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An analogue of oxytocin containing a nitro group ortho to the phenolic hydroxyl group of the tyrosyl residue was prepared by nitration of the hormone with tetranitromethane. [2-(3-Nitro-l-tyrosine)]oxytocin was bound by neurophysin although its pharmacological activity was virtually abolished. The oxytocic activity of the analogue on the isolated rat uterus was 1.1i.u./mg.
The present study was designed to examine the effects of ET-1 (endothelin-1) and serum from PE (pre-eclamptic), HP (healthy pregnant) and HNP (healthy non-pregnant) women on uterine arterial perfusion pressure and uterine contractility. Swine uteri (n = 25) were perfused for a period of up to 11 h, with the aim being to preserve a viable organ. Various concentrations of ET-1 as well as serum from PE, HP and HNP women (n = 10 per group) were administered to the perfused swine uteri and IUP (intrauterine pressure) and IAP (intra-arterial pressure) were recorded. ET-1 produced dose-dependent increases in IUP and IAP. The ET-1 concentration in serum was higher in serum from PE women than in HP and HNP women (P > 0.05). Administration of all serum samples had a contractile effect on the swine uterus, with the greatest effect being seen in HNP women (12.8 +/- 5.3 mmHg), followed by PE (9.06 +/- 4.2 mmHg) and HP (6.1 +/- 4.1 mmHg) women. Statistically significant differences were observed between HNP and PE women (P = 0.048), and PE and HP women (P = 0.021). Increases in IAP following administration of serum from PE women (48.8 +/- 20.0 mmHg) were significantly higher (P = 0.024) compared with the effect of serum from HP women (28.4 +/- 13.7 mmHg). In conclusion, the findings show that serum from PE women has significant vasoconstrictive and oxytocic effects compared with serum from HP women. In pre-eclampsia, the balance between vasorelaxing and vasoactive substances is disturbed.
In rats euhydrated or dehydrated for two or four days the neurohypophysial vasopressin and oxytocin content was estimated. Rats were given intracerebroventricularly (i.c.v.) isoprenaline in a daily dose of 10 micrograms dissolved in 10 microliters of 0.9% sodium chloride. The neurohypophysial vasopressor and oxytocic activity diminished progressively during deprivation of water. A single dose of isoprenaline diminished the neurohypophysial content of vasopressin in euhydrated rats. In animals dehydrated for two or four days the depletion of neurohypophysial vasopressin storage (as brought about by osmoreceptor stimulation) was distinctly less marked under treatment with isoprenaline. The neurohypophysial oxytocin storage was diminished by a single dose of isoprenaline; on the contrary, during dehydration isoprenaline distinctly intensified the oxytocin depletion in the neurohypophysis.
Oxytocin and the related peptide [Arg8]vasopressin (AVP) have previously been shown to bind with equally high affinity to oxytocin binding-sites (presumed oxytocin receptors) present within the uterus and oviduct of oestrous ewes. There is a possibility, therefore, that AVP mediates oxytocic actions through these binding sites. For the present study, ewes in seasonal anoestrus were treated with oestradiol-17 beta (50 micrograms subcutaneously, daily for 2-4 days). It was shown initially that this treatment stimulated the development of high-affinity oxytocin binding-sites (Kd 4.4 +/- 0.8 nmol L-1) which had similar affinity for AVP (Kd 4.2 +/- 0.9 nmol L-1) in the myometrium. The efficacy of oxytocin and AVP in vivo were compared by recording electromyographic (EMG) activity from the ampullary-isthmic junction of the left oviduct and the left uterine horn of four conscious ewes. Before oestradiol treatment there was no EMG response to oxytocin even at supraphysiological (1000 mU) doses. During oestradiol treatment, EMG activity was consistently increased in response to injections of 25 mU and 100 mU oxytocin via the jugular vein, but not to saline or 100 mU AVP. Higher doses of AVP were not investigated because of the possibility of cardiovascular side effects. A subsequent blood sampling experiment showed that maximal concentrations of oxytocin and AVP (achieved in peripheral plasma during the first 2 min following injection into the jugular vein) were of a similar order of magnitude after injection of equivalent doses of the two peptides. It is concluded that AVP probably does not mediate biological activity through the oxytocin receptor in non-pregnant ewes.(ABSTRACT TRUNCATED AT 250 WORDS)
This paper describes the synthesis and biological activity of [5-L-asparagine-alpha,beta,beta-d(3)]-deamino-oxytocin. The model peptide S-benzyl-beta-mercaptopropionyl-L- asparaginyl-alpha,beta,beta-d(3)-glycinamide was also prepared to observe the effect of the conditions of peptide synthesis on the deuterium content. It was found that normal synthetic procedures could be used without a significant loss in the deuterium content.The [5-L-asparagine-alpha,beta,beta-d(3)]-deamino-oxytocin had, within experimental error, the same avian vasodepressor and oxytocic activities as deamino-oxytocin itself.
