MUSCARINIC RECEPTORS AND CONTROL OF AIRWAY SMOOTH-MUSCLE

Contraction of airway smooth muscle is mediated by M-3 muscarinic rece ptors on the airway smooth muscle. However, there is no evidence sugge sting that hyperresponsiveness results from any alterations in functio n of these M-3 muscarinic receptors. In contrast, there is clearly inc reased release of the neurotransmitter acetylcholine in animal models of hyperactivity and in asthma. Release of acetylcholine is controlled by inhibitory M-2 muscarinic receptors, and it appears that it is the se M-2 receptors that are dysfunctional in animal models of hyperrespo nsiveness. Allergen-induced M-2 receptor dysfunction is absolutely dep endent upon an influx of eosinophils into the airways. Activated eosin ophils release major basic protein, which binds to M-2 receptors and p revents binding of acetylcholine. Thus, the normal negative feedback c ontrol of acetylcholine release is lost, and acetylcholine release is increased. In conclusion, loss of function of inhibitory M-2 muscarini c receptors on the airway parasympathetic nerves causes vagally mediat ed bronchoconstriction and hyperresponsiveness following antigen chall enge.