Premium
Dysfunction of muscarinic M 2 receptors after the early allergic reaction: possible contribution to bronchial hyperresponsiveness in allergic guinea‐pigs
Author(s) -
Berge Donald E.J.,
Santing Ruud E.,
Hamstra Jacob Jan,
Roffel Ad F.,
Zaagsma Johan
Publication year - 1995
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 - 10.1111/j.1476-5381.1995.tb13286.x
Subject(s) - muscarinic acetylcholine receptor , methacholine , methoctramine , histamine , medicine , endocrinology , bronchial hyperresponsiveness , bronchoconstriction , pilocarpine , muscarinic acetylcholine receptor m3 , histamine receptor , muscarinic acetylcholine receptor m2 , acetylcholine , chemistry , receptor , antagonist , asthma , respiratory disease , lung , psychiatry , epilepsy
1 Using a guinea‐pig model of allergic asthma, in which the animals display early (0–5 h) and late phase (8–23 h after antigen challenge) bronchoconstrictor reactions, the function of prejunctional inhibitory M 2 and postjunctional M 3 receptors in isolated tracheal preparations have been investigated. In addition, cardiac M 2 receptor function in vitro and bronchial responsiveness to histamine in vivo were evaluated. 2 Sensitivity to inhaled histamine was increased 3.1 fold and 1.6 fold after the early and late allergic reactions (i.e. at 5 h and 23 h after a single ovalbumin challenge), respectively. At 23 h after the last of four allergen challenges, executed on four consecutive days, bronchial hyperresponsiveness to histamine was diminished to 1.3 fold. 3 After the early response, there was no change in cardiac muscarinic M 2 receptor function, since in left atria pD 2 (‐log EC 50 ) and E max values of pilocarpine and p K B values of AQ‐RA 741, a selective M 2 receptor antagonist, were not significantly different from controls (unchallenged sensitized animals), and this also applied to methacholine pD 2 values for muscarinic M 3 receptors in tracheal smooth muscle. 4 Prejunctional inhibitory muscarinic M 2 autoreceptors in airway smooth muscle were markedly dysfunctional after the early allergic response, since potentiation of electrically evoked twitch contractions of tracheal preparations by low concentrations of the M 2 ‐selective muscarinic receptor antagonists, gallamine, methoctramine, AQ‐RA 741 and AF‐DX 116, which is the result of M 2 receptor blockade, was clearly and significantly diminished compared to controls. However, after the late response, both in single and repeatedly challenged animals, twitch potentiation was not significantly different from and similar to controls, indicating restoration of M 2 receptor function during the late allergic reaction. 5 It is concluded that dysfunction of muscarinic M 2 autoreceptors in the airways of sensitized and challenged guinea‐pigs is already present after the early allergic reaction, and that it has recovered after the late response. Since histamine‐induced bronchoconstriction involves vagal pathways, the present results suggest that bronchial hyperresponsiveness to histamine is partly due to M 2 autoreceptor dysfunction, leading to increased release of acetylcholine.