SCH-37224, AN EXPERIMENTAL ANTIALLERGY COMPOUND, INHIBITS THE NEUROPEPTIDE COMPONENT OF HYPERVENTILATION-INDUCED AND NICOTINE-INDUCED BRONCHOCONSTRICTION IN GUINEA-PIGS

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.