DYSFUNCTIONAL MUSCARINIC M(2) AUTORECEPTORS IN VAGALLY INDUCED BRONCHOCONSTRICTION OF CONSCIOUS GUINEA-PIGS AFTER THE EARLY ALLERGIC REACTION

We studied the function of autoinhibitory muscarinic M(2) receptors on vagal nerve endings in the airways of conscious, unrestrained, ovalbu min-sensitized guinea pigs after the early and late allergic reaction. For this purpose, the effects of the selective muscarinic M(2) recept or antagonist gallamine were examined on unilateral vagus nerve stimul ation-induced bronchoconstriction, which was determined as an increase in basal respiration amplitude, measured as changes in pleural pressu re. Under control conditions, i.e., before antigen challenge, a signif icant increase in the pleural pressure was found after inhalation of 0 .1 mM and, even more pronounced, 1.0 mM gallamine, at medium stimulati on frequencies (2-16 Hz), leading to a leftward shift of the frequency -response curve. After inhalation of 10 mM of gallamine, a complete re versal of the left-shift was observed and the frequency-response curve was depressed. However, 6 h after challenge with ovalbumin (i.e., aft er the early allergic reaction) no increase in nerve stimulation-induc ed bronchoconstriction by gallamine was found; a decrease in this bron choconstriction was again observed with the highest concentration. At this moment, bronchial responsiveness to histamine was enhanced 4.5-fo ld compared to control, i.e., prior to antigen provocation. Both after the late allergic response (24 h after challenge; 1.6-fold histamine hyperresponsiveness) and 4 days after allergen challenge (normal hista mine responsiveness) the gallamine-induced potentiation of the broncho constriction was restored, similar to the responses under control cond itions. The results clearly demonstrate that prejunctional muscarinic M(2) receptors control bronchoconstriction in conscious, unrestrained guinea pigs in vivo. Furthermore, these autoinhibitory receptors appea r to be completely dysfunctional after the early allergic phase, but t heir function is largely restored after the late phase. The results in dicate that dysfunction of autoinhibitory muscarinic M(2) receptors mi ght contribute to the strongly enhanced responsiveness to histamine af ter the early allergic response.