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Can J Physiol Pharmacol. 1994 Jan;72(1):11-8.

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

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  • 1Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire, Dorval, QC, Canada.

Abstract

Bronchoconstriction induced by inhaled neurokinins, leukotriene D4 (LTD4), and histamine was examined in conscious guinea pigs, using a double-chamber plethysmography. 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 microM, 3 min aerosol) with an IC50 value of 65 +/- 16 nM. Inhaled neurokinin A (NKA), substance P (SP), [beta Ala8]NKA(4-10), or [Sar9,Met(O2)11]SP at concentrations up to 10 microM 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 > [beta Ala8]NKA(4-10) approximately NKA > [Sar9,Met(O2)11]SP approximately SP >> 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 microM, 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 microM, 10 min aerosol) inhibited the responses to SP by 70% but had no effect on NKA-induced responses at concentrations up to 10 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID:
8012892
[PubMed - indexed for MEDLINE]
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