Rapid effects of estrogen on intracellular Ca2+ regulation in human airway smooth muscle

The severity of asthma, a disease characterized by airway hyperresponsiveness and inflammation, is enhanced in some women during the menstrual cycle and during pregnancy but relieved in others. These clinical findings suggest that sex steroids modulate airway tone. Based on well-known relaxant effects of estrogens on vascular smooth muscle, we hypothesized that estrogens relax airway smooth muscle (ASM), thus facilitating bronchodilation. In ASM tissues from female patients, Western and immunocytochemical analyses confirmed the presence of both estrogen receptor (ER) isoforms, ERalpha and ERbeta. In fura 2-loaded, dissociated ASM cells maintained in culture, acute exposure to physiological concentrations of 17beta-estradiol (E(2); 100 pM to 10 nM) decreased the intracellular Ca(2+) ([Ca(2+)](i)) response to 1 muM histamine, an effect reversed by the ER antagonist ICI-182,780. The ERalpha-selective agonist (R,R)-THC had a greater reducing effect on [Ca(2+)](i) responses to histamine and 1 muM ACh compared with the ERbeta-selective agonist (DPN). The effects of E(2) on [Ca(2+)](i) were mediated, at least in part, via decreased Ca(2+) influx through l-type channels and store-operated Ca(2+) entry but not via Ca(2+)-activated K(+) channels, receptor-operated entry, or sarcoplasmic reticulum reuptake. Overall, these data support our hypothesis that estrogens relax ASM and suggest a potentially novel therapeutic target in airway hyperresponsiveness.