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The respiratory responses, including changes in pulmonary resistance (RL) and dynamic compliance (Cdyn), to the neurokinin peptides substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) were assessed in anaesthetised normal Suffolk-cross and conscious Texel-cross asthmatic sheep In normal sheep (n=l 1) intravenous SP was a more potent bronchoconstrictor than NKA (n=9) and this was similar to findings in sheep with a naturally acquired airway allergy to Ascaris suum antigen (asthmatic) (n=5) where peptides were administered by inhalation. NKB (n=4) was assessed only in normal sheep and caused insignificant changes in bronchomotor tone. Intravenous SP and NKA, in normal anaesthetised sheep, caused a dose-dependent reduction in respiratory rate and this was similar for both peptides. The bronchomotor response to SP in normal sheep demonstrated age-related changes. In sheep under 6 months of age there was a pronounced bronchoconstriction, with a subsequent reduction in the response as animals approach maturity. In old sheep, aged approximately four years, there was minimal bronchomotor response, however, there was dose-dependent apnoea. The bronchomotor response to SP in anaesthetised normal sheep was significantly antagonised after pre-treatment with atropine (lmg/kg; n=6), hexamethonium (20mg/Kg; n=3) and the NK-1 antagonist CP 96,345 (0.1 and 0.5mg/Kg; n=5), but not by the HI receptor antagonist chlorpheniramine (2mg/Kg; n=5) or the neurokinin antagonist spantide (lOug/kg/min; n=3). The anti-asthma drug nedocromil sodium (0.1 and l.Omg/kg; n=4) had a variable effect on the response. In the isolated sheep trachealis muscle preparation the contractile effect of SP was inhibited by atropine (n=4) and the Ml receptor antagonist pirenzepine (n=8), with IC₅₀ values of 5.6xl0⁻⁸ and 5xl0⁻¹⁰ M respectively, while spantide (n=7) and the NK-2 receptor antagonist L-659,874 (n=6) were ineffective. In several normal sheep (n=10) intravenous SP consistently caused augmented breaths. Bilateral vagotomy (n=7) abolished, and cooling of the right cervical vagus (n=7), after section of the left vagus, to temperatures below 7° C significantly attenuated the bronchomotor response to SP in normal sheep. The conclusion of this study is that the order of potency for the bronchomotor effects of the neurokinins is similar to rabbits and pigs but different from that reported for most other species, including man. The mechanism of action of SP is largely indirect, involving activation of vagal reflex mechanisms and/or modulation of ganglionic neurotransmission and acetylcholine release from cholinergic nerve endings.