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1 Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390; and 2 Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912
Nitric oxide
synthase (NOS) contributes to estradiol-17
(E2)-induced uterine vasodilation, but additional
mechanisms are involved, and the cellular pathways remain unclear. We
determined if 1) uterine artery myocytes express potassium
channels, 2) E2 activates these channels, and
3) channel blockade plus NOS inhibition alters
E2-induced uterine vasodilation. Studies of
cell-attached patches identified a 107 ± 7 pS calcium-dependent
potassium channel (BKCa) in uterine artery myocytes that
rapidly increased single-channel open probability 70-fold
(P < 0.05) after exposure to 100 nM E2 through an apparent cGMP-dependent mechanism. In ovariectomized nonpregnant ewes (n = 11) with uterine artery flow
probes and catheters, local BKCa blockade with
tetraethylammonium (TEA; 0.05-0.6 mM) dose dependently inhibited
E2-induced uterine vasodilation (n = 37, R = 0.77, P < 0.0001), with maximum
inhibition averaging 67 ± 11%. Mean arterial pressure (MAP) and
E2-induced increases (P 
0.001) in heart
rate (13%) and contralateral uterine blood flow (UBF, ~5-fold) were
unaffected. Local NOS inhibition plus BKCa blockade, using
submaximal doses of nitro-L-arginine methyl ester (5 mg/ml)
and TEA (0.3 mM), did not alter basal UBF but completely inhibited
ipsilateral E2-induced uterine vasodilation without
affecting MAP and E2-induced increases in contralateral UBF and heart rate. Acute E2-mediated uterine
vasodilation involves rapid activation of uterine artery
BKCa and NOS, and the pathway for their interaction appears
to include activation of guanylyl cyclase.
uterine blood flow; estradiol-17; nonpregnant sheep
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