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PubMed1993

Oxytocin, PGE2 and PGF2 alpha stimulate the production of inositol phosphates in the rabbit myometrium.

Phosphoinositide breakdown is thought to be important in regulating a variety of transmembrane signal transduction in the action of oxytocic agent during uterine smooth muscle contraction. We investigated the effects of oxytocin and prostaglandins (PGE2 and PGF2 alpha) on phosphoinositide hydrolysis in the myometrium taken from non-pregnant and pregnant rabbits by measuring the accumulation of total inositol phosphates (IP). Oxytocin strongly, and PGE2 and PGF2 alpha slightly but significantly, stimulated IP production in both the non-pregnant and pregnant myometria. Oxytocin more markedly accelerated the IP production in pregnant myometrium than in non-pregnant myometrium. However, IP production stimulated by PGE2 and PGF2 alpha was much the same in non-pregnant and pregnant myometria. The amount and time course of the increase in the production of the total IPs by oxytocin are quite different from those by PGs. It seems that the mechanism by which oxytocin stimulates phospholipase C is different from that of the PGs. It is suggested that transmembrane signalling pathways of phosphoinositide hydrolysis play an important role in the each mechanism.

Animals↗
PubMed1975

The efficacy and safety of intramuscularly administered 15(S) 15 methyl prostaglandin E2 methyl ester for induction of artificial abortion.

The practicability of an intramuscular dose schedule of 10 mug of 15(S) 15 methyl prostaglandin E2 methyl ester [15(S) Me PGE2] administered every 4 hours was evaluated in 42 subjects from 7 to 20 menstrual weeks' gestation. Half of the subjects served as controls (Group I) and half of the subjects (Group II) were treated with a medication regimen of prochlorperazine, acetylsalicylic acid, diphenoxylate hydrochloride, and atropine sulfate to evaluate the regimen's effects. Although the 15(S) Me PGE2 dose schedule appeared to be effective (74 per cent aborted in 24 hours and 95 per cent aborted within 48 hours in a mean time of 18.9 hours), Group I (control) subjects frequently had side effects: 62 per cent had emesis, 86 per cent had diarrhea, 76 per cent had shivering, and 76 per cent had fever (greater than 100 degrees F.). Fewer Group II (medicated) subjects had side effects: 43 per cent had emesis, 19 per cent had diarrhea, 52 per cent had shivering, and 43 per cent had fever. The medication regimen did not appear to interfere with the abortifacient or oxytocic effects of the 15(S) Me PGE2 dose schedule, since Group I and Group II subjects had similar cumulative abortion rates, mean abortion times, and uterine activity. Although this 15(S) Me PGE2 dose schedule is effective in first-trimester patients, it is probably less satisfactory than the conventional method of vacuum aspiration. While intramuscularly administered 15(S) Me PGE2 with medications to attenuate side effects may be practicable for inducing midtrimester abortion, especially between 12 and 16 weeks' gestation, large controlled comparative studies of the intramuscular 15(S) Me PGE2 method and other experimental and conventional methods will be necessary to determine the most satisfactory method of performing midtrimester abortions.

Abortion, Induced↗
PubMed1976

Effects of progesterone, prostaglandin F2alpha and its analogue ICI 81008 on the excitability and threshold of the uterus.

Forty-eight uterine strips were excised from 24 New Zealand white rabbits and studied in vitro. Sixteen strips were examined when eight animals were 25 days pregnant, 24 strips when 12 animals were about 12 hours postpartum, and eight strips about 12 hours after four animals received a single dose of 5 mg. progesterone (P) at spontaneous delivery. When after repeated exposures to electric fields (60 cycles per second, alternating current, of optimum strength, four seconds' duration at intervals of 30 seconds) the approximately 0.5 Gm. strips developed approximately 40-50g wall tension (WT) in steady state, the field strength was reduced in graded steps from 12 v per 5 cm. to 10, 8, 6, 4 and 3 v per 5 cm. and WT recorded. By measuring the effect on WT of "decreasing electric field stimulation" (DEFS), myometrical excitably and threshold were characterized and quantitated. The technique is based on the relationship between the fraction of myometrial cells activated in the total cell population and WT. As the stimulus is decreased in graded steps from optimal to increasingly suboptimal, DEFS activates fewer and fewer cells reflected by the decrease in WT. Threshold is defined by the strength of the minimum electric field which provokes WT and subthreshold by the field strength which fails to excite. Thus fractional WT averages the excitability of cells in the tissue and thus DEFS characterizes this important parameter of uterine function and quantitates threshold under a variety of regulatory conditions. The comparative study of excised uteri in three different endocrine states showed that the regulatory conditions of normal pregnancy (P levels 9 ng. per milliliter) suppressed excitability and increased threshold (to 6 v per 5 cm.). Post partum (P levels 1 ng. per milliliter) excitability increased and threshold decreased (to 4 v per 5 cm.), unless P treatment prevented this characteristic change by suppressing excitability and increasing threshold (to 6 v per 5 cm.). Both regulatory agents, prostaglandin F2alpha (PGF2alpha) and its analogue ICI 81008, increased excitability and decreased threshold significantly in picogram per milliliter concentrations. However, this effect was observed only when the P levels were low. These compounds had little effect, even in manogram per milliliter concentrations, when the P levels were high. The studies also revealed a close relationship between threshold and spontaneous uterine activity. Low threshold promoted while high threshold suppressed spontaneous activity. In similar concentrations the oxytocic actions of PGF2alpha and ICI 81008 were similar but the effect of ICI 81008 was prolonged through strong binding at myometrical sites.

