Decrease In Uterine Blood Flow Research Articles

283 Awardee Talk: Effects of Late Gestational Maternal Nutrient Balance on Nutrient Partitioning to the Gravid Uterus in Beef Cattle

Abstract Successful intrauterine growth relies on adequate placental nutrient transfer capacity and is determined by placental size, placental morphology, uteroplacental blood supply, nutrient transporter abundance, and the nutrients available in maternal circulation. The majority of bovine fetal growth occurs during late gestation and must be accompanied by similar exponential increases in uteroplacental development to allow for necessary nutrient delivery. Competition for nutrients in young females between maternal growth and satisfying pregnancy, lactation, and maintenance requirements is still poorly understood. Our current work investigated the relationships between maternal, fetal, and uteroplacental factors and the impacts of late gestational nutrient restriction on prenatal nutrient delivery to the calf. Analysis of 113 full-term expelled placentas revealed that primiparous dams and dams in thin body condition had smaller placentas than their older or fleshier counterparts, suggesting the addition of growth requirements or exhausted nutrient reserves limited placental and fetal development. Calf size at birth and placental weight were positively correlated among all females, but it is still unknown which controls and signals for the growth of the other. Uterine blood flow measured during late gestation was positively correlated with calf birth weight; however, uterine blood flow and placental weight were only positively correlated closer to parturition at 40 and 20 d before calving. Additionally, contralateral uterine blood flow may have a disproportionately greater contribution to placental and fetal growth as it more closely resembled total blood flow associations than did ipsilateral. In 2 experiments, primiparous females fed 70% of energy and protein requirements during late gestation lost body weight and condition, had less metabolites in circulation, and had lower maternal heart rates than those fed to meet requirements. In Exp. 1, nutrient restricted dams had less contralateral placental growth, yet total uterine blood flow and placental weight were maintained and ensured fetal growth similar to control offspring. In Exp. 2, nutrient restriction reduced calf birth weight by 15%. Fetal growth perturbations were largely driven by a 17% reduction in placental size along with less nutrients available from maternal circulation, independent of a concomitant decrease in uterine blood flow. At 48 h of age, calf visceral organs were smaller due to nutrient restriction, but asymmetrical growth allowed for growth of the brain, lungs, and bone to be spared. Ongoing analysis of cotyledonary nutrient transporter and angiogenic factor gene expression will provide crucial insight into another determinant of placental nutrient transfer capacity. These findings demonstrate that pregnant beef females in a negative nutrient balance will attempt to spare fetal growth but at a certain threshold placental adaptation can be compromised, resulting in intrauterine growth restriction. A better understanding of nutrient delivery to the gravid uterus will allow for improved management strategies to ensure optimal fetal growth.

PENGARUH AROMATERAPI LAVENDER TERHADAPPENGURANGAN NYERI PERSALINAN KALA I AKTIF

Labor Pain is caused by uterine contractions through increased secretion of catecholamine and cortisol levels, leading to a decrease in uterine blood flow and decreased uterine activity that will result in prolonged labor. Lampung Province has one maternal mortality case caused by prolonged-labor. The incidence of prolonged labor at midwife private practice Opsi Okta HN in June was 20% (2 cases), July was 27% (3 cases), and in August was 20% (2 cases). Lavender aromatherapy is one of the non-pharmacological useful methods to reduce the pain, relax the mind, reduce tension and anxiety and give peace to the maternity mother. This study aims to determine the influence of lavender aromatherapy on the reduction of labor pain during the active phase I. This study was conducted with the experimental design of the final and post test group. The sample technique used purposive sampling on 15 people. The collection of pain data using the scale of assessment of pain and lavender aromatherapy with the observational method. The univariate analysis of data using mean and bivariate analysis with parametric statistical test dependent Paired t Test. The result of the average intensity of pain in maternal mothers before given lavender aromatherapy was 7.07 (Pain Weight) and after given lavender aromatherapy was 5.53 (moderate pain). The result of Paired t Test is obtained p value 0,000 (p <α 0,05).The Conclusion of the research is the influence of lavender aromatherapy on the reduction of labor pain during the active phase I. It is expected that midwives can apply lavender aromatherapy and non-pharmacological practical method as an alternative in reducing labor pain.

