Effect of tachykinins on airway function in cynomolgus monkeys

Tachykinins have been implicated as important mediators of asthma. This study used neurokinin A (NKA) and substance P (SP) to evaluate the effect of tachykinins on airway mechanics in cynomolgus monkeys. NK(1)-(CP 99,994) and NK(2)-(SR 48968) receptor antagonists were used to evaluate the role of NK(1)and NK(2)receptors on responses to NKA and SP. Lung resistance (R(L)) and dynamic lung compliance (C(Dyn)) were measured in anesthetized, mechanically ventilated cynomolgus monkeys following aerosol or intravenous challenge with NKA, SP or the standard bronchoconstrictor, histamine. Inhaled NKA or SP had variable effects on R(L)and C(Dyn)whereas aerosolized histamine (0.01-1 mg/ml) dose-dependently increased R(L)and decreased C(Dyn). Intravenous NKA (1-100 microg/kg), SP (1-30 microg/kg) or histamine (1-100 microg/kg) increased R(L)and decreased C(Dyn). Pretreatment with SR 48968 (0.1 and 1 mg/kg, i.v.) blocked bronchoconstrictor responses to i.v. NKA, whereas CP 99,994 (0.1 and 1 mg/kg, i.v.) was without effect. Bronchoconstrictor responses to i.v. SP were partially blocked by SR 48968 and CP 99,994. In conclusion, both NKA and SP produce bronchonconstriction in cynomolgus monkeys and this effect is more pronounced when they are given by the iv route. Furthermore, both NK(1)and NK(2)receptors are involved in the bronchonconstrictor response to exogenously administered tachykinins in cynomolgus monkeys.