ISSN:
1365-2222
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Zardaverine is a novel phosphodiesterase III/IV inhibitor, developed as a potential therapeutic agent for asthma. In this study we evaluated the effect of zardaverine in an in vivo animal model of airway inflammation and hyperresponsiveness. Endotoxin exposure in rats causes a transient increase in airway responsiveness and a neutrophilic inflammation of the bronchi, which are both at least partly mediated through the secondary release of tumour necrosis factor a (TNFα), Groups of 10 animals each were pretreated with placebo or zardaverine (1, 10, 30μmol/kg) i.p., 30 min prior to exposure to aerosolized endotoxin (LPS) or saline. Ninety minutes later, airway responsiveness to 5-HT was assessed and bronchoalveolar lavage (BAL) performed. Zardaverine did not influence basehne lung resistance (RL), but inhibited dose dependently the 5-HT induced increase in RL in control animals. In placebo pretreated animals LPS exposure caused a signiflcant decrease in PC50RL5-HT (provocative concentration of 5-HT causing a 50% increase in RL), compared to the saline exposed control group (1.1 ± 0.1 vs 2.7± 0.4μg/kg) (P〈0.01). This decrease in PC50RL-HT was significantly inhibited by zardaverine 30μmol/kg (5.4 ± 1.8 vs 1.1 ± 0.1μg/kg) (P〈0.05). Compared to placebo pre-treated, LPS exposed animals, zardaverine 30 μmol/kg also significantly inhibited to LPS induced neutrophil increase (193.0 ± 50.0 vs 915.6± 181.3 × 103) (P 〈 0.05), increase in elastase activity (23 ± 11 vs 54 ± 9 nmol substrate/h/ml) (P〈0.05) and TNFα release in BAL fluid (93.1 ± 19.5 vs 229.5 ± 24.8 U/ml BAL fluid) (P〈0.01).These results indicate that zardaverine suppresses the endotoxin indueed airway inflammation and hyperresponsiveness in rats. Protection against the increase in responsiveness can be attributed both to inhibition of TNFα release and to functional antagonism towards 5-HT induced bronehoconstriction.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1111/j.1365-2222.1993.tb03240.x
