DYSFUNCTION OF MUSCARINIC M(2) RECEPTORS AFTER THE EARLY ALLERGIC REACTION - POSSIBLE CONTRIBUTION TO BRONCHIAL HYPERRESPONSIVENESS IN ALLERGIC GUINEA-PIGS

1 Using a guinea-pig model of allergic asthma, in which the animals di splay early (0-5 h) and late phase (8-23 h after antigen challenge) br onchoconstrictor reactions, the function of prejunctional inhibitory M t and postjunctional Mg receptors in isolated tracheal preparations ha ve been investigated. In addition, cardiac Mt receptor function in vit ro 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 afte r a single ovalbumin challenge), respectively. At 23 h after the last of four allergen challenges, executed on four consecutive days, bronch ial hyperresponsiveness to histamine was diminished to 1.3 fold. 3 Aft er the early response, there was no change in cardiac muscarinic Mt re ceptor function, since in left atria pD(2) (-log EC(50)) and E(max) va lues of pilocarpine and pK(B) values of AQ-RA 741, a selective M(2) re ceptor antagonist, were not significantly different from controls (unc hallenged sensitized animals), and this also applied to methacholine p ot values for muscarinic Mg receptors in tracheal smooth muscle. 4 Pre junctional inhibitory muscarinic M(2) autoreceptors in airway smooth m uscle were markedly dysfunctional after the early allergic response, s ince potentiation of electrically evoked twitch contractions of trache al preparations by low concentrations of the M(2)-selective muscarinic receptor antagonists, gallamine, methoctramine, AQ-RA 741 and AF-DX 1 16, which is the result of M(2) receptor blockade, was clearly and sig nificantly diminished compared to controls. However, after the late re sponse, both in single and repeatedly challenged animals, twitch poten tiation was not significantly different from and similar to controls, indicating restoration of M(2) receptor function during the late aller gic reaction. 5 It is concluded that dysfunction of muscarinic M(2) au toreceptors in the airways of sensitized and challenged guinea-pigs is already present after the early allergic reaction, and that it has re covered after the late response. Since histamine-induced bronchoconstr iction involves vagal pathways, the present results suggest that bronc hial hyperresponsiveness to histamine is partly due to M(2) autorecept or dysfunction, leading to increased release of acetylcholine.