Estrogen reduces carbachol-induced constriction of asthmatic airways by stimulating large-conductance voltage and calcium-dependent potassium channels.
Both the incidence and severity of asthma in women are influenced by fluctuations in estrogen (E(2)) levels, raising the possibility that E(2)s may reduce the hyperresponsiveness that is characteristic of asthma. We examined the effect of E(2) 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 E(2) shifted the carbachol concentration-response curve (CCRC) toward that of CTR. The E(2) 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 E(2) effect on ATR. In patch-clamp studies, E(2) 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, E(2) 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.
Dimitropoulou
Christiana
C
Department of Pharmacology and Toxicology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912-2300, USA. cdimitro@mail.mcg.edu
White
Richard E
RE
Ownby
Dennis R
DR
Catravas
John D
JD
D000402:Airway Obstruction / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D002217:Carbachol / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D051036:Large-Conductance Calcium-Activated Potassium Channels; D051379:Mice; D008810:Mice, Inbred C57BL; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects
D004967:Estrogens; D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D002217:Carbachol