SCH-37224, AN EXPERIMENTAL ANTIALLERGY COMPOUND, INHIBITS THE NEUROPEPTIDE COMPONENT OF HYPERVENTILATION-INDUCED AND NICOTINE-INDUCED BRONCHOCONSTRICTION IN GUINEA-PIGS
Pj. Mauser et al., SCH-37224, AN EXPERIMENTAL ANTIALLERGY COMPOUND, INHIBITS THE NEUROPEPTIDE COMPONENT OF HYPERVENTILATION-INDUCED AND NICOTINE-INDUCED BRONCHOCONSTRICTION IN GUINEA-PIGS, Pharmacology, 54(1), 1997, pp. 8-15
Sch 37224 is an experimental antiallergy coumpound that inhibits hyper
ventilation-induced bronchoconstriction (HIB) in guinea pigs and cold
air bronchospasm in human asthmatics. HIB in guinea pigs may involve t
he release of tachykinins, such as neurokinin A (NKA) and substance P
(SP), and the action of Sch 37224 in this model may relate to inhibiti
on of these neuropeptides. We studied the effect of Sch 37224 on the n
europeptide component of HIB that was enhanced In guinea pigs treated
with the neutral endopeptidase inhibitors, thiorphan and phosphoramido
n. Pulmonary resistance (R(L)) and dynamic lung compliance (C-Dyn) wer
e measured in anesthetized, mechanically ventilated guinea pigs. R(L)
and C-Dyn were measured at baseline (1 ml/100 g tidal volume and 50 br
eaths/min) and after a 10-min period of hyperventilation (1 ml/100 g,
150 breaths/min). Hyperventilation produced modest changes in R(L) (+4
1 +/- 12%) and C-Dyn (-12 +/- 3%) which mere markedly enhanced by trea
tment with 3 mg/kg of either thiorphan or phosphoramidon (R(L) + 269 /- 43% for thiorphan, + 292 +/- 63% for phosphoramidon and C-Dyn -65 /- 3% for thiorphan, -51 +/- 13% for phosphoramidon). In the presence
of thiorphan or phosphoramidon, the bronchospasm to hyperventilation w
as significantly reduced (>70%) with 5 mg/kg, p.o., of Sch 37224. In o
ther studies, the peptidergic (conducted in the presence of ipratropiu
m bromide and phosphoramidon) bronchoconstrictor response to intraveno
us nicotine (1 mg/kg) was also inhibited by Sch 37224 (0.3-10 mg/kg, p
.o.). However, Scfr 37224 (5 mg/kg, p.o.) had no effect on the broncho
constrictor response to intravenous NKA. These results indicate that S
ch 37224 inhibits the neuropeptide component of IIIB and nicotine in g
uinea pigs and this effect appears to be mediated by the inhibition of
the release of tachykinins from airway C fibers.