ISSN:
1432-1912
Keywords:
Key words SCA40
;
Cyclic nucleotide
;
phosphodiesterase inhibitors
;
Human isolated bronchus
;
Airway relaxation
;
Human eosinophils
;
Leukotriene
;
C4 production
;
Sensitized guinea-pig
;
Airway
;
hyperreactivity
;
Airway eosinophil infiltration
;
Airway
;
microvascular leakage
;
Tracheal mucosal blood flow
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract 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 (∼ 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 μM) 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 μM). 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 × 106; 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 anti-spasmogenic 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/PL00005121
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