Stress-induced decrease of uterine blood flow in sheep is mediated by alpha 1-adrenergic receptors

Prenatal maternal stress can be transferred to the fetus via a catecholamine-dependent decrease of uterine blood flow (UBF). However, it is unclear which group of adrenergic receptors mediates this mechanism of maternal–fetal stress transfer. We hypothesized that in sheep, alpha 1-adrenergic receptors may play a key role in catecholamine mediated UBF decrease, as these receptors are mainly involved in peripheral vasoconstriction and are present in significant number in the uterine vasculature. After chronic instrumentation at 125 ± 1 days of gestation (dGA; term 150 dGA), nine pregnant sheep were exposed at 130 ± 1 dGA to acute isolation stress for one hour without visual, tactile, or auditory contact with their flockmates. UBF, blood pressure (BP), heart rate (HR), stress hormones, and blood gases were determined before and during this isolation challenge. Twenty-four hours later, experiments were repeated during alpha 1-adrenergic receptor blockage induced by a continuous intravenous infusion of urapidil. In both experiments, ewes reacted to isolation with an increase in serum norepinephrine, cortisol, BP, and HR as typical signs of activation of sympatho-adrenal and the hypothalamic-pituitary-adrenal axis. Stress-induced UBF decrease was prevented by alpha 1-adrenergic receptor blockage. We conclude that UBF decrease induced by maternal stress in sheep is mediated by alpha 1-adrenergic receptors. Future studies investigating prevention strategies of impact of prenatal maternal stress on fetal health should consider selective blockage of alpha 1-receptors to interrupt maternal–fetal stress transfer mediated by utero-placental malperfusion.

Effects of estradiol on uterine perfusion in anesthetized cyclic mares affected with uterine vascular elastosis

Uterine vascular elastosis in mares is characterized by degeneration of uterine vasculature through thickening of the elastin layers. Factors commonly associated with this degeneration include age, parity, and chronic uterine endometritis. Affected mares have also been shown to exhibit decreases in uterine blood flow and perfusion of the uterus. Due to the increased thickness of the elastin layers, we hypothesize that vasodilatation of the uterine vasculature is also impaired. To test the functionality of these vessels, we evaluated the vasodilatory effects of estradiol on the uterine vascular bed in mares with normal vasculature and mares with severe elastosis. Both groups were tested in estrus and diestrus. Fluorescent microspheres were used to determine basal blood perfusion, followed by the intravenous administration of 1.0μg/kg of 17β-estradiol. After 90min, perfusion was measured once again to determine the vascular response to estradiol. Control mares in estrus displayed a significant increase in total uterine blood flow after the administration of estradiol when compared to baseline levels. No other group had a significant increase in total blood flow and perfusion after estradiol administration. The administration of estradiol in control mares induced regional increases in perfusion in the uterine horns and uterine body during estrus and only in the uterine horns during diestrus. Mares affected by elastosis exhibited no regional differences in perfusion levels post-estradiol administration. The difference in the vasodilatory response induced by estradiol between reproductively healthy mares and mares affected with elastosis indicates that the functionality of the affected vessels is compromised.

