The effect of zardaverine, an inhibitor of phosphodiesterase isoenzymes III and IV, on endotoxin‐induced airway changes in rats

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Abstract
Summary: 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) (P50RL‐HT was significantly inhibited by zardaverine 30μmol/kg (5.4 ± 1.8 vs 1.1 ± 0.1μg/kg) (P3) (P < 0.05), increase in elastase activity (23 ± 11 vs 54 ± 9 nmol substrate/h/ml) (PP<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.

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