Jc. Kips et al., THE EFFECT OF ZARDAVERINE, AN INHIBITOR OF PHOSPHODIESTERASE ISOENZYME-III AND ISOENZYME-IV, ON ENDOTOXIN-INDUCED AIRWAY CHANGES IN RATS, Clinical and experimental allergy, 23(6), 1993, pp. 518-523
Zardaverine is a novel phosphodiesterase III/IV inhibitor, developed a
s a potential therapeutic agent for asthma. In this study we evaluated
the effect of zardaverine in an in vivo animal model of airway inflam
mation and hyperresponsiveness. Endotoxin exposure in rats causes a tr
ansient increase in airway responsiveness and a neutrophilic inflammat
ion of the bronchi, which are both at least partly mediated through th
e secondary release of tumour necrosis factor alpha (TNFalpha). Groups
of 10 animals each were pretreated with placebo or zardaverine (1, 10
, 30 mumol/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 d
id not influence baseline lung resistance (R(L)), but inhibited dose d
ependently the 5-HT induced increase in R(L) in control animals. In pl
acebo pretreated animals LPS exposure caused a significant decrease in
PC50R(L)5-HT (provocative concentration of 5-HT causing a 50% increas
e in R(L)), compared to the saline exposed control group (1.1 +/- 0.1
vs 2.7 +/- 0-4 mug/kg) (P < 0.01). This decrease in PC50R(L)5-HT was s
ignificantly inhibited by zardaverine 30 mumol/kg (5.4 +/- 1.8 vs 1.1
+/- 0.1 mug/kg) (P < 0.05). Compared to placebo pre-treated, LPS expos
ed animals, zardaverine 30 mumol/kg also significantly inhibited to LP
S induced neutrophil increase (193.0 +/- 50.0 vs 915.6 +/- 181.3 x 10(
3)) (P < 0.01), increase in elastase activity (23 +/- 11 vs 54 +/- 9 n
mol substrate/h/ml) (P < 0.05) and TNFalpha 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 induced airway infl
ammation and hyperresponsiveness in rats. Protection against the incre
ase in responsiveness can be attributed both to inhibition of TNFalpha
release and to functional antagonism towards 5-HT induced bronchocons
triction.