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 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)
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire, Dorval, QC, Canada.
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Chan
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Tousignant
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Ho
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Brideau
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Savoie
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Rodger
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010276:Parasympatholytics / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010991:Plethysmography; D011422:Propionates / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology
D001549:Benzamides; D001993:Bronchodilator Agents; D010276:Parasympatholytics; D010880:Piperidines; D011422:Propionates; D011804:Quinolines; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; C059141:verlukast; C073839:SR 48968; D017998:Leukotriene D4; D006632:Histamine; D015288:Neurokinin A; D011738:Pyrilamine; D007213:Indomethacin