Epinephrine evokes shortening of human airway smooth muscle cells following β adrenergic receptor desensitization.

Epinephrine (EPI), an endogenous catecholamine involved in the body's fight-or-flight responses to stress, activates α-adrenergic receptors (αARs) expressed on various organs to evoke a wide range of physiological functions, including vasoconstriction. In the smooth muscle of human bronchi, however, the functional role of EPI on αARs remains controversial. Classically, evidence suggests that EPI promotes bronchodilation by stimulating β-adrenergic receptors (βARs). Conventionally, the selective βAR agonism of EPI was thought to be, in part, due to a predominance of βARs and/or a sparse, or lack of αAR activity in human airway smooth muscle (HASM) cells. Surprisingly, we find that HASM cells express a high abundance of (the αAR subtype B) and identify a spontaneous "switch-like" activation of αARs that evokes intracellular calcium, myosin light chain phosphorylation, and HASM cell shortening. The switch-like responses, and related EPI-induced biochemical and mechanical signals, emerged upon pharmacological inhibition of βARs and/or under experimental conditions that induce βAR tachyphylaxis. EPI-induced procontractile effects were abrogated by an αAR antagonist, doxazosin mesylate (DM). These data collectively uncover a previously unrecognized feed-forward mechanism driving bronchospasm via two distinct classes of G protein-coupled receptors (GPCRs) and provide a basis for reexamining αAR inhibition for the management of stress/exercise-induced asthma and/or β-agonist insensitivity in patients with difficult-to-control, disease subtypes.