title: Uterine blood flow responses to ICI 182 780 in ovariectomized oestradiol-17beta-treated, intact follicular and pregnant sheep.
abstract: Oestrogen dramatically increases uterine blood flow (UBF) in ovariectomized (Ovx) ewes. Both the follicular phase and pregnancy are normal physiological states with elevated levels of circulating oestrogen. ICI 182 780 is a pure steroidal oestrogen receptor (ER) antagonist that blocks oestrogenic actions in oestrogen-responsive tissue. We hypothesized that an ER-mediated mechanism is responsible for in vivo rises in UBF in physiological states of high oestrogen. The purpose of the study was to examine the effect of an ER antagonist on exogenous and endogenous oestradiol-17beta (E2beta)-mediated elevations in UBF. Sheep were surgically instrumented with bilateral uterine artery blood flow transducers, and uterine and femoral artery catheters. Ovx animals (n = 8) were infused with vehicle (35% ethanol) or ICI 182 780 (0.1-3.0 microg min(-1)) into one uterine artery for 10 min before and 50 min after E2beta was given (1 microg kg(-1) I.V. bolus) and UBF was recorded for an additional hour. Intact, cycling sheep were synchronized to the follicular phase using progesterone, prostaglandin F2alpha(PGF2alpha) and pregnant mare serum gonadotrophin (PMSG). When peri-ovulatory rises in UBF reached near peak levels, ICI 182 780 (1 or 2 microg (ml uterine blood flow)-1) was infused unilaterally (n = 4 sheep). Ewes in the last stages of pregnancy (late pregnant ewes) were also given ICI 182 780 (0.23-2.0 microg (ml uterine blood flow)-1; 60 min infusion) into one uterine artery (n = 8 sheep). In Ovx sheep, local infusion of ICI 182 780 did not alter systemic cardiovascular parameters, such as mean arterial blood pressure or heart rate; however, it maximally decreased ipsilateral, but not contralateral, UBF vasodilatory responses to exogenous E2beta by approximately 55-60% (P < 0.01). In two models of elevated endogenous E2beta, local ICI 182 780 infusion inhibited the elevated UBF seen in follicular phase and late pregnant ewes in a time-dependent manner by approximately 60% and 37%, respectively; ipsilateral >> contralateral effects (P < 0.01). In late pregnant sheep ICI 182 780 also mildly and acutely (for 5-30 min) elevated mean arterial pressure and heart rate (P < 0.05). We conclude that exogenous E2beta-induced increases in UBF in the Ovx animal and endogenous E2beta-mediated elevations of UBF during the follicular phase and late pregnancy are partially mediated by ER-dependent mechanisms.
authors.affiliation: Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin-Madison, Atrium B Meriter Hospital, Madison, WI 53715, USA. rmagness@facstaff.wisc.edu
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Magness
authors.forename: Terrance M
authors.initials: TM
authors.lastname: Phernetton
authors.forename: Tiffini C
authors.initials: TC
authors.lastname: Gibson
authors.forename: Dong-Bao
authors.initials: DB
authors.lastname: Chen
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D005498:Follicular Phase / Q000187:drug effects / Q000502:physiology*; D000077267:Fulvestrant; D010052:Ovariectomy; D021041:Placental Circulation / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects / Q000502:physiology*; D012756:Sheep; D014599:Uterus / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D020847:Estrogen Receptor Modulators; D047629:Estrogen Receptor beta; D000077267:Fulvestrant; D004958:Estradiol