Animals↗
PubMed1978

The comparative actions of uterine inhibiting drugs.

Currently there is not an in vitro or in vivo method of quantitating the potency of uterine inhibiting drugs. Electric field stimulation (EFS) of pregnant and parturient rabbit myometrial strips has been effectively used to assay oxytocic potency of prostaglandins and it is shown in this study to be useful in assaying potency of beta-sympathomimetic compounds. Decreasing electric field stimulation (DEFS) provides three measureable endpoints: tension, excitability, and threshold voltage. Three compounds were tested for these parameters: isoproterenol, ritodrine, and isoxsuprine. It is also revealed that so-called uterine inhibition by these compounds represents the creation of a chaotic fibrillating muscle which is unable to respond in a synchronous way to produce a contraction of maximal tension.

Animals↗
PubMed1978

Induction of labor with oral prostaglandin E2 in normal and high-risk pregnancies.

There were 153 oral prostaglandin (PG) E2 inductions attempted in 149 patients. For various reasons nine cases were dropped from the study. Of the remaining 144 induction attempts, 96 were judged successful, with a success rate of 67 per cent. Details of these inductions are presented, including summaries of three patients with uterine hypertonus and three with uterine hyperstimulation. As a rule, the labor pattern established with oral PGE2 was effective and indistinguishable from normal spontaneous labor. After review of the data we feel that induction of labor with oral PGE2 is no more hazardous to mother or infant than with other oxytocic agents. In our opinion oral PGE2 offers the obstetrician an additional means for induction of labor in normal and high-risk pregnancies. The need for close observation of the progress of labor during PGE2 inductions is emphasized.

Administration, Oral↗
PubMed1979

Induction of preterm labor in the rat by antiprogesterone.

The validity of a new concept, predicting that preterm labor can be induced without oxytocic stimulation by a regulatory imbalance, generated by antiprogesterone (A-P)-provoked P withdrawal (Pw), has been examined in the rat model. At day 19 of pregnancy a single oral dose of the steroidal A-O isoxazol, which inhibits P synthesis, significantly reduced uterine P levels, increased uterine estradiol and prostaglandin F levels, and induced preterm labor. This precocious regulatory imbalance and preterm labor were prevented, by blocking the A-P-induced Pw with P treatment. The regulatory imbalance which triggered the onset of spontaneous labor in the control animals was similar, but it occurred at term rather than before term. The potential of this method in improving the management of medically indicated induction of preterm labor is discussed.

Administration, Oral↗
PubMed1982

Plasma levels of oxytocin and 13, 14-dihydro-15-keto prostaglandin F2 alpha in preterm labor and the effect of ethanol and ritodrine.

