Our results demonstrate differences between normal and asthmatic subjects in terms of agonist-agonist interaction. Whereas in normal subjects prior muscarinic stimulation suppressed the histamine-induced bronchoconstriction, no such suppression was observed in subjects with asthma. It is possible that lack of suppressive action of methacholine on histamine-induced bronchoconstriction in asthmatic subjects may be related to two factors: (a) lower SGaw, and (b) lower PD50. It is unlikely that a lower baseline SGaw in asthmatic subjects would have altered the deposition of methacholine in such a way as to affect the subsequent airway responsiveness to histamine. Because of their sensitive airways, asthmatic subjects required a markedly lower PDgo of methacholine, resulting in a smaller total dose of methacholine deposited in the airways, which could be responsible for lack of suppressive action. starlix medication

In vitro data of Ishii and Kato10 do not support this concept, as methacholine could suppress the histamine-induced contraction of guinea pig ileum at a concentration as low as 10~M or lower, indicating that a high concentration of methacholine was not needed for the suppressive action. This is further supported by our observations in five normal subjects, in whom prior exposure to higher or lower doses of methacholine (19 vs 5 breath units) caused an equivalent suppression of subsequent histamine-induced bronchoconstriction (Fig 4). Thus, lack of suppressive effect of methacholine on subsequent histamine-induced bronchoconstriction in asthmatic subjects is probably related to the disease state.
The mechanism of the suppressive action of muscarinic stimulation on histamine-induced bronchoconstriction is unclear. It is unlikely to be related to heterologous desensitization, because prolonged treatment with methacholine was not required and methacholine specifically suppressed histamine effects and not those of methacholine. It is now widely accepted that muscarinic receptors can be further divided into at least three subtypes, Mu M2 and M3 receptors. Ishii and Kato10 observed in vitro that methacholine-induced suppression of contractile action of histamine was probably mediated by M2-muscarinic receptors, as pirenzipine, a M^receptor antagonist, failed to modify the suppressive action of methacholine. This concept is further supported by recent findings of Minette and Barnes in human and guinea pig airway smooth muscle. Those investigators observed that the muscarinic agonist, pilocarpine, inhibited the contractile response to electrical field stimulation, which was reversed by prejunctional M2-receptor antagonist, gallamine, and not by the Mj-receptor antagonist, pirenzepine. Based upon in vitro observations in human and guinea pig airway smooth muscle, existence of inhibitory muscarinic receptors (“auto-receptors”) has been suggested in the parasympathetic nerves.71819 Minette and Barnes also demonstrated that gallamine enhanced the contractile response to electrical field stimulation, thus confirming the functional existence of prejunctional inhibitory M2-recep-tors.