EVALUATION OF BRONCHOCONSTRICTION INDUCED BY NEUROKININS AND ITS INHIBITION BY SELECTIVE NONPEPTIDE ANTAGONISTS IN CONSCIOUS GUINEA-PIGS, USING A DOUBLE-CHAMBER PLETHYSMOGRAPH TECHNIQUE

Bronchoconstriction induced by inhaled neurokinins, leukotriene D4 (LTD4), and histamine was examined 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 muM, 3 min aerosol) with an IC50 value of 65 +/- 16 nM. Inhaled neurokinin A (NKA), substance P (SP), [betaAla8]NKA(4-10), or [Sar9,Met(O2)11]SP at concentrations up to 10 muM 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 > [betaAla8]NKA(4-10) almost-equal-to NKA > [Sar9,Met(O2)11]SP almost-equal-to SP much greater than histamine. Hyporesponsiveness 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 muM, 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 muM, 10 min aerosol) inhibited the responses to SP by 70% but had no effect on NKA-induced responses at concentrations up to 10 muM. 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.