Role of catecholamines in maternal-fetal stress transfer in sheep

We sought to evaluate whether in addition to cortisol, catecholamines also transfer psychosocial stress indirectly to the fetus by decreasing uterine blood flow (UBF) and increasing fetal anaerobic metabolism and stress hormones. Seven pregnant sheep chronically instrumented with uterine ultrasound flow probes and catheters at 0.77 gestation underwent 2 hours of psychosocial stress by isolation. We used adrenergic blockade with labetalol to examine whether decreased UBF is catecholamine mediated and to determine to what extent stress transfer from mother to fetus is catecholamine dependent. Stress induced transient increases in maternal cortisol and norepinephrine (NE). Maximum fetal plasma cortisol concentrations were 8.1 ± 2.1% of those in the mother suggesting its maternal origin. In parallel to the maternal NE increase, UBF decreased by maximum 22% for 30 minutes (P < .05). Fetal NE remained elevated for >2 hours accompanied by a prolonged blood pressure increase (P < .05). Fetuses developed a delayed and prolonged shift toward anaerobic metabolism in the presence of an unaltered oxygen supply. Adrenergic blockade prevented the stress-induced UBF decrease and, consequently, the fetal NE and blood pressure increase and the shift toward anaerobic metabolism. We conclude that catecholamine-induced decrease of UBF is a mechanism of maternal-fetal stress transfer. It may explain the influence of maternal stress on fetal development and on programming of adverse health outcomes in later life especially during early pregnancy when fetal glucocorticoid receptor expression is limited.

Outcome and Hemodynamic Alternation in Uterine Artery Following Hysteroscopic Roller-Ball Endometrial Ablation

Objectives: To detect the outcome and changes in uterine arteries blood flow after hysteroscopic roller-ball endometrial ablation. Methods: 84 women with menorrhagia refused to continue or had failed medical treatment with uterine size <12 weeks were included in this study. Diagnostic hysteroscopy was done for women included in this study prior to endometrial ablation. A rigid operative hysteroscopy, with normal saline distention media and roller-ball electrode were used for endometrial ablation procedure. Preoperative findings of studied women including Doppler findings were compared to 3, 6 and 12 months post-operative findings to detect outcome and changes in uterine arteries blood flow after hysteroscopic roller-ball endometrial ablation. Results: 77/84 (91.7%) women were satisfied and their HMB was improved after rollerball endometrial ablation (33/84 (39.30%) amenorrhea, 27/84 (32.14%) hypo-menorrhea and 17/84 (20.24%) euomenorrhea = normal menstrual flow). ED (End Diastolic velocity), (9.2±7.4 cm/s before ablation) was significantly decreased 6 and 12 months after roller-ball endometrial ablation (5.0±6.0 and 4.6±6.1; respectively), also, TAMX (Time-averaged maximum velocity), (21.8±8.2 cm/s before ablation) was significantly decreased 6 and 12 months after roller-ball ablation (14.8±6.4 and 13.9±6.3; respectively). PI (Pulsatiliy Index), (1.32±0.5 cm/s before ablation) was significantly increased 6 and 12 months after roller-ball ablation (1.64±0.45 and 1.69±0.4; respectively), also, RI (Resistance Index), (0.80±0.2 cm/s before ablation) was significantly increased 3, 6 and 12 months after roller-ball ablation (0.84±0.4, 0.89±0.2 and 0.90±0.3; respectively). Conclusion: Hysteroscopic roller-ball endometrial ablation is a safe and effective therapeutic option for selected cases of menorrhagia. It increases stiffness and decreases mobility of uterine arteries during cardiac cycle, also, it induces rise in impedance with subsequent decrease in uterine blood flow and menstrual flow which completed 6-12 months following ablation procedure.

Elevated testosterone levels during rat pregnancy cause hypersensitivity to angiotensin II and attenuation of endothelium-dependent vasodilation in uterine arteries.

