Role of tachykinin NK1 and NK2 receptors in allergen-induced early and late asthmatic reactions, airway hyperresponsiveness, and airway inflammation in conscious, unrestrained guinea pigs.
Using a guinea pig model of allergic asthma, we investigated the effects of the inhaled, highly selective nonpeptide tachykinin NK1 and NK2 receptor antagonists SR 140333 and SR 48968, respectively, on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions, and infiltration of inflammatory cells in the airways. Both SR 140333 (100 nM, 3 min) and SR 48968 (100 nM, 3 min) had no effect on the severity of the EAR, while the NK2 receptor antagonist SR 48968, but not the NK1 receptor antagonist SR 140333, caused significant inhibition of the LAR. SR 140333 significantly reduced the allergen-induced AHR to histamine, both after the EAR and the LAR. By contrast, SR 48968 did not affect the AHR after the EAR, but significantly attenuated the AHR after the LAR. Bronchoalveolar lavage studies performed after the LAR indicated that SR 140333 caused significant inhibition of allergen-induced infiltration of eosinophils, neutrophils and lymphocytes, while SR 48968 attenuated the infiltration of neutrophils and lymphocytes, but not of eosinophils. Both NK receptor antagonists tended to reduce the accumulation of ciliated epithelial cells in the airways. These results indicate that NK1 and NK2 receptors are importantly, but differentially, involved in the development of allergen-induced airways obstruction, AHR and infiltration of inflammatory cells in the airways. Therefore, both NK1 and NK2 receptor antagonists, or dual NK1 and NK2 antagonists, could be useful in the treatment of allergic asthma.
Schuiling
M
M
Department of Molecular Pharmacology, University Centre for Pharmacy, Groningen, The Netherlands.
Zuidhof
A B
AB
Zaagsma
J
J
Meurs
H
H
D000485:Allergens / Q000009:adverse effects; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D001549:Benzamides / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D001985:Bronchial Provocation Tests; D001991:Bronchitis / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D006168:Guinea Pigs; D008214:Lymphocytes / Q000276:immunology; D064729:Neurokinin-1 Receptor Antagonists; D009504:Neutrophils / Q000276:immunology; D010047:Ovalbumin / Q000009:adverse effects; D010880:Piperidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000502:physiology*
D000485:Allergens; D001549:Benzamides; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C085215:SR 140333; C073839:SR 48968; D010047:Ovalbumin