We have measured the concentrations of circulating oxytocin and the 13, 14-dihydro, 15-keto-metabolite of prostaglandin F2 alpha (PGFM) in women during preterm labor. Twelve women were given intravenous ethanol and 11 women received intravenous ritodrine for the prevention of preterm birth. Blood samples were obtained before and 1/2, 1, 2, 4, 12, and/or 24 hours after treatment began. On admission, the plasma concentrations of both oxytocin and PGFM were raised over levels observed in women with normal pregnancies of similar gestational age, 25 to 36 weeks. The initial oxytocin level was 58.5 +/- 8.2 pg/ml (mean +/- SE, n = 23) and the mean initial PGFM level was 264 +/ 33.1 pg/ml (n = 15); both values were significantly higher than in 10 control subjects (17.4 +/- 4.8 and 156 +/- 21.8 pg/ml, respectively). During infusion of ethanol, the plasma oxytocin level fell rapidly, the levels at 1/2 and 1 hour after infusion being significantly lower than before the infusion (29.0 +/- 5.5 and 27.8 +/- 3.5 pg/ml, respectively). The plasma oxytocin level remained low in women in whom the treatment arrested labor and prevented preterm birth (n = 8) but rose 2 to 4 hours after the infusion began in women in whom the treatment failed to arrest labor (n = 4). Ritodrine, on the other hand, had no significant effect on circulating oxytocin levels. The plasma PGFM level decreased significantly during ritodrine treatment only in the successfully treated patients. Ethanol had no consistent effect on plasma PGFM levels in the four patients in whom PGFM levels were measured. In the ritodrine-treated patients, the plasma PGFM level was positively correlated with the frequency of uterine contractions whereas in the ethanol-treated patients a correlation of plasma oxytocin to the frequency of contractions was observed. Thus, oxytocin secretion is increased during preterm labor, and the release of prostaglandin F is also increased. While it is not possible to determine whether any or both of these oxytocic agents actually trigger preterm labor, both seem to play a role in its mechanism.

Dinoprost↗
PubMed1982

Effect of nickel on uterine contraction and ultrastructure in the rat.

The in vitro effects of nickel chloride (NiCl2) on uterine contractile activity and ultrastructure were studied in uterine strips isolated from 20-day-pregnant Wistar rats. Ni2+ had a dual action on uterine spontaneous contractions. In low concentrations (10(-7) M to 10(-5) M), NiCl2 increased basal tone significantly but had no effect on the amplitude or frequency of development of isometric force. High concentrations of NiCl2 (10(-4) M to 10(-3) M inhibited spontaneous contractile activity and decreased basal tone, which was antagonized by elevation of the extracellular concentration of Ca2+. Electron microscopic localization of Ni by the dimethyl glyoxime cytochemical technique showed that, after incubation of uterine strips in a physiologic medium that contained 10(-6) M NiCl2, electron-dense Ni-dimethyl glyoxime particles could be observed in the cytoplasm and in the mitochondria of uterine smooth muscle cells. Exposition of Ni caused mitochondrial structural damage and accumulation of glycogen. The experimental results indicate that, because of its oxytocic action, the increase in the serum level of Ni in the advanced stage of human labor (Rubányi and associates, 1982) may support separation of the placenta and/or may contribute to the prevention of atonic bleeding in the postpartum period.

Animals↗
PubMed1990

Controlling refractory atonic postpartum hemorrhage with Hemabate sterile solution.

The customary use of Hemabate sterile solution for postpartum hemorrhage was studied at 12 cooperating obstetrics units for a 12-month period. Outcomes of interest were the characteristics of patients chosen by the attending physicians to receive the drug, conditions of drug use, and patient status after drug use. Cessation of bleeding was considered a successful outcome and in 208 of 237 cases (87.8%) the hemorrhage was controlled directly after the administration of Hemabate sterile solution. An additional 17 successful outcomes were achieved with further administration of oxytocics for an overall success rate of 94.9%. Twelve cases of postpartum hemorrhage were considered pharmacologic treatment failures, requiring surgical intervention. Among the patients in whom pharmacologic treatment failed were factors that may have played a significant role in the cause of the hemorrhage including peripheral coagulopathy, retained products of conception, lacerations, chorioamnionitis, oxytocin-induced or augmented labor, increased fetal weight, magnesium-treated preeclampsia, and cesarean delivery. However, no combination of factors could be consistently associated with pharmacologic treatment failure.

Adult↗
PubMed1990

Production of prostaglandin E2 by human amnion in vitro in response to addition of media conditioned by microorganisms associated with chorioamnionitis and preterm labor.

To examine the potential role of bacterial infection in the cause of spontaneous preterm labor, human amnion cells in tissue culture were exposed to medium conditioned by culturing each of 21 microorganisms previously found in association with chorioamnionitis and preterm labor. At a final concentration of 0.1% bacterial conditioned medium, a significant stimulation of prostaglandin E2 production from amnion cells was observed for this range of microorganisms. Conditioned medium obtained from culturing Bacteroides fragilis caused a dose-related increase in prostaglandin production, final concentrations of 0.02% to 0.1% being stimulatory but greater concentrations (0.1% to 10%) causing a progressive inhibition of prostaglandin synthesis. A similar concentration-related response in which stimulation was followed by inhibition occurred on addition of increasing concentrations of phospholipase A2 to amnion cells. These data suggest that bacterial phospholipase may release arachidonic acid from amnion leading to prostaglandin E2 synthesis, but excessive addition of phospholipase and consequent increased arachidonic acid availability may give rise to substrate inhibition of cyclooxygenase enzyme and inhibit prostaglandin E2 synthesis. Overall it appears that a wide variety of microorganisms associated with preterm labor may secrete phospholipase, which liberates amnion arachidonic acid for conversion to the oxytocic agent prostaglandin E2.

