MUSCARINIC CONTROL OF AIRWAY FUNCTION

Muscarinic M(1), M(2), and M(3) receptor subtypes have been shown to b e involved in the pre- and postjunctional control of airway diameter o f various species, including man. In a guinea pig model of allergic as thma, the prejunctional M(2) receptor was shown to become dysfunctiona l already during the early allergic reaction, thereby contributing to exaggerated vagal reflex activity and airway hyperreactivity. Moreover , a deficiency of endogenous nitric oxide was observed after allergen provocation, which may also contribute to an enhanced postjunctional M (3) receptor-mediated cholinergic response. Both in human and in anima l airway preparations it was shown that enhanced cholinergic contracti ons are relatively resistent to beta-adrenoceptor-mediated relaxation. The reduced beta-adrenoceptor function may primarily be due to transd uctional cross-talk between PI metabolism and adenylyl cyclase, includ ing protein kinase C-induced uncoupling of the beta-adrenoceptor from the effector system. Cross-talk between postjunctional M(2) receptor-m ediated inhibition and beta-adrenoceptor-induced activation of adenyly l cyclase appears to be of minor functional importance, but could be e nhanced in allergic asthma due to increased expression of the inhibito ry G protein as induced by cytokines.