Elevated testosterone levels increase maternal blood pressure and decrease uterine blood flow in pregnancy, resulting in abnormal perinatal outcomes. We tested whether elevated testosterone alters uterine artery adaptations during pregnancy, and whether these alterations depend on endothelium-derived factors such as nitric oxide, endothelium-derived hyperpolarizing factor, and prostacyclin, or endothelium-independent mechanisms such as angiotensin II (Ang-II). Pregnant Sprague-Dawley rats were injected with vehicle (n=20) or testosterone propionate (0.5 mg/kg per day from gestation day 15 to 19; n=20). Plasma testosterone levels increased 2-fold in testosterone-injected rats compared with controls. Elevated testosterone significantly decreased placental and pup weights compared with controls. In endothelium-intact uterine arteries, contractile responses to thromboxane, phenylephrine, and Ang-II were greater in testosterone-treated rats compared with controls. In endothelium-denuded arteries, contractile responses to Ang-II (pD2=9.1±0.04 versus 8.7±0.04 in controls; P<0.05), but not thromboxane and phenylephrine, were greater in testosterone-treated rats. Ang-II type 1b receptor expression was increased, whereas Ang-II type 2 receptor was decreased in testosterone-exposed arteries. In endothelium-denuded arteries, relaxations to sodium nitroprusside were unaffected. Endothelium-dependent relaxation to acetylcholine was significantly lower in arteries from testosterone-treated dams (Emax=51.80±6.9% versus 91.98±1.4% in controls; P<0.05). The assessment of endothelial factors showed that nitric oxide-, endothelium-derived hyperpolarizing factor-, and prostacyclin-mediated relaxations were blunted in testosterone-treated dams. Endothelial nitric oxide synthase, small conductance calcium-activated potassium channel-3, and prostacyclin receptor expressions were significantly decreased in arteries from testosterone-treated dams. Hypoxia-inducible factor-1α, Ankrd37, and Egln were significantly increased in testosterone-exposed placentas. These results suggest that elevated maternal testosterone impairs uterine vascular function, which may lead to an increased vascular resistance and a decrease in uterine blood flow.

Reproductive outcomes associated with noise exposure - a systematic review of the literature.

Introduction: High noise exposure during critical periods in gestation is a potential stressor that may result in increased risk of implantation failure, dysregulation of placentation or decrease of uterine blood flow. This paper systematically reviews published evidence on associations between reproductive outcomes and occupational and environmental noise exposure. Methods: The Web of Science, PubMed and Embase electronic databases were searched for papers published between 1970 to June 2014 and via colleagues. We included 14 epidemiological studies related to occupational noise exposure and nine epidemiological studies related to environmental noise exposure. There was some evidence for associations between occupational noise exposure and low birthweight, preterm birth and small for gestational age, either independently or together with other occupational risk factors. Five of six epidemiologic studies, including the two largest studies, found significant associations between lower birthweight and higher noise exposure. There were few studies on other outcomes and study design issues may have led to bias in assessments in some studies. Conclusions: There is evidence for associations between noise exposure and adverse reproductive outcomes from animal studies. Few studies in have been conducted in humans but there is some suggestive evidence of adverse associations with environmental noise from both occupational and epidemiological studies, especially for low birthweight.

Effects of exogenous oxytocin on uterine blood flow in puerperal dairy cows: The impact of days after parturition and retained fetal membranes

The objective of this study was to examine whether an oxytocin challenge test (OCT), evaluated by measuring the changes in uterine blood flow using transrectal colour Doppler ultrasonography, is a suitable non-invasive method to determine uterine contractility in puerperal dairy cows. The changes in uterine blood flow during uterine contractions induced by oxytocin were evaluated on days 2 and 5 postpartum (pp). Twelve clinically healthy Holstein cows were randomly assigned into two groups: (1) oxytocin group (n=7), 50 IU oxytocin injected IM and (2) control group (n=5), 5 mL saline injected IM. Blood flow volume (BFV) and pulsatility index (PI) in the uterine arteries were determined before and after injection for 120 min on days 2 and 5 pp. BFV declined and PI increased rapidly after oxytocin injection on day 2 (P<0.05), whereas oxytocin on day 5 pp did not cause changes in blood flow parameters. The result confirmed that uterine responsiveness to oxytocin decreases with time postpartum in healthy cows. The same OCT was applied in cows with retained fetal membranes (n=6) on day 2 pp, however uterine blood flow showed no change after oxytocin injection. The results showed that an OCT on day 2 pp may be a useful method for investigating the uterine contractile response to oxytocin (reflected as the decrease of uterine blood flow) and the potential pathophysiology of uterine involution in cows.

Effect of human chorionic gonadotropin on uterine blood flow in intact and ovariectomized gilts.

