Epinephrine evokes shortening of human airway smooth muscle cells following β 2 adrenergic receptor desensitization.

Epinephrine (EPI), an endogenous catecholamine involved in the body's fight-or-flight responses to stress, activates α 1 -adrenergic receptors (α 1 ARs) 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 α 1 ARs remains controversial. Classically, evidence suggests that EPI promotes bronchodilation by stimulating β 2 -adrenergic receptors (β 2 ARs). Conventionally, the selective β 2 AR agonism of EPI was thought to be, in part, due to a predominance of β 2 ARs and/or a sparse, or lack of α 1 AR activity in human airway smooth muscle (HASM) cells. Surprisingly, we find that HASM cells express a high abundance of ADRA1B (the α 1 AR subtype B) and identify a spontaneous "switch-like" activation of α 1 ARs 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 β 2 ARs and/or under experimental conditions that induce β 2 AR tachyphylaxis. EPI-induced procontractile effects were abrogated by an α 1 AR 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 α 1 AR inhibition for the management of stress/exercise-induced asthma and/or β 2 -agonist insensitivity in patients with difficult-to-control, disease subtypes.