Laird Wilson

Peritoneal fluid prostaglandins and prostanoids in women with endometriosis, chronic pelvic inflammatory disease, and pelvic pain

Peritoneal fluid obtained at laparoscopy from 49 women was measured for its content of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha), 6-keto-prostaglandin F1 alpha (6-KF), and thromboxane B2 (TxB2) by specific radioimmunoassays. In normal women (n = 10), the concentrations of prostaglandins in peritoneal fluid were (mean +/- SE): PGE2 = 0.79 +/- 0.26, PGF2 alpha = 0.60 +/- 0.18, 6-KF = 0.48 +/- 0.19, and TxB2 = 0.23 +/- 0.09 ng/ml; in women with endometriosis (n = 16): PGE2 = 1.43 +/- 0.72, PGF2 alpha = 1.52 +/- 0.59, 6-KF = 3.32 +/- 0.71, and TxB2 = 1.14 +/- 0.69 ng/ml; in women with chronic pelvic inflammatory disease and/or obstructed tubes (n = 19): PGE2 = 1.94 +/- 1.04, PGF2 alpha = 1.20 +/- 0.61, 6-KF = 1.55 +/- 0.40, and TxB2 = 0.64 +/- 0.24 ng/ml; in women with pelvic pain without any visible pathologic condition (n = 4): PGE2 = 1.11 +/- 0.66, PGF2 alpha = 0.73 +/- 0.55, 6-KF = 1.35 +/- 0.35, and TxB2 = 0.39 +/- 0.17. The mean volumes of peritoneal fluid recovered were 10 to 16 ml and were not significantly different between the groups. Except for a significantly elevated concentration of 6-KF in the peritoneal fluid of women with endometriosis compared to normal women (p = less than 0.02), the prostaglandins measured did not differ significantly between the groups of women studied. The possible significance of elevated 6-KF in the peritoneal fluid of women with endometriosis is discussed.

Forward shift in the initiation of the nocturnal estradiol surge in the pregnant baboon: Is this the genesis of labor?

Daily (9 AM and 6 PM) blood samples were obtained from the inferior vena cava during the last trimester of pregnancy in a tethered baboon model. In addition, three 24-hour (hourly blood sampling) studies were performed at days 143 to 147, 158 to 162, and 172 to 177 of pregnancy. Dramatic 24-hour rhythms in progesterone and estradiol were detected, with both steroids surging nocturnally. Early in the third trimester the estradiol surge followed the progesterone surge. However, approximately 10 to 12 days before delivery, the initiation of the nocturnal estradiol surge shifted forward, thus preceding the progesterone surge. This forward shift in the estradiol surge created a daily (3 to 5 hours) window of elevated estradiol-to-progesterone ratio and appears to coincide with the initiation of nocturnal uterine contractions. The nocturnal uterine contractions can be inhibited by an oxytocin antagonist. We hypothesize that this forward shift in the initiation of the estradiol surge induces nocturnal uterine contractions by oxytocin release and/or increase in uterine oxytocin receptors and generates molecular messages that are the genesis for labor and delivery in the baboon.

Inhibition of spontaneous uterine contractions during the last trimester in pregnant baboons by an oxytocin antagonist

The effect of a potent oxytocin antagonist, produced in our laboratories, on spontaneous uterine contractions in the pregnant baboon was examined. Three types of uterine contractions were studied: immediately after operation, during the nocturnal period, and near or at labor. Bolus intravenous injections of oxytocin antagonist were given and uterine activity was examined +/- 1 hour after the injection. The oxytocin antagonist caused a precipitate decrease (approximately 70%) in contractile force (mean amplitude x frequency) in the first 15 minutes after injection (p less than 0.05); this force diminished to approximately 90% at the end of 1 hour for both nocturnal and labor contractions. In contrast, uterine contractions immediately after operation were diminished by only 60% within 60 minutes after the oxytocin antagonist. These results indicate that the oxytocin antagonist is a potent inhibitor and suggest that oxytocin is a primary regulator of spontaneous nocturnal and labor uterine contractions in the pregnant baboon.

A new tocolytic agent: development of an oxytocin antagonist for inhibiting uterine contractions.

A potent oxytocin antagonist has been developed and tested on both the rat and human uterus. In the rat the oxytocin antagonist: (1) inhibited in vitro and in vivo uterine contractions in the nonpregnant animal in response to exogenous oxytocin, (2) inhibited milk letdown, and (3) disrupted the progress of labor. In addition, the oxytocin antagonist inhibited the in vitro contractile response to exogenous oxytocin of human myometrial tissue obtained by cesarean section at term. The results of these studies suggest that the oxytocin antagonist can be used to study the role of oxytocin in labor and has the potential of inhibiting preterm labor in humans.