Amnion↗
PubMed1991

Uterine rupture at term pregnancy with the use of intracervical prostaglandin E2 gel for induction of labor.

Prostaglandin E2 is a powerful oxytocic agent that reliably initiates labor, even in the presence of an unripe cervix. The low incidence of fetomaternal complication contributes to its universal use. We report a rare case of uterine rupture after intracervical application of prostaglandin E2 gel. Thus far no prostaglandin compound or method of administration seems to be exempt from such a complication.

Administration, Intravaginal↗
PubMed1984

Stimulatory action of oxytocin on neurones of the dorsal motor nucleus of the vagus nerve.

Extracellular recordings were obtained from spontaneously active neurones located in the dorsal motor nucleus of vagus nerve ( DMX ) in slices of the rat brainstem. Oxytocin applied to the bath at concentrations of 10(-7) M or 10(-6) M excited 79% of these cells in a concentration-dependent, reversible manner. The remaining cells were unaffected. The stimulatory effect of oxytocin was reversibly antagonized by a synthetic structural analogue known to block the peripheral, endocrine effects of neurohypophysial peptides. A selective oxytocic agonist was as potent as oxytocin, whereas vasopressin exerted a much weaker effect. We therefore suggest that neurones located in DMX are endowed with receptors for oxytocin.

Animals↗
PubMed1988

125I-labelled d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)]OVT: a selective oxytocin receptor ligand.

An oxytocic antagonist, [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid,2-O-methyltyrosine,4-threonine, 8-ornithine,9-tyrosylamide]vasotocin (d(CH2)5[Tyr(Me)2, Thr4,Tyr-NH2(9)]OVT [corrected], was monoiodinated at the phenyl moiety of the tyrosylamide residue at position 9. 125I-labelling was performed with 1,3,4,6-tetrachloro-3 alpha,6 alpha-diphenyl-glycoluril. Iodination resulted in an increased affinity for rat uterine oxytocin receptors. A considerably lower affinity for rat vascular V1- and renal V2-receptors was found, resulting in a highly specific oxytocin receptor ligand. 125I-labelled d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)]OVT [corrected] was demonstrated to bind selectively to one population of binding sites in rat uterus and ventral hippocampal membrane preparations. Dissociation constants ranged between 0.03 and 0.06 nM. After 3 days of exposure autoradiography revealed binding in regions known to contain oxytocin receptors as well as labelling in some new regions, while no binding was found in the lateral septum, a structure containing mainly [8-arginine]vasopressin receptors. The high specific radioactivity of 125I-labelling allowed important reductions in membrane protein amount, gain in precision of binding analysis as well as considerably lower exposure times for autoradiography.

Animals↗
PubMed1987

In vitro effect of prostaglandins on the accumulation of cyclic AMP in the avian oviduct.

The effects of prostaglandins E1, E2, and F2 alpha (PGE1, PGE2, and PGF2 alpha, respectively) on cyclic AMP production in tissue samples from the uterus (U), uterovaginal sphincter (UVS), and vagina (V) of regularly laying hens as well as the effects of PGE2 and forskolin on U and V of Japanese quail were studied. Both PGE1 and PGE2 enhanced cyclic AMP production in the hen oviductal segments, particularly in the V in a dose-related manner, PGE1 being the more effective agonist. PGF2 alpha had no significant effect. Quail U appeared to be less responsive to PGE2 which caused a 40% increase in cyclic AMP levels at the highest concentration tested (28 microM), whereas forskolin at 10 microM increased cyclic AMP production in quail U and V 7- and 20-fold, respectively. It is suggested that the primary function of PGE2 and PGE1 is to relax the terminal portion of the oviduct, allowing the expulsion of the egg under the contractile influence of PGF2 alpha and other oxytocic factors.

Animals↗
PubMed1990

A comparative randomized study of oral prostaglandin E2 (PGE2) tablets and intravenous oxytocin in induction of labor in patients with premature rupture of membranes before 37 weeks of pregnancy.

