed 24 h after exposure of conscious guinea-pigs to
aerosol antigen. Eosinophil lung accumulation that accompanied airway hyperreactivity was also inhibited by
SCA40 (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 produced 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 slowly recovered with time. These data support previous work showing that PDE inhibition results in antispasmogenic and anti-inflammatory effects.
SCA40 was effective in vitro and in vivo and these effects are probably related to its activity as a mixed PDE inhibitor.