Dysfunctional muscarinic M2 autoreceptors in vagally induced bronchoconstriction of conscious guinea pigs after the early allergic reaction

Abstract

We studied the function of autoinhibitory muscarinic M2 receptors on vagal nerve endings in the airways of conscious, unrestrained, ovalbumin-sensitized guinea pigs after the early and late allergic reaction. For this purpose, the effects of the selective muscarinic M2 receptor antagonist gallamine were examined on unilateral vagus nerve stimulation-induced bronchoconstriction, which was determined as an increase in basal respiration amplitude, measured as changes in pleural pressure. Under control conditions, i.e., before antigen challenge, a significant increase in the pleural pressure was found after inhalation of 0.1 mM and, even more pronounced, 1.0 mM gallamine, at medium stimulation frequencies (2-16 Hz), leading to a leftward shift of the frequency-response curve. After inhalation of 10 mM of gallamine, a complete reversal of the left-shift was observed and the frequency-response curve was depressed. However, 6 h after challenge with ovalbumin (i.e., after the early allergic reaction) no increase in nerve stimulation-induced bronchoconstriction by gallamine was found; a decrease in this bronchoconstriction was again observed with the highest concentration. At this moment, bronchial responsiveness to histamine was enhanced 4.5-fold 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 histamine responsiveness) the gallamine-induced potentiation of the bronchoconstriction was restored, similar to the responses under control conditions. The results clearly demonstrate that prejunctional muscarinic M2 receptors control bronchoconstriction in conscious, unrestrained guinea pigs in vivo. Furthermore, these autoinhibitory receptors appear to be completely dysfunctional after the early allergic phase, but their function is largely restored after the late phase. The results indicate that dysfunction of autoinhibitory muscarinic M2 receptors might contribute to the strongly enhanced responsiveness to histamine after the early allergic response.