Evaluation of bronchoconstriction induced by neurokinins and its inhibition by selective nonpeptide antagonists in conscious guinea pigs, using a double-chamber plethysmograph technique

Abstract

Bronchoconstriction induced by inhaled neurokinins, leukotriene D4 (LTD4), and histamine was examined in conscious guinea pigs, using a double-chamber plethysmograph. The reliability of the plethysmograph was established by obtaining stable baseline values of key pulmonary parameters, including specific airway resistance, over a 4-day period. As well, the usefulness of the setup was confirmed using LTD4 and the LTD4 antagonist MK-571. Aerosols of MK-571 inhibited the bronchoconstriction induced by LTD4 (0.3 μM, 3 min aerosol) with an IC50 value of 65 ± 16 nM. Inhaled neurokinin A (NKA), substance P (SP), [βAla8]NKA(4–10), or [Sar9,Met(O2)11]SP at concentrations up to 10 μM had no bronchoconstrictive effect, unless the guinea pigs were pretreated with the neutral endopeptidase inhibitor thiorphan (0.2 mg/mL, 5 min aerosol). The rank order of bronchoconstriction potency was LTD4 > [βAla8]NKA(4–10) ≈ NKA > [Sar9,Met(O2)11]SP ≈ SP [Formula: see text] histamine. Hyperresponsiveness to NKA-induced bronchoconstriction was evident after 1 day and lasted for 4 days. The response to NKA was not inhibited by mepyramine, indomethacin, or MK-571 but was significantly reduced by atropine and hexamethonium, suggesting the involvement of a cholinergic mechanism. Aerosols of SR-48,968, a selective NK2 antagonist, had potent effects on the bronchoconstriction induced by NKA (1 μM, 3 min aerosol), with an IC50 value of 17 ± 3 nM. SR-48,968 was also active when administered intraperitoneally. The NK1 antagonist CP-99,994 (0.1 μM, 10 min aerosol) inhibited the responses to SP by 70% but had no effect on NKA-induced responses at concentrations up to 10 μM. Interestingly, combination of SR-48,968 (3 nM) and CP-99,994 (100 nM) resulted in more complete inhibition of the NKA-induced bronchoconstriction than was obtained with either antagonist alone. It is concluded that NKA-induced bronchoconstriction in conscious guinea pigs is mediated predominantly by NK2 receptors, with only a minor involvement of NK1 receptors. Although a direct comparison of the potency of SR-48,968 in man and guinea pig is not feasible, our data suggest that it is in the same range in these two species.Key words: neurokinins, NK1 antagonist, NK2 antagonist, conscious guinea pigs, plethysmography.