The effect of acupuncture on uterine contraction induced by oxytocin.

Preterm labor (PTL) is one of the main causes of fetal mortality and morbidity in obstetrical medicine. Current methods of treatment are not very effective and often have significant side effects. For this reason new methods of preventing PTL are currently being sought. In Western medicine the newest development is oxytocin antagonists. In Oriental medicine acupuncture and moxibustion are being utilized for the purpose of stopping PTL. The goals of this study were to determine if acupuncture in pregnant rats can suppress oxytocin induced uterine contractions and to compare these results with those inhibited by an oxytocin antagonist. Uterine contractions were induced by continuous infusion of exogenous oxytocin. The first fetus in one uterine horn near the ovarian end was removed and distilled water-filled catheter was inserted into that vacated amniotic sac to measure uterine contractions as intrauterine pressure changes. Two acupoints of Ho-Ku (LI-4) and San-Yin-Chiao (Sp-6) were selected for acupuncture and Kuan-Yüan (Co-4) was used for moxibustion. The oxytocin-induced uterine contractions were significantly suppressed by acupuncture on the LI-4 (p < 0.05), but not by Sp-6. Stimulation of Co-4 by moxibustion had no significant (p > 0.05) tocolytic effect. The administration of oxytocin antagonist eliminated all the uterine contractions induced by oxytocin. The application of acupuncture to re-stimulate the activity that was suppressed by the oxytocin antagonist did not produce any positive results. However, prostaglandins did cause the uterus to contract. In conclusion, acupuncture on LI-4 was found to suppress uterine contractions induced by oxytocin in the pregnant rat. If acupuncture is similarly effective in counteracting the effects of oxytocin in women, then this may an alternative medical treatment for women in preterm labor.

Cocaine use and its effect on umbilical artery prostacyclin production

Cocaines association with adverse perinatal outcome has been attributed to its inhibition of norepinephrine uptake. This study examined the effect of cocaine on umbilical artery prostacyclin (PGI2) production. Umbilical arteries from pregnant cocaine users and controls were incubated in vitro and PGI2 levels in the media determined by measuring its stable metabolite, 6-keto-PGF1 alpha, by RIA. Cocaine users showed a significant decrease (p less than .05) in PGI2 production from their umbilical arteries when compared to controls. This appears to be through a direct effect of cocaine, as it decreases PGI2 production when added in vitro to umbilical arteries from controls. In addition, in vitro phospholipase A2 activity is inhibited by cocaine in a dose-dependent manner. These results suggest that the adverse perinatal outcome associated with cocaine use may be due in part to reduced vascular PGI2 production in the fetus.

Effects of estradiol and progesterone on uterine prostaglandin levels in the pregnant rat

The purpose of this study was to delineate the effects of estradiol and progesterone treatment on uterine prostaglandin F (PGF), PGE, Thromboxane B2 (TxB2) and 6-Keto-PGF1 alpha (6KF) levels in the pregnant rat. Rats were ovariectomized on day 19 of pregnancy (sperm in vagina = day 0) and received the following treatments via silastic inserts placed s.c.: controls; estradiol (E); progesterone (P); estradiol + progesterone (EP). Twenty-four hours later (day 20 of pregnancy) uterine venous blood and uterine tissue were obtained and assayed for PGE, PGF, TxB2 and 6KF by radioimmunoassay. E treatment significantly enhanced (p less than .05) uterine PGF, TxB2 and PGE (4.5, 2.8 and 1.8 fold increase, respectively) but did not alter 6KF levels when compared to C. Concomitant administration of P with E (EP) blocked the stimulatory effects of estradiol. P treatment by itself was ineffective. Steroid treatment induced no significant alterations (p greater than .05) in uterine venous plasma PG levels. These results suggest that estradiol can provoke a dramatic increase in uterine PGF, TxB2 and PGE levels in the pregnant rat but has no effect on net production of 6KF. These data are compatible with the hypothesis that an increase in the ratio of E/P at the end of pregnancy in the rat contributes to enhanced uterine concentrations of PGF, TxB2 and PGE at term, but they do not explain the augmented 6KF concentrations reported at parturition.

