Abstract
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 C 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, E2 can prevent cholinergic-induced constriction of asthmatic tracheal rings by activating the nitric oxide-cGMP-protein kinase G pathway to increase BKCa channel activity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 239-247 |
| Number of pages | 9 |
| Journal | American Journal of Respiratory Cell and Molecular Biology |
| Volume | 32 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2005 |
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Keywords
- Airway smooth muscle
- Asthma
- Estrogen
- Large conductance voltage and calcium-dependent potassium channels
- Nitric oxide
ASJC Scopus subject areas
- Molecular Biology
- Pulmonary and Respiratory Medicine
- Clinical Biochemistry
- Cell Biology
Cite this
Estrogen reduces carbachol-induced constriction of asthmatic airways by stimulating large-conductance voltage and calcium-dependent potassium channels. / Dimitropoulou, Christiana; White, E.; Ownby, Dennis Randall; Catravas, John D.
In: American Journal of Respiratory Cell and Molecular Biology, Vol. 32, No. 3, 01.03.2005, p. 239-247.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Estrogen reduces carbachol-induced constriction of asthmatic airways by stimulating large-conductance voltage and calcium-dependent potassium channels
AU - Dimitropoulou, Christiana
AU - White, E.
AU - Ownby, Dennis Randall
AU - Catravas, John D.
PY - 2005/3/1
Y1 - 2005/3/1
N2 - 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 C 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, E2 can prevent cholinergic-induced constriction of asthmatic tracheal rings by activating the nitric oxide-cGMP-protein kinase G pathway to increase BKCa channel activity.
AB - 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 C 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, E2 can prevent cholinergic-induced constriction of asthmatic tracheal rings by activating the nitric oxide-cGMP-protein kinase G pathway to increase BKCa channel activity.
KW - Airway smooth muscle
KW - Asthma
KW - Estrogen
KW - Large conductance voltage and calcium-dependent potassium channels
KW - Nitric oxide
UR - http://www.scopus.com/inward/record.url?scp=15044340297&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=15044340297&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2004-0331OC
DO - 10.1165/rcmb.2004-0331OC
M3 - Article
VL - 32
SP - 239
EP - 247
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 3
ER -