Dysfunction of muscarinic M2 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 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.
ten Berge
R E
RE
Department of Medicinal Chemistry and Molecular Pharmacology, University Centre for Pharmacy, Groningen, The Netherlands.
Santing
R E
RE
Hamstra
J J
JJ
Roffel
A F
AF
Zaagsma
J
J
D000280:Administration, Inhalation; D000485:Allergens / Q000009:adverse effects; D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D001570:Benzodiazepinones / Q000008:administration & dosage / Q000633:toxicity; D016535:Bronchial Hyperreactivity / Q000209:etiology* / Q000503:physiopathology; D003959:Diamines / Q000008:administration & dosage / Q000633:toxicity; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005260:Female; D005703:Gallamine Triethiodide / Q000008:administration & dosage / Q000633:toxicity; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006632:Histamine / Q000008:administration & dosage / Q000633:toxicity; D006967:Hypersensitivity / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists; D009130:Muscle, Smooth / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects; D010276:Parasympatholytics / Q000008:administration & dosage / Q000633:toxicity; D010862:Pilocarpine / Q000008:administration & dosage / Q000633:toxicity; D010880:Piperidines / Q000008:administration & dosage / Q000633:toxicity; D010890:Pirenzepine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D011976:Receptors, Muscarinic / Q000378:metabolism / Q000502:physiology*; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D000485:Allergens; D001570:Benzodiazepinones; D003959:Diamines; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D010880:Piperidines; D011976:Receptors, Muscarinic; D010862:Pilocarpine; C069054:AQ-RA 741; D010890:Pirenzepine; D006632:Histamine; C054938:methoctramine; C048593:otenzepad; D005703:Gallamine Triethiodide