Estradiol-17 ␤ (E 2 ␤ ), a potent vasodilator, has its greatest effects on the uterine vasculature, blood flow (UBF) increasing Ն 10-fold. The mechanism(s) responsible for E 2 ␤ -induced vasodilation is unclear. We determined if nitric oxide (NO)-induced increases in cGMP modulate estrogen-induced increases in UBF, and if cyclooxygenase inhibition modifies E 2 ␤ responses. Nonpregnant ( n ϭ 15) and pregnant ( n ϭ 8) ewes had flow probes implanted on main uterine arteries and catheters in branches of the uterine vein and artery bilaterally for blood sampling and infusion of the NO synthase inhibitor L -nitro-arginine methyl ester ( L -NAME), respectively. In nonpregnant ewes E 2 ␤ (1 g/kg) caused parallel increases ( P Ͻ 0.001) in UBF (15 Ϯ 3 to 130 Ϯ 16 ml/ min) and uterine cGMP secretion (23 Ϯ 10 to 291 Ϯ 38 pmol/ min); uterine venous cGMP also rose (4.98 Ϯ 1.4 to 9.43 Ϯ 3.2 pmol/ml; P Ͻ 0.001). Intra-arterial L -NAME partially inhibited increases in UBF dose-dependently (r ϭ 0.66, n ϭ 18, P Յ 0.003) while completely inhibiting cGMP secretion ( P ϭ 0.025). Indomethacin, 2 mg/kg intravenously, did not alter E 2 ␤ -induced responses. After E 2 ␤ -induced increases in UBF, intraarterial L -NAME partially decreased UBF dose dependently (r ϭ 0.73, n ϭ 46, P Ͻ 0.001) while inhibiting cGMP secretion (178 Ϯ 48 to 50 Ϯ 24 pmol/min; n ϭ 5, P ϭ 0.006); both were reversed by L -arginine. In pregnant ewes, E 2 ␤ increased UBF and venous cGMP (9.1 Ϯ 0.96 to 13.2 Ϯ 0.96 pmol/ml, P Ͻ 0.01); however, intraarterial L -NAME decreased basal cGMP secretion 66% (P ϭ 0.02), but not UBF. Acute estrogen-induced increases in UBF are associated with NO-dependent increases in cGMP synthesis, but other mechanisms may also be involved. However, vasodilating prostanoids do not appear to be important. In ovine pregnancy NO is not essential for maintaining uteroplacental vasodilation. ( J. Clin. Invest. 1996. 98:2158-2166.)

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

An experimental and computational approach to categorizing UVCBs according to chemical and biological similarities.

Uterine blood flow (UBF) increases >30-fold during ovine pregnancy. During the last trimester, this reflects vasodilation, which may be due to placentally derived estrogens. In nonpregnant ewes, estradiol-17 beta (E(2)beta) increases UBF >10-fold by activating nitric oxide synthase and large conductance calcium-dependent potassium channels (BK(Ca)). To determine whether BK(Ca) channels modulate basal and E(2)beta-induced increases in UBF, studies were performed in near-term pregnant ewes with uterine artery flow probes and catheters for intra-arterial infusions of tetraethylammonium (TEA), a selective BK(Ca) channel antagonist at <1 mM, in the absence or presence of E(2)beta (1 microg/kg iv). Uterine arteries were collected to measure BK(Ca) channel mRNA. TEA (0.15 mM) decreased basal UBF (P < 0.0001) 40 +/- 8% and 55 +/- 7% (n = 11) at 60 and 90 min, respectively, and increased resistance 175 +/- 48% without affecting (P > 0.1) mean arterial pressure (MAP), heart rate, or contralateral UBF. Systemic E(2)beta increased UBF 30 +/- 6% and heart rate 13 +/- 1% (P < or = 0.0001, n = 13) without altering MAP. Local TEA (0.15 mM) inhibited E(2)beta-induced increases in UBF without affecting increases in heart rate (10 +/- 4%; P = 0.006). BK(Ca) channel mRNA was present in uterine artery myocytes from pregnant and nonpregnant ewes. Exponential increases in ovine UBF in late pregnancy may reflect BK(Ca) channel activation, which may be mediated by placentally derived estrogens.