Effect of pregnancy on the metabolic clearance rate and the volume of distribution of oxytocin in the baboon

Pharmacokinetic parameters of oxytocin (OT) metabolism were determined during the last third of pregnancy and again 4-8 wk after delivery in the baboon. Animals were placed on a tether system with venous and arterial access and a continuous monitoring of uterine contractions during gestation. Two methods of determining OT pharmacokinetics were utilized (bolus injection vs. continuous infusion). The metabolic clearance rate of OT as determined during the bolus trials (n = 7) was 22.2 +/- 1.5 ml.min-1.kg-1 in pregnancy and 16.3 +/- 1.4 ml.min-1.kg-1 postpartum (P < 0.05), respectively, and 23.7 +/- 2.8 vs. 16.9 +/- 3.7 ml.min-1.kg-1 (P < 0.05), respectively, as determined during the 1-h infusion trials (n = 4). The initial dilution volume and the volume of distribution at steady state of OT after administration did not differ between pregnant and postpartum animals (P > 0.05). The mean residence time (MRT) of OT was shorter during pregnancy, 7.7 +/- 0.8 vs. 10.8 +/- 1.2 min postpartum (P < 0.05). In summary, OT metabolism during pregnancy in the baboon is characterized by 1) increased clearance rate (1.4-fold), 2) accelerated turnover due to the shorter MRT, and 3) unaltered distribution.

Oxytocin antagonist inhibitory effect on the rat and baboon uterus may be overcome by prostaglandins

OBJECTIVE A potent, long-acting oxytocin antagonist produced in our laboratory (ANTAG-III) can inhibit uterine response to oxytocin in the rat and baboon for hours and even days. The purpose of this study was to evaluate uterine response to prostaglandins subsequent to the administration of ANTAG-III. STUDY DESIGN For the rat study one cannula was inserted in the jugular vein, and another cannula to measure uterine activity was inserted in the uterus. In study 1 saline solution or 5 micrograms of ANTAG-III was administered to five rats each, followed by 100 mU of oxytocin at 0.1, 1, and 2 hours. In study 2 six rats each were infused with saline solution of 5 micrograms of ANTAG-III, followed 1 hour later by 5 micrograms of 15-methyl-prostaglandin F2 alpha and uterine activity monitored. After baseline activity returned to normal 100 mU of oxytocin was infused and the uterine response reassessed. For the baboon study ANTAG-III was administered into the aorta of tethered pregnant baboons (n = 2). An oxytocin challenge test was performed starting with 10 mU/min and going up to 400 mU/min. After a significant uterine contractile response was established and activity returned to baseline, a 15-methyl-prostaglandin F2 alpha challenge test was performed. RESULTS During the period in which the response to oxytocin was inhibited the uterine response to 15-methyl-prostaglandin F2 alpha of the estrous rat and pregnant baboon was maintained. CONCLUSIONS The inhibition of the estrous rat and pregnant baboon uterus to oxytocin caused by ANTAG-III may be prolonged. During this period uterine response to prostaglandins is not altered.

Effects of progesterone withdrawal on uterine prostaglandin levels in the ovariectomized pregnant rat

Prostaglandin (PG) levels increase dramatically just before parturition in the rat. Coincident with this dramatic increase in uterine PGs is a precipitous decrease in plasma progesterone and enhanced plasma estradiol levels. The purpose of the present study was to mimic the progesterone withdrawal phenomenon in the presence and absence of estradiol in ovariectomized pregnant rats and determine the effects on uterine PGF, PGE, thromboxane B2 (TxB2) and 6-keto-PGF1a (6KF) levels. Rats were ovariectomized on day 16 of pregnancy and silastic inserts containing progesterone and estradiol placed s.c. in two groups of rats (I and II) while the third group (III) received progesterone only. On day 19 of pregnancy progesterone was withdrawn from groups II and III and rats sacrificed 0, 6, 12 and 24 hours later. Uterine tissue was assayed for PGs by radioimmunoassay. Progesterone withdrawal in the absence of estradiol (III) administration significantly (p less than .05) elevated PGE, TxB2 and 6KF, but not PGF, at the 24 hour period compared to controls (I). When progesterone was withdrawn in the presence of exogenously administered estradiol (II) only PGF showed enhancement (p less than .05) over III at the 24 hour period thus indicating a specific effect of estradiol on the PGF metabolic pathway. In conclusion, these data indicate that: (1) progesterone withdrawal is a potent stimulus for uterine PG production and is probably a major contributor to the augmented uterine PGE, TxB2 and 6KF levels at term in the pregnant rat; and (2) progesterone withdrawal in the presence of exogenously administered estradiol enhances uterine PGF production thus indicating a specific effect of estradiol on PGF production.