This experiment was designed to test the hypothesis that human chorionic gonadotropin (hCG) can directly influence uterine blood flow in pigs. In the study, 18 crossbred gilts (95-100 kg) which had exhibited at least one estrous cycle were used: 8 cyclic gilts in the luteal phase of the estrous cycle and 10 gilts ovariectomized (OVX) three weeks before the experiment began. The OVX animals received i.m. injections of 1 mg estradiol benzoate and 50 mg progesterone daily for five consecutive days before transducer implantation. Precalibrated electromagnetic blood flow transducers were surgically implanted around the uterine artery under general anaesthesia. Beginning at 120 min (0 h) following the placement of probes, i.e. after recording had stabilized, blood flow values were recorded at 10 min intervals for the next 360 min. At 0 h, cyclic (n = 4) and OVX (n = 5) gilts received a bolus injection (5 ml) of 1000 IU hCG intravenously through an indwelling catheter and then the same dose of hCG continuously during 4 hours in 40 ml of saline. The remaining cyclic (n = 4) and OVX (n = 5) gilts were infused with saline only and served as control. The mean (SEM) uterine blood flow at 0 h in cyclic (n = 8) and OVX (n = 10) gilts was 104.0 +/- 25.7 and 58.6 +/- 6.0 ml/min, respectively. Because of the variability of initial blood flow, especially in the cyclic gilts, hCG induced changes were expressed as a percent change from the initial flow and were compared to pretreatment period 0 (-30 - 0 h). hCG produced a significant increase in the uterine blood flow in both treated groups (p < 0.05) reaching at 70 min 110.2 +/- 3.4 vs 80.0 +/- 10.5 and 122.4 +/- 12.1 vs 90.6 +/- 3.8, and then at 230 min 116.7 +/- 9.3 vs 62.0 +/- 10.0 and 121.8 +/- 13.2 vs 85.4 +/- 2.3 percent of initial blood flow in cyclic and OVX gilts, respectively. A comparison of nine 30-min periods (periods 1-9) to period 0 showed a significant decrease of uterine blood flow in both (cyclic and ovariectomized) saline control groups in periods 2-9 (50-360 min). The comparison of the same periods in cyclic and ovariectomized hCG treated gilts revealed a significant increase during periods 7-9 (250-360 min) and in period 6, 9 (210-240 and 330-360 min), respectively. Serum estradiol levels increased significantly from 7.4 +/- 1.5 to 351.9 +/- 50.2 pg/ml in cyclic, and from 43.3 0 +/- 7.0 to 224.8 +/- 24.1 in OVX hCG treated gilts at 180 and 120 min, respectively, and returned to the levels of the control groups 240-300 min after the beginning of hCG infusion. Those results indicate that the early response in uterine blood flow is produced directly by hCG, which overcomes the inhibitory pharmacological effect of pentobarbital on uterine blood flow. The second phase of response to hCG could be caused by estradiol which significantly increased an hour earlier before uterine blood flow elevation. We have also shown a novel source of estradiol in castrated pigs which is released by hCG.

Direct Effects of Nicotine on Contractility of the Uterine Artery in Pregnancy

Recent studies indicate that smoking/nicotine increases maternal blood pressure and decrease in uterine blood flow in pregnancy. However, the mechanisms are not fully understood. The present study was designed to test the hypothesis that nicotine exposure decreases endothelium-dependent relaxation and increases vascular contractility of the uterine artery in pregnancy. Uterine arteries were isolated from near-term ( approximately 140 days gestation) pregnant ewes. Arteries were subjected to acute (20 min) or chronic (48 h) nicotine treatment, and agonist-induced contractions and relaxations were measured in tissue bath. Endothelial eNOS was detected by immunohistochemistry in situ in arteries and by Western blotting in isolated endothelial cells. Chronic nicotine treatment produced a concentration-dependent increase in alpha(1)-adrenoceptor agonist phenylephrine-induced contractions. In contrast, the acute treatment showed no effect. Inhibition of eNOS with N(G)-nitro-L-arginine (L-NNA) significantly increased phenylephrine-induced contractions, which was abolished in uterine arteries after chronic nicotine treatment. In the presence of L-NNA, there was no significant difference in phenylephrine-induced contractions between control and nicotine-treated vessels. Chronic, but not acute, nicotine treatment significantly attenuated the calcium ionophore A23187-induced relaxations. Unlike A23187, the endothelium-independent relaxation mediated by sodium nitroprusside was not affected by nicotine. Endothelial eNOS protein levels and the phosphorylation levels of eNOS(Ser1179) were significantly decreased in nicotine-treated uterine arteries. The results suggest that nicotine impairs uterine vascular function in pregnancy, which may lead to an increased vascular resistance and a decrease in uterine blood flow.

