Glucocorticoid decreases airway tone via a nongenomic pathway

Nocturnal asthma is associated with circadian rhythms. Although glucocorticoids have contributed to therapeutic success, the underlying mechanism has not been studied thoroughly in asthma. Here, we report that cortisol, a member of glucocorticoids, ameliorate guinea pig tracheal spasm via a nongenomic effect. We set a concentration gradient of cortisol to mimic the functional circadian fluctuation. When administrated over a threshold (150 ng/ml), cortisol could synergize with the spasmolytic action of β-agonist (isoprenaline) in histamine-sensitized tracheal spirals in vitro. This permissive action was abolished by the glucocorticoid receptor antagonist, RU486, indicating that cortisol acts via its receptor. Using the RNA polymerase inhibitor, actinomycin D, we showed that this permissive action was not affected by transcription. PMA, activator of protein kinase C (PKC), could partially imitate this rapid effect, while PKC inhibition also blocked this action to some extent. It is likely that this nongenomic effect of glucocorticoid underlies the onset and susceptibility of asthma, implying novel medication target in clinical practice.