Dysfunction of muscarinic M₂ receptors after the early allergic reaction: possible contribution to bronchial hyperresponsiveness in allergic guinea‐pigs

Abstract

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 M2 and postjunctional M3 receptors in isolated tracheal preparations have been investigated. In addition, cardiac M2 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 M2 receptor function, since in left atria pD2 (-log EC50) and Emax values of pilocarpine and pKB values of AQ-RA 741, a selective M2 receptor antagonist, were not significantly different from controls (unchallenged sensitized animals), and this also applied to methacholine pD2 values for muscarinic M3 receptors in tracheal smooth muscle. 4. Prejunctional inhibitory muscarinic M2 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 M2-selective muscarinic receptor antagonists, gallamine, methoctramine, AQ-RA 741 and AF-DX 116, which is the result of M2 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 M2 receptor function during the late allergic reaction.5. It is concluded that dysfunction of muscarinic M2 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 M2 auto receptor dysfunction, leading to increased release of acetylcholine.

Effect of M2 and M3 Muscarinic Receptors on Airway Responsiveness to Carbachol in Bronchial-Hypersensitive (BHS) and Bronchial-Hyposensitive (BHR) Guinea Pigs.

“…Therefore, the dysfunction of M 2 muscarinic autoreceptors might increase vagally-mediated airway contraction. Furthermore, histamine-induced airway contractions may be caused by a decrease in M 2 muscarinic autoreceptors [29]. Therefore, increased airway response to histamine in BHS [2,[22][23][24] may also be due to the dysfunction of M 2 muscarinic autoreceptors.…”

Pulmonary neuronal M2 muscarinic receptor function in asthma and animal models of hyperreactivity

“…These findings have subsequently been confirmed in other experiments using diVerent models of antigen challenge. [39][40][41][42] Increased concentrations of acetylcholine have been reported in the airways of other antigen challenged animals including mice, 43 dogs, 44 and guinea pigs, 43 providing indirect supportive evidence that there is loss of function of neuronal M 2 muscarinic receptors in the airways of animal models of hyperreactivity.…”

Bronchoprotection by Olodaterol Is Synergistically Enhanced by Tiotropium in a Guinea Pig Model of Allergic Asthma

“…In addition, although not synergistic, it was found that olodaterol, tiotropium, and their combination fully inhibited the AHR after the LAR. The cause of the lack of synergism in protecting against the AHR after the LAR is unknown, but could well be related to a relatively lower cholinergic tone after the LAR than after the EAR (Ten Berge et al, 1995), thereby not exposing a potential synergism. Nevertheless, from a clinical perspective, the protection against the AHR after the LAR by both olodaterol and tiotropium, as well as their combination, is of importance.…”