Epinephrine evokes shortening of human airway smooth muscle cells following b₂ adrenergic receptor desensitization

Epinephrine (EPI), an endogenous catecholamine involved in the body’s fight-or-flight responses to stress, activates a₁-adrenergic receptors (a₁ARs) 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 a₁ARs remains controversial. Classically, evidence suggests that EPI promotes bronchodilation by stimulating b₂-adrenergic receptors (b₂ARs). Conventionally, the selective b₂AR agonism of EPI was thought to be, in part, due to a predominance of b₂ARs and/or a sparse, or lack of a₁AR activity in human airway smooth muscle (HASM) cells. Surprisingly, we find that HASM cells express a high abundance of ADRA1B (the a₁AR subtype B) and identify a spontaneous “switch-like” activation of a₁ARs 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 b₂ARs and/or under experimental conditions that induce b₂AR tachyphylaxis. EPI-induced procontractile effects were abrogated by an a₁AR 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 a₁AR inhibition for the management of stress/exercise-induced asthma and/or b₂-agonist insensitivity in patients with difficult-to-control, disease subtypes.