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Effects of tachykinin NK 1 receptor antagonists on vagal hyperreactivity and neuronal M 2 muscarinic receptor function in antigen challenged guinea‐pigs
Author(s) -
Costello Richard W,
Fryer Allison D,
Belmonte Kristen E,
Jacoby David B
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701822
Subject(s) - bronchoconstriction , muscarinic acetylcholine receptor , endocrinology , medicine , tachykinin receptor , histamine , guinea pig , muscarinic acetylcholine receptor m1 , agonist , receptor , biology , substance p , neuropeptide , asthma
The role of tachykinin NK 1 receptors in the recruitment of eosinophils to airway nerves, loss of inhibitory neuronal M 2 muscarinic receptor function and the development of vagal hyperreactivity was tested in antigen‐challenged guinea‐pigs. In anaesthetized guinea‐pigs, the muscarinic agonist, pilocarpine (1–100 μg kg −1 , i.v), inhibited vagally induced bronchoconstriction, in control, but not in antigen‐challenged guinea‐pigs 24 h after antigen challenge. This indicates normal function of neuronal M 2 muscarinic receptors in controls and loss of neuronal M 2 receptor function in challenged guinea‐pigs. Pretreatment of sensitized guinea‐pigs with the NK 1 receptor antagonists CP99994 (4 mg kg −1 , i.p.), SR140333 (1 mg kg −1 , s.c.) or CP96345 (15 mg kg −1 , i.p.) before antigen challenge, prevented M 2 receptor dysfunction. Neither administration of the NK 1 antagonists after antigen challenge, nor pretreatment with an NK 2 receptor antagonist, MEN10376 (5 μmol kg −1 , i.p.), before antigen challenge, prevented M 2 receptor dysfunction. Electrical stimulation of the vagus nerves caused a frequency‐dependent (2–15 Hz, 10 V, 0.2 ms for 5 s) bronchoconstriction that was significantly increased following antigen challenge. Pretreatment with the NK 1 receptor antagonists CP99994 or SR140333 before challenge prevented this increase. Histamine (1–20 nmol kg −1 , i.v.) caused a dose‐dependent bronchoconstriction, which was vagally mediated, and was significantly increased in antigen challenged guinea‐pigs compared to controls. Pretreatment of sensitized animals with CP99994 before challenge prevented the increase in histamine‐induced reactivity. Bronchoalveolar lavage and histological studies showed that after antigen challenge significant numbers of eosinophils accumulated in the airways and around airway nerves. This eosinophilia was not altered by pretreatment with the NK 1 receptor antagonist CP99994. These data indicate that pretreatment of antigen‐sensitized guinea‐pigs with NK 1 , but not with NK 2 receptor antagonists before antigen challenge prevented the development of hyperreactivity by protecting neuronal M 2 receptor function. NK 1 receptor antagonists do not inhibit eosinophil accumulation around airway nerves.