A Neuroactive Steroid Inhibits Guinea Pig Airway Sensory Nerves via Maxi-K+ Channel Activation

Abstract

Background: Although neurogenic inflammation via the activation of C-fibers in the airway may have an important role in the pathogenesis of asthma, their regulatory mechanism remains uncertain. Objective: The pharmacological profiles of a neuroactive steroid, allotetrahydrocorticosterone, on the activation of C-fibers in airway tissues were investigated, and the mechanism how a neuroactive steroid regulates airway inflammatory reactions was clarified. Methods: The effects of allotetrahydrocorticosterone on electrical field stimulation-induced bronchial smooth muscle contraction in guinea pig airway tissues were investigated. The influences of K⁺ channel blockers and intracellular protein inhibitors on the effects of allotetrahydrocorticosterone were examined. Results: Allotetrahydrocorticosterone dose-dependently inhibited electrical field stimulation-induced guinea pig bronchial smooth muscle contraction. The inhibitory effects of allotetrahydrocorticosterone on electrical field stimulation-induced bronchial contraction were reduced by the pretreatment of Maxi-K⁺ channel blockers, iberiotoxin and charybdotoxin, but not other K⁺ channel blockers, dendrotoxin or glibenclamide. Pretreatment with pertussis toxin diminished the inhibitory effect of allotetrahydrocorticosterone, but not an adenylate cyclase inhibitor, SQ 22536, nor a specific inhibitor of mitogen-activated protein kinase kinase, PD 98059. Conclusions: These findings suggest that allotetrahydrocorticosterone negatively modulates the activation of C-fibers in guinea pig airway tissues via the opening of Maxi-K⁺ channels and a pertussis toxin-sensitive G-protein-coupled mechanism.