Effect of nicotine on uterine artery contractility

The present study was designed to test the hypothesis that nicotine exposure increases vascular contractility and decreases endothelium-dependent relaxation of pregnant uterine arteries (UAs). UAs were isolated from near-term pregnant ewes. Arteries were subjected to nicotine treatment for a short-term of 20 min or a long-term of 48 h. Agonist-induced contractions and relaxations were measured in tissue baths. Endothelial cells were isolated from the UAs and eNOS was detected with Western blotting and immunohistochemistry. Nicotine produced a doses-dependent increase in phenylephrine (PE)-induced contractions after long-term, but not short-term, treatment. Pretreatment of vessels with L-NNA significantly increased PE-induced contractions, which were abolished after chronic nicotine treatment. Chronic but not acute nicotine treatment significantly attenuated A23187-induced relaxations of UAs. Unlike A23187, endothelium-independent relaxations mediated by SNP were not altered in either acute or chronic nicotine-treated UAs. eNOS immunoreactivity was only detected in the endothelium of UAs, and eNOS protein levels were significantly decreased in UAs after chronic nicotine treatment. The results indicate impaired uterine vascular function by nicotine, which may lead to an increase in vascular resistance and a decrease in uterine blood flow. (Supported in part by TRDRP Award # 14FT-0075)

Decreased Porcine Uterine Blood Flow During Laparoscopic Nissen Fundoplication

Background: Laparoscopy produces significant hemodynamic alterations that could affect blood flow through various systems, such as the cerebral, splanchnic, and renal circulations. While laparoscopic surgery is indicated for obstetrical and non-obstetrical conditions in pregnant patients, the effect of laparoscopy on uterine blood flow has hitherto been unclear. This experiment measures uterine blood flow in pigs undergoing laparoscopic Nissen fundoplication using radioactive microspheres. Methods: Six (6) pigs were subjected to a standard laparoscopic Nissen fundoplication. Microspheres (15 µm) labeled with five different radioisotopes were injected directly into the left ventricle at five different stages of the procedure. After the procedure, the pigs were euthanized and the uterus of the pig was harvested to measure blood flow. Results: There was a decrease in uterine blood flow at all stages of the procedure, with a statistically significant maximal drop in blood flow of –82%. These changes were associated with a simultaneous increase in paCO2 in all stages from baseline excepting the last time-point. Conclusions: Laparoscopy produces significant alterations in uterine blood flow. These changes can have profound effects on the fetus and maternal wellbeing by possibly worsening fetal acidosis. (J GYNECOL SURG 20:113)

Ovarian reserve after uterine artery embolization for leiomyomata

Ovarian reserve after uterine artery embolization for leiomyomata

Local cold stress to the soles induces retroplacental hemorrhage in rats.

The aim of this study was to investigate the effect of local cold stress to the soles on placental histology in rats. Pregnant rats were subjected to a cold provocation (0 degrees C, 12 degrees C) and room temperature (23 degrees C) for 15 and 30 minutes. During cold stimulation and at the control temperature, uterine blood flow and uterine contraction were measured simultaneously. Histological studies of the placentas of these rats were also performed. Cold stress at 0 degrees C and 12 degrees C significantly decreased uterine blood flow (P < .005, P < .02) compared with controls (23 degrees C). The decrease in uterine blood flow was greater at 0 degrees C than at 12 degrees C stress. Cold-induced stress (0 degrees C) also evoked an isometric tension with increased frequency and amplitude in the rat uterus (P < .003, P < .0002) compared with controls (23 degrees C). Stimulation at 12 degrees C did not induce any uterine contractions. Placental histology of rats stressed at 0 degreesC revealed hemorrhages into the decidua basalis. These findings suggest that local cold stress decreases uterine blood flow and increases uterine contraction, resulting in retroplacental hemorrhage in rats. This model may account for human abruptio placentae.

