Involvement of NK2 receptors rather than NK1 receptors in bronchial hyperresponsiveness induced by allergic reaction in guinea-pigs.
1. In this study, the role of neuropeptides in antigen-induced bronchoconstriction and bronchial responsiveness in guinea-pigs was evaluated by use of phosphoramidon, the inhibitor of neutral endopeptidases (NEP), the NK1 receptor antagonist, FK888, and the dual NK1/NK2 receptor antagonist, FK224. The role of endogenous tachykinins in bronchial hyperresponsiveness induced by inhaled capsaicin was also observed with FK888 and FK224. 2. Allergic bronchoconstriction and bronchial responsiveness was evoked by inhalation of ovalbumin (OA), and increasing doses of methacholine were inhaled at 5-min intervals for 30 min after OA challenge in passively sensitized and artificially ventilated guinea-pigs. Animals were treated with a 30 s inhalation of phosphoramidon (10(-3)M) or saline 10 min before the OA challenge. FK888 (1.0 or 10 mg kg-1) or FK224 (1.0 or 10 mg kg-1) was administered intravenously 5 min before the OA challenge. 3. Treatment with phosphoramidon did not alter the increase in the lateral pressure at the tracheal tube (Pao) caused by OA inhalation or the increase in bronchial response to methacholine following the allergic reaction. Pretreatment with FK224 did not inhibit the increase in Pao after antigen provocation but did significantly inhibit antigen-induced bronchial hyperresponsiveness in a dose-dependent manner, while FK888 did not affect either allergic bronchoconstriction or post-allergic bronchial hyperresponsiveness. 4. Histamine, 25, 50, 100 or 200 micrograms ml-1 was inhaled for 20 s at 5-min intervals in non-sensitized guinea-pigs which were pretreated with inhalation of subthreshold dose of capsaicin (10(-7) M). FK888 or FK224, each at a dose of 0.1 or 1.0 mg kg-1, or vehicle was given to guinea-pigs intravenously 3 min before inhalation of capsaicin. The capsaicin inhalation significantly potentiated bronchial responsiveness to histamine, compared with control. The capsaicin-induced bronchial hyperresponsiveness was completely blocked by FK224 in a dose-dependent manner but not by FK888. 5. These results suggest that NK2 receptors rather than NK1 receptors may play an important role in bronchial hyperresponsiveness induced by antigen challenge as well as capsaicin while tachykinins do not play a primary role in the acute bronchospasm elicited by antigen challenge in passively sensitized guinea-pigs.
Mizuguchi
M
M
Third Department of Internal Medicine, Kanazawa University School of Medicine, Japan.
Fujimura
M
M
Amemiya
T
T
Nishi
K
K
Ohka
T
T
Matsuda
T
T
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000503:physiopathology*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000187:drug effects*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D012130:Respiratory Hypersensitivity / Q000503:physiopathology*
D016085:Bronchoconstrictor Agents; D004151:Dipeptides; D006020:Glycopeptides; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D016210:Methacholine Chloride; C075570:FK 224; C078949:FK 888; D006632:Histamine; D002211:Capsaicin; C008890:phosphoramidon