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Estrogen Reduces Carbachol-Induced Constriction of Asthmatic Airways by Stimulating Large-Conductance Voltage and Calcium-Dependent Potassium Channels

Department of Pharmacology and Toxicology, Department of Pediatrics, and Vascular Biology Center, Medical College of Georgia, Augusta, Georgia

Correspondence and requests for reprints should be addressed to Christiana Dimitropoulou, Ph.D., Department of Pharmacology and Toxicology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912-2300. E-mail: cdimitro{at}mail.mcg.edu

Both the incidence and severity of asthma in women are influenced by fluctuations in estrogen (E₂) levels, raising the possibility that E₂s may reduce the hyperresponsiveness that is characteristic of asthma. We examined the effect of E₂ and its downstream signaling pathways in isolated mouse bronchial and tracheal rings passively sensitized either with serum from patients with atopic asthma (ATR) or with serum from control subjects (CTR). ATR exhibited significantly higher sensitivity to carbachol than CTR. Pretreatment of ATR with E₂ shifted the carbachol concentration–response curve (CCRC) toward that of CTR. The E₂ effect was abolished by the nitric oxide synthase inhibitor, L-nitroarginine methyl ester, the soluble guanyl cyclase inhibitor, quinoxalin-1, or the protein kinase G inhibitor, KT5823. Inhibition of the large-conductance, calcium-activated potassium (BK_Ca) channel activity with iberiotoxin also attenuated the E₂ effect on ATR. In patch-clamp studies, E₂ increased by 50-fold the BK_Ca channel activity in freshly isolated airway smooth muscle cells. This increase was completely blocked by KT5823. These studies suggest that, at physiologic concentrations, E₂ can prevent cholinergic-induced constriction of asthmatic tracheal rings by activating the nitric oxide–cGMP–protein kinase G pathway to increase BK_Ca channel activity.

Key Words: airway smooth muscle • asthma • estrogen • large conductance voltage and calcium-dependent potassium channels • nitric oxide

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