Coronary and uterine vascular responses to raloxifene in the sheep

Objective:We sought to determine whether raloAfene increases coronary and uterine blood flow in ovariectomized ewes. Study Design:Twelve ewes were chronically instrumented for measurement of mean arterial pressure, heart rate, cardiac output, coronary blood flow, and uterine blood flow. Sheep received 17ß-estradiol, Estrace, raloxifene, or KY Jelly vehicle on separate days. Results:17ß-Estradiol increased uterine blood flow from 21 ± 3 to 254 ± 36 mpl/min and coronary blood flow by 21% ± 2% within 2 hours. Estrace increased uterine blood flow from 30 ± 7 to 260 ± 62 ml/min and coronary blood flow by 8% ± 4% within 3 hours. Raloxifene increased uterine blood flow from 20 ± 3 ml/min to 220 ± 53 mUmin by 6 hours and coronary blood flow by 22% ± 5% within 24 hours. To determine whether hemodynamic responses were mediated by nitric oxide, l-nitroarginine methyl ester was administered and produced an approximate 50% decrease in uterine blood flow for all 3 compounds. l-Nitroarginine methyl ester attenuated increases in coronary blood flow induced by I7ß-estradiol, Estrace, and raloxifene. Conclusions:Raloxifene has significant coronary and uterine vascular effects in the ovariectomized ewe. The coronary and uterine responses are partially mediated by nitric oxide.

Angiotensin II indirectly vasoconstricts the ovine uterine circulation.

The uterine vasculature of women and sheep predominantly expresses type 2 ANG II receptors that do not mediate vasoconstriction. Although systemic ANG II infusions increase uterine vascular resistance (UVR), this could reflect indirect mechanisms. Thus we compared systemic and local intra-arterial ANG II infusions in six near-term pregnant and five ovariectomized nonpregnant ewes to determine how ANG II increases UVR. Systemic ANG II dose-dependently (P > 0.001) increased arterial pressure (MAP) and UVR and decreased uterine blood flow (UBF) in pregnant and nonpregnant ewes; however, nonpregnant responses exceeded pregnant (P < 0.001). In contrast, local ANG II infusions at rates designed to achieve concentrations in the uterine circulation comparable to those seen during systemic infusions did not significantly decrease UBF in either group, and changes in MAP and UVR were absent or markedly attenuated. When MAP rose during local ANG II, which only occurred with doses > or =2 ng/ml, increases in MAP were delayed more than twofold compared with responses during systemic ANG II infusions and always preceded decreases in UBF, resembling that observed during systemic ANG II infusions. These observations demonstrate attenuated uterine vascular responses to systemic ANG II during pregnancy and suggest that systemic ANG II may increase UVR through release of another potent vasoconstrictor(s) into the systemic circulation.

Functional role of angiotensin II type 1 and 2 receptors in regulation of uterine blood flow in nonpregnant sheep.