Extracellular recordings were obtained from a class of nonpyramidal neurones in hippocampal slices. Oxytocin applied to the bath at concentrations of 1 nM or greater excited these cells. This effect was reversibly antagonized by a synthetic structural analogue known to block the peripheral endocrine effects of oxytocin. The effect of oxytocin was mimicked by a selective oxytocic agonist and, with less potency, by vasopressin and by other structural analogues. The potencies of oxytocin, vasopressin, and of these analogues in the hippocampus correlated well with their uterotonic activities but not with their vasopressor or antidiuretic activities. The data suggest that a class of hippocampal neurones is endowed with receptors for oxytocin that are similar to those of uterine smooth muscle cells.
Extracellular recordings were obtained from single neurons located in the lateral septum, an area known to receive a vasopressinergic innervation in the rat brain. Approximately half of the neurons tested responded to 8-L-arginine vasopressin (AVP) by a marked increase in firing rate at concentrations greater than 1 nM. The effect of vasopressin was blocked by synthetic structural analogues possessing antagonistic properties on peripheral vasopressin and oxytocin receptors. Oxytocin was much less potent than vasopressin in firing septal neurons, and a selective oxytocic agonist was totally ineffective. The action of vasopressin on neuronal firing was mimicked by the vasopressor agonist [2-phenylalanine,8-ornithine]vasotocin but not by the selective antidiuretic agonist 1-deamino[8-D-arginine]vasopressin. In a parallel study, sites that bind [3H]AVP at low concentration (1.5 nM) were found by in vitro autoradiography in the lateral septum. Adjacent sections were also incubated with 1.5 mM [3H]AVP and, in addition, with 100 nM [2-phenylalanine,8-ornithine]vasotocin or 1-deamino[8-D-arginine]vasopressin--i.e., the same compounds as those used for the electrophysiological study. Results showed that the vasopressor agonist, but not the antidiuretic agonist, displaced [3H]AVP, thus indicating that the vasopressin binding sites detected by autoradiography in the septum were V1 (vasopressor type) rather than V2 (antidiuretic type) receptors. Based on the electrophysiological evidence, we conclude that these receptors, when occupied, lead to increased firing of lateral septal neurons.
Trypsin was found to generate depressor substances from human plasma protein fraction IV-4 at all pH values from 2.0-10.0. The depressor substances generated at three representative pH values, i.e., 3.2, 5.0, and 8.0 were purified and isolated. The procedures used for the isolation were: (a) gel-filtration through Sephadex G-25; (b) desalting by ion retardation chromatography on AG 11 A8; (c) equilibrium chromatography on SP-Sephadex C-25; (d) desalting by AG 11 A8 again, and (e) partition chromatography on a high pressure liquid chromatograph. Upon high pressure liquid chromatography, the depressor substances formed at each of the three pH values were separated into two fractions. In thin layer electrophoresis, the two depressor substances moved with mobilities identical with those of synthetic bradykinin and synthetic [des-Pro3]-bradykinin but not those of methionyl-lysyl- or lysyl-bradykinin. The amino acid analysis of the hydrolysate of the depressor substance 1 generated at pH 3.2 showed the following proportional composition: Arg, 2; Pro, 2; Gly, 1; Phe, 2; Ser, 1. The product thus lacked 1 mol of proline residue as compared with bradykinin, and the retention time of this depressor substance 1 was identical with that of synthetic [des-Pro3]-bradykinin on high pressure liquid chromatography. The depressor substance 2 showed Arg, 2; Pro, 3; Gly, 1; Phe, 2; Ser, 1. This is identical with the composition of bradykinin. Finally, substances 1 and 2 showed oxytocic activities identical to those of synthetic [des-Pro3]-bradykinin and synthetic bradykinin, respectively. Substance 1 showed a bradykinin-potentiating activity similar to that of synthetic [des-Pro3]-bradykinin.
