β-Adrenergic Receptor Antagonism of Cholinergic Stimulation of Airway Smooth Muscle Contraction: An Old Receptor Requires a Fresh Look.

The control of air flow resistance in the airways during breathing cycles is governed by a fine balance between the parasympathetic and sympathetic branches of the autonomic nervous system targeting airway smooth muscle cells.1,2 During eupnea, airway smooth muscle exhibits basal tone that is controlled by postganglionic input from parasympathetic cholinergic and noncholinergic nerves and sympathetic adrenergic nerves. This basal airway smooth muscle tone is primarily driven by parasympathetic cholinergic nerves, and is opposed in most species by sympathetic nerve fibers that promote relaxation through β-adrenergic receptor signaling. There is also evidence for the involvement of parasympathetic noncholinergic postganglionic nerves, which mediate a relaxation on a slower time course than the cholinergic contraction and appear to be primarily involved in reflexively countering bronchospastic activity of the airways triggered by an insult such as coughing or exposure to a noxious substance. Autonomic regulation of basal tone during eupnea is profoundly regulated by bronchopulmonary as well as extrapulmonary afferent nerve fibers that reflexively enhance or attenuate airway smooth muscle tone by opposing or relieving postganglionic cholinergic contraction. Although the distribution and function of parasympathetic cholinergic nerve fibers responsible for maintaining airway smooth muscle tone is widespread across species, sympathetic and noncholinergic innervation of the airways is not a common denominator and varies widely in different species. For example, sympathetic adrenergic innervation is poorly developed in human airways, but is prominent in dogs where it promotes relaxation. Mice and rats are devoid of any kind of relaxant innervation. Nevertheless, both αand β-adrenergic receptors are expressed in human airways and can modulate smooth muscle tone when stimulated by circulating or locally released autacoids. Dysfunction of the autonomic nervous system is a major contributor to the enhanced bronchospastic activity of the airways in chronic obstructive pulmonary disease (COPD) and asthma, and blocking cholinergic muscarinic receptors and/or stimulating β-adrenergic receptors have proven efficacious in alleviating bronchospastic activity.3,4 Airway smooth muscle cells express both the M2 and M3 subclasses of muscarinic receptors targeted by the neurotransmitter acetylcholine (ACh).5 The dogmatic view has been that the bronchoconstriction mediated by parasympathetic cholinergic stimulation mainly involves activation of the M3 receptor subtype, while the M2 receptor antagonizes the relaxation caused by β-adrenergic receptors but produces little direct contractile effect on airway smooth muscle. In contrast to the dogma, a study by Struckmann et al.6 using M2, M3, or double M2/M3 receptor knockout (KO) mice showed that both receptor subtypes were required to produce the maximal bronchoconstriction elicited by ACh, albeit the M3 receptor produced greater responses. Another concept that recently emerged is the possibility that the M2 receptor may sensitize the M3 receptor yielding greater contractile responses to electric field stimulation (EFS) at low frequencies of stimulation, or to subthreshold concentrations of the muscarinic receptor agonist carbachol.5 In a recent issue published in this journal, Alkawadri et al.7 revisited this question in mouse airways by using a combination of pharmacological agents targeting various muscarinic and β-adrenergic