The objective was to determine the receptor subtype of angiotensin II (ANG II) that is responsible for vasoconstriction in the nonpregnant ovine uterine and systemic vasculatures. Seven nonpregnant estrogenized ewes with indwelling uterine artery catheters and flow probes received bolus injections (0.1, 0.3 and 1 microg) of ANG II locally into the uterine artery followed by a systemic infusion of ANG II at 100 ng x kg(-1) x min(-1) for 10 min to determine uterine vasoconstrictor responses. Uterine ANG II dose-response curves were repeated following administration of the ANG II type 2 receptor (AT(2)) antagonist PD-123319 and then repeated again in the presence of an ANG II type 1 receptor (AT(1)) antagonist L-158809. In a second experiment, designed to investigate the mechanism of ANG II potentiation that occurred in the presence of AT(2) blockade, nonestrogenized sheep received a uterine artery infusion of L-158809 (3 mg/min for 5 min) prior to the infusion of 0.03 microg/min of ANG II for 10 min. ANG II produced dose-dependent decreases in uterine blood flow (P < 0.03), which were potentiated in the presence of the AT(2) antagonist (P < 0.02). Addition of the AT(1) antagonist abolished the uterine vascular responses and blocked ANG II-induced increases in systemic arterial pressure (P < 0.01). Significant uterine vasodilation (P < 0.01) was noted with AT(1) blockade in the second experiment, which was reversed by administration of the AT(2) antagonist or by the nitric oxide synthetase inhibitor N(omega)-nitro-L-arginine methyl ester. We conclude that the AT(1)-receptors mediate the systemic and uterine vasoconstrictor responses to ANG II in the nonpregnant ewe. AT(2)-receptor blockade resulted in a potentiation of the uterine vasoconstrictor response to ANG II, suggesting that the AT(2)-receptor subtype may modulate uterine vascular responses to ANG II potentially by release of nitric oxide.

Bolus maternal cocaine administration does not produce a large increase in fetal sheep cerebral cortical glutamate concentration.

Human cocaine use during pregnancy may result in postnatal neurologic dysfunction and abnormal behavior. L-Glutamate, the major excitatory neurotransmitter in the brain, plays an important role in cerebral cortical development. An optimal level of glutamate is required for normal neuronal development. We tested whether acute cocaine exposure produces large increases in glutamate release in the intact cerebral cortex of the near-term fetal sheep. Cocaine 3.0 mg kg(-1) IV bolus produced the expected increase in maternal and fetal mean arterial pressure, increase in fetal heart rate, decrease in uterine blood flow, and decrease in fetal arterial blood pO2 (N = 5). The percentage increases in extracellular glutamate concentration in the fetal cerebral cortex measured by in utero microdialysis were 7%, 15%, 17%, 17%, and 43% in each fetus (upper 95% confidence bound for the median = 43%). We conclude that if cocaine increases glutamate concentration in the developing cerebral cortex, the increase in magnitude is small relative to the changes produced by other interventions such as ethanol or umbilical cord occlusion. Mechanisms other than increases in cerebral cortical glutamate concentration probably contribute to the neurologic injury associated with prenatal cocaine exposure.

The effects of medetomidine on maternal and fetal cardiovascular and pulmonary function, intrauterine pressure and uterine blood flow in pregnant goats.

To investigate the effects of medetomidine on late pregnant goats, medetomidine induced changes in maternal or fetal circulation and acid-base balance, as well as changes in intrauterine pressure (IUP) and uterine blood flow (UBF), were studied. Intramuscular administration of medetomidine (40 micrograms/kg b.w.) decreased the heart rate (HR) and arterial blood pressure (ABP) of the mother, and the change in HR was significant statistically (p < 0.05). In the fetus, HR and ABP showed a transient decrease and increase (p < 0.05), respectively. A decrease in maternal arterial blood pH and oxygen partial pressure (PO2) and an increase in carbon dioxide partial pressure (PCO2) were recorded after the injection, but none was significant. In the fetus, arterial blood PO2 decreased significantly (p < 0.05) after 5 min of administration, and a significant metabolic acidemia supported by a decrease in base excess was observed. Within 1 to 4 min after the administration of medetomidine, IUP began to rise and remained high for 10 to 14 min. Thereafter, the rise in IUP was frequent and periodical. After the injection, UBF significantly (p < 0.05) decreased, and the fall in UBF was associated with a rise in IUP. The maternal and fetal serum medetomidine concentration increased remarkably after the injection of medetomidine into the mother. These observations in late pregnant goats suggested that medetomidine induced a decrease in maternal cardiac output, a decrease in UBF arising from the induction of uterine contractions, and transplacental medetomidine can have a suppressive effect on the fetus.