Endothelins (ETs) caused concentration-dependent contraction in pregnant rat myometrium. ET-2 was as potent as ET-1 in affecting contractile responses, whereas ET-3 was considerably less potent than ET-1 or ET-2. ETs also increased inositol phosphate (IP) production in a dose-dependent manner, with IP production paralleling the contractile response. The rank order of potency for both the contractile responses and IP production was ET-1 = ET-2 > ET-3. When we compared the important oxytocic agent oxytocin, we found that oxytocin (10(-7) M) strongly increased contractility and IP production, and the responses were comparable to those elicited by ET-1 (10(-7) M) and ET-2 (10(-7) M). These results suggest that ET-induced myometrial contraction involves phospholipase C activation, and that a subtype of endothelin receptor existing in pregnant rat myometrium could be classified as ETA.
Most cases of postpartum haemorrhage are caused by uterine atony, maternal soft-tissue trauma, retained placenta or its parts, and obstetric coagulopathy. The factors most significantly associated with haemorrhage include advanced maternal age, prolonged labour, pre-eclampsia, obesity of mother, multiple pregnancy, a birth weight of more than 4000g, and previous postpartum haemorrhage. It seems that multiparity itself is only a weakly associated factor. The prophylactic use of oxytocic drugs (oxytocin or its combination with ergometrine at the third stage of labour is always recommended for decreasing the bleeding. Prostaglandins should be used as a second line treatment if uterine atony cannot be abolished by uterine massage and oxytocin infusion. In the surgical management, the role of hypogastric artery ligation is decreasing. The stepwise uterine devascularization may be a reasonable method in the most severe uncontrollable postpartum bleeding. The uterine tamponade with gauze or specific tubes may also be a useful alternative in some cases. Selective arterial embolization is a promising new method that seems to have success in controlling the heavy postpartum bleeding unresponsive to more usual measures. However, the value of this method should be evaluated in bigger series.
Abruptio placentae rarely produces severe maternal complications while the fetus is alive in utero. The advent of fetal death (grade III) indicates a severe form of abruptio placentae and a real risk that an overt coagulopathy might develop (grade IIIB). Overt coagulopathy associated with a live fetus is, however, uncommon. The advent of an overt coagulopathy should be viewed as ominous. Treatment of abruptio placentae with overt coagulopathy should be directed toward obtaining a rapid and atraumatic vaginal delivery. Once delivery has occurred, spontaneous reversal of the coagulopathy can be anticipated. In the opinion of one of the authors (G.S.), the advent of severe consumption coagulopathy and/or uterine inertia is an indication for intravenous therapy with aprotinin. It has been shown that such therapy will limit DIC, reverse fibrinolysis, reawaken uterine activity, and lead to rapid vaginal delivery within 6-8 hours. Aprotinin is not commercially available for clinical use in the United States. Prolongation of the abruption-delivery interval will worsen maternal prognosis. Accordingly, the advent of uterine inertia prior to complete cervical dilatation is an indication for immediate cesarean section in circumstances where aprotinin is not available. Following delivery, the physician should be on the lookout for postpartum hemorrhage, which may necessitate immediate transfusion, the administration of oxytocics, and/or uterine manipulation. Surgical intervention is rarely indicated in such cases. The patient should also be carefully observed over the ensuing days and weeks for the evolution and resolution of complications, such as renal failure, pulmonary insufficiency, and panhypopituitarism.
The etiology of PROM is multifactorial. It is clear that maternal enzymes, maturational and mechanical forces, chorionicamniotic membrane phospholipid content, collagen disruption, amniotic cell cytokines induced by fetal signals, and bacterial phospholipases and collagenases all play major and interrelated roles. It is also clear that the production of oxytocic prostaglandins is a major, if not exclusive, common pathway leading to PROM and preterm delivery. The increasing awareness of the fetal role, i.e., fetal interleukins, fetal polymorphonuclear leukocytes and type V collagenase, make this area of research ripe for further investigation. The complex host defense mechanisms and biologic variability make any universal treatment impossible. Even with a specific etiology determined, the reduced availability of pharmacologic interventions for the fetal compartment portend suboptimal success. Therefore, it appears that continued research and aggressive measures to optimize the quality and availability of prenatal care are the best foci of our efforts.
Although endothelin-1 is synthesized by human amnion, its physiologic role and its ability to be transferred to myometrium for oxytocic action remain unclear. We investigated the transfer of endothelin-1 itself and the effects of endothelin-1 on the transfer of tritiated water across human amnion or amnion/chorion/decidua in vitro with an Ussing chamber technique. Permeability coefficients (mean +/- standard error) for 3H2O across amnion/chorion/decidua in the fetal to maternal direction were 1.26 +/- 0.21 and 1.25 +/- 0.10 x 10(-4) cm/second (N = 6) and in the maternal to fetal direction 0.90 +/- 0.07 and 0.98 +/- 0.15 x 10(-4) cm/second (N = 5) in the absence or presence, respectively, of 10(-9) mol/L endothelin-1 in the fetal reservoir. Comparable values were found in either direction with 10(-9) mol/L endothelin-1 in the maternal reservoir. Apparent permeability coefficients for 125I endothelin-1 in the fetal to maternal direction were 3.34 +/- 0.79 and 2.43 +/- 0.68 x 10(-5) cm/second (N = 5) for amnion or amnion/chorion/decidua. However, appreciable trapping of 125I endothelin-1 by the fetal membranes was apparent. Endothelin-1 does not appear to affect water movement across the human fetal membranes, and only a small proportion of endothelin-1 itself is transferred across the membranes.
OBJECTIVE: To assess the effects of oxytocin bolus or infusion on maternal hemodynamics in the third stage of labor. METHODS: In a randomized, double-blind, double-dummy fashion, 99 women received an intravenous oxytocin bolus (10 IU push) and 102 women received an infusion (10 IU in 500 mL saline at 125 mL/h) at delivery of the anterior shoulder. Mean arterial pressure and heart rate were measured every minute for 10 minutes, then every 5 minutes for the next 20 minutes. These serial measurements were analyzed using a 2-factor analysis of variance for repeated measures. RESULTS: Serial mean arterial pressure measures varied significantly between groups (interaction effect, P = .002). Mean arterial pressure (+/- standard deviation) nadirs were reached after 10 minutes, 80.9 (+/- 11.0) mm Hg in the bolus group compared with 77.0 (+/- 12.1) mm Hg in the dilute infusion group. The mean difference (95% confidence interval) between groups was 4.0 (0.7-7.2) mm Hg. Serial heart rate measures also varied between groups (interaction effect, P < .001). Mean heart rate (+/- standard deviation) peaked 1 minute after the oxytocin infusion, 115 (+/- 27) beats per minute (bpm) in the bolus group compared with 109 (+/- 21) bpm in the dilute infusion group. The mean difference (95% confidence interval) between groups was 6.6 bpm (-0.1 to 13.3). The dilute oxytocin infusion group experienced a greater mean estimated blood loss (423.7 mL compared with 358.1 mL, P = .029, t test), increased use of additional oxytocics (35.3% compared with 22.2%, P = .044, Fisher exact test) and a greater drop in hemoglobin (admission minus postpartum) (17.4g/L compared with 11.4g/L, P = .002, t test) compared with the oxytocin bolus group. CONCLUSION: Bolus oxytocin of 10 IU is not associated with adverse hemodynamic responses and can safely be administered to women with intravenous access in the third stage of labor for postpartum hemorrhage prophylaxis. LEVEL OF EVIDENCE: I.
OBJECTIVE: To determine the benefit of membrane sweeping at initiation of labor induction in conjunction with formal methods of labor induction. METHODS: Two hundred seventy-four women at term with a singleton fetus in cephalic presentation and intact membranes were randomly assigned to receive membrane sweeping or no membrane sweeping at initiation of formal labor induction with either dinoprostone pessary or amniotomy. Outcome measures included mode of delivery, induction-to-delivery interval, dinosprostone dose, any oxytocin use and duration of oxytocin use in labor, visual analog score for pain associated with sweeping, and visual analog score for satisfaction with the birth process. RESULTS: Two hundred sixty-four women (136 sweep and 128 no sweep) had their data analyzed. Ten women (4 sweep and 6 no sweep) were excluded because of exclusion criteria infringements. Swept women had higher spontaneous vaginal delivery rate (69% compared with 56%, P = .041), shorter induction to delivery interval (mean 14 compared with 19 hours, P = .003), fewer that required oxytocin use (46% compared with 59%, P = .037), shorter duration of oxytocin infusion (mean 2.6 compared with 4.3 hours, P = .001) and improved visual analog score for birth process satisfaction (mean 4.0 compared with 4.7, P = .015). The reduction in dinoprostone dose used (mean 1.2 compared with 1.3, P = .082) was not significant. Postsweeping visual analog score for pain (mean 4.7 compared with 3.5, P < .001) was significantly increased. CONCLUSION: Membrane sweeping at initiation of labor induction increased the spontaneous vaginal delivery rate, reduced oxytocic drug use, shortened induction to delivery interval, and improved patient satisfaction. LEVEL OF EVIDENCE: I.
We studied 86 primiparous women with uncomplicated pregnancy and labour requesting extradural analgesia in labour. All the women were over 36 weeks of gestation with a cephalic-presenting singleton fetus. The women were allocated randomly to two groups: group A, who received an extradural infusion of lignocaine 0.75%, after an initial dose of 10 ml of lignocaine 1.5%, and group B, who received an infusion of bupivacaine 0.125% after an initial dose of 10 ml of bupivacaine 0.25%. All the women had their labour actively managed. Assessment of analgesia during labour and delivery, and the requirements for additional top-ups were noted, as were mode of delivery, requirement for oxytocic augmentation and incidence of fetal distress. Maternal and umbilical cord plasma concentrations of lignocaine were measured at delivery in 12 women receiving extradural lignocaine. There were no statistically significant differences between the two groups in terms of the mode of delivery, incidence of fetal distress, fetal heart rate abnormalities, or Apgar scores of the babies. Women in the bupivacaine group had a significantly better quality of analgesia during both the first and second stages of labour (p = 0.0005) and required fewer top-ups than those in the lignocaine group. However, the requirement for oxytocin augmentation during the first and second stages of labour was significantly less in the lignocaine group (p = 0.004). Similarly, the duration of the second stage was shorter compared with the bupivacaine group. In spite of high plasma concentrations of lignocaine, no side effects were noted in either mothers or babies.
[D-alle3]-retro-D-deaminotocinamide (I), retro-L-deaminotocinamide (III) and their respective N-formyl derivatives (II and IV) were synthesized by the stepwise active ester method: deaminotocinamide was prepared by the solid-phase method. The retro-analogs of deaminotocinamide, tested at concentrations up to 10)-5)M, were found to be without activity as agonists or antagonists in the oxytocic assay. At 10(-4)M,[D-alle]-retro-D-deaminotocinamide is a weak competitive inhibitor of oxytocin. [D-alle3, Gly7]-retro-D-deaminooxytocin (V) was synthesized either by the active ester method or by a fragment condensation method employing the retro-D-RING, [D-alle3]-retro-D-deaminotocinamide, and D-tail, Boc-Gly-D-Leu-Gly, as the fragments...
The neurohypophyseal hormones of three species of Australian marsupials belonging to the family Macropodidae (Macropus rufus, Macropus giganteus, Macropus robustus) have been investigated. In these species three active peptides have been disclosed, one with oxytocic activity and two with pressor activity. The three hormones are present in all the individual glands which have been examined. Purification has been undertaken by ion-exchange chromatography and paper chromatoelectrophoresis. The more abundant of the pressor hormones (about 80% of the total pressor activity) has been identified as lysine-vasopressin by its biological properties, its chromatographic behaviour and its amino acid composition. The second pressor principle, more basic, has not yet been chemically characterized but its pharmacological properties and its chromatographic behaviour suggest that it is closely related or identical to arginine-vasopressin. Dimorphism of vasopressins seems peculiar to Metatheria since it has not been observed in Protheria and very rarely in Eutheria.