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Published ahead of print on December 30, 2004, doi:10.1165/rcmb.2004-0331OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 3, March 2005, 239-247

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Submitted on October 25, 2004
Revised on December 30, 2004

Estrogen reduces carbachol-induced constriction of asthmatic airways by stimulating BKCa channels

Christiana Dimitropoulou1*, Richard E White1, Dennis R Ownby2, and John D Catravas3

1 Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia, USA, 2 Department of Pediatrics, Medical College of Georgia, Augusta, Georgia, USA, 3 Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia, USA; Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, USA

* To whom correspondence should be addressed. E-mail: cdimitro{at}mail.mcg.edu.

Both the incidence and severity of asthma in women are influenced by fluctuations in estrogen levels, raising the possibility that estrogens may reduce the hyper-responsiveness that is characteristic of asthma. We examined the effect of estrogen and its downstream signaling pathways in isolated mouse bronchial and tracheal rings passively sensitized either with serum from atopic asthmatic patients (ATR) or with serum from control subjects (CTR). ATR exhibited significantly higher sensitivity to carbachol than CTR. Pretreatment of ATR with estrogen (E2) shifted the carbachol concentration-response curve (CCRC) towards that of CTR. The E2 effect was abolished by the NOS inhibitor, L-NAME, the soluble guanyl cyclase inhibitor, ODQ, or the PKG inhibitor, KT5823. Inhibition of the large-conductance, calcium-activated potassium (BKCa) channel activity with iberiotoxin also attenuated the E2 effect on ATR. In patch-clamp studies, E2 increased by 50-fold the BKCa channel activity in freshly isolated airway smooth muscle cells. This increase was completely blocked by KT5823. These studies suggest that, at physiologic concentrations, estrogen can prevent cholinergic-induced constriction of asthmatic tracheal rings by activating the NO-cGMP-PKG pathway to increase BKCa channel activity.




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