In a randomized prospective study, we compared the use of intravenous oxytocin with oral PGE2 tablets for stimulation of labor in cases of premature rupture of membranes (PROM) before term, where the onset of spontaneous labor did not occur within the first 3 h. This study represents the first of its kind in which oral PGE2 and oxytocin have been directly compared as oxytocic agents for PROM before 37 weeks. Labor induction was successful in 96% of patients in the PGE2 group compared with 84% in the oxytocin group. The incidence of cesarean section (CS) was 5% and 16% in the PGE2 and the oxytocin groups, respectively. While 10% of the CS were performed due to fetal bradycardia in the oxytocin group, none was performed in the PGE2 group despite the fact that the latter group had relatively lower Bishop scores. The data presented indicate that oral PGE2 is safe and effective in initiating active labor in healthy women at pre-term with PROM. Thus we recommend its use to induce labor 3 h after rupture of membranes before 37 weeks gestation.

Administration, Oral↗
PubMed1986

Studies on the mechanisms of action of progesterone antagonists.

Antigestagens of RU-38.486-type were investigated in different pregnancy models reflecting either "endometrial" or "myometrial" effects. All antigestagens were found effective inhibitors of nidation in guinea pigs. This was evidence for a role of embryonic progesterone in the earliest events of nidation. No comparable inhibition could be obtained by ovariectomy. A more complex pharmacology was found around day 43 p.c. when the abortion was brought about by expulsion. RU-38.486 had marginal activity only. Antigestagens with reduced anti-glucocorticoid activity tended to induce abortions more effectively and faster. Some antigestagen-prostaglandin combinations were found of extreme abortifacient activity. Surprisingly it seemed that anti-glucocorticoid properties in addition to (or rather than) antigestagenic activities bring about this synergism with prostaglandin. The employed guinea pig model for pregnancy termination thus characterized two types of antigestagens: ideal ones for monotherapy or combined use with prostaglandin, respectively. Antigestagens induced a highly sensitive myometrium to prostaglandin-stimulation (Sulprostone) and a marked softening and dilatation of the cervix. Antigestagens perfectly prime the genital tract for oxytocic stimuli, they do not overcome the arrested uterine prostaglandin-secretion of the pregnant uterus at the same time.

Abortifacient Agents, Steroidal↗
PubMed1986

Vasopressin and oxytocin reduce plasma prolactin levels of conscious rats in basal and stress conditions. Study of the characteristics of the receptor involved.

Subcutaneous administration of arginine vasopressin (AVP) to conscious rats induced a dose-dependent increase of plasma ACTH and beta-endorphin levels and decrease of plasma prolactin (PRL) levels 30 min later. AVP similarly reduced PRL increase induced by exposure to a novel environment stress. Oxytocin (OT) was also active but 5-fold less potent than AVP. The study of several analogs with specific agonistic and antagonistic activity on the oxytocic, vasopressor and antidiuretic receptors of OT and AVP suggests that the receptor involved in this effect does not fit into this classification.

Adrenocorticotropic Hormone↗
PubMed1977

Elective induction of labor conducted under lumbar epidural block. II. Labor induction by amniotomy and intravenous prostaglandin.

Labor was electively induced at term in 117 clinically normal nulliparae and parous women by combining low amniotomy with intravenous administration of prostaglandin F2 alpha (n = 64) or prostaglandin E2 (n = 53). Analgesia was obtained by continuous lumbar epidural block with bupivacaine. The procedure was very effective in producing vaginal delivery within 24 h after prostaglandin infusion (n = 115), but it was accompanied by an extremely high incidence of uterine hypertonus. Tentative explanations for the transient uterine hyperstimulation are a direct stimulatory effect of the local anesthetic on the contractility of the myometrial fiber and/or a temporarily higher amount of circulating oxytocic compound reaching the myometrium due to local vasodilatation as a result of sympathetic nerve blockade. In some cases uterine hypertonus was associated with slowing of the basal fetal heart rate and, when severe, with the appearance of late deceleration patterns and fetal acidosis. In other cases the fetal heart rate deceleration is explained by the toxic effect of bupivacaine on the myocard. Since both the myometrial hyperactivity and the FHR alterations were temporary, fetal biochemical parameters were unaffected at completion of the first stage of labor. Because with intravenous prostaglandin uterine hyperstimulation is more difficult to avoid and regional analgesia further increases the hazard of both hypertonus and fetal heart rate deceleration, the combined application of an intravenous prostaglandin and continuous epidural analgesia should not be introduced into obstetrical practice.

Adult↗