Calcium-activated potassium channels and nitric oxide coregulate estrogen-induced vasodilation.
Nitric oxide synthase (NOS) contributes to estradiol-17beta (E(2)beta)-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) E(2)beta activates these channels, and 3) channel blockade plus NOS inhibition alters E(2)beta-induced uterine vasodilation. Studies of cell-attached patches identified a 107 +/- 7 pS calcium-dependent potassium channel (BK(Ca)) in uterine artery myocytes that rapidly increased single-channel open probability 70-fold (P < 0.05) after exposure to 100 nM E(2)beta through an apparent cGMP-dependent mechanism. In ovariectomized nonpregnant ewes (n = 11) with uterine artery flow probes and catheters, local BK(Ca) blockade with tetraethylammonium (TEA; 0.05-0.6 mM) dose dependently inhibited E(2)beta-induced uterine vasodilation (n = 37, R = 0.77, P < 0.0001), with maximum inhibition averaging 67 +/- 11%. Mean arterial pressure (MAP) and E(2)beta-induced increases (P </= 0.001) in heart rate (13%) and contralateral uterine blood flow (UBF, approximately 5-fold) were unaffected. Local NOS inhibition plus BK(Ca) 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 E(2)beta-induced uterine vasodilation without affecting MAP and E(2)beta-induced increases in contralateral UBF and heart rate. Acute E(2)beta-mediated uterine vasodilation involves rapid activation of uterine artery BK(Ca) and NOS, and the pathway for their interaction appears to include activation of guanylyl cyclase.
Rosenfeld
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Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA. crosen@mednet.swmed.edu
White
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Roy
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Cox
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D000704:Analysis of Variance; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D010052:Ovariectomy; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated; D012756:Sheep; D019789:Tetraethylammonium / Q000494:pharmacology; D014599:Uterus / Q000098:blood supply*
D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D009569:Nitric Oxide; D004958:Estradiol; D019789:Tetraethylammonium; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester