Synthetic Analogues Of Oxytocin Research Articles

The effect of carbetocin on the mammary gland of pigs

Carbetocin (deamino-1-monocarba-(2-Omethylthyrosine)-oxytocin) refers to a prolonged-acting, synthetic analogue of oxytocin, has pharmacodynamic properties similar to natural oxytocin. Drugs containing carbetocin have been used in the pathology of childbirth and the postpartum period. However, there is limited information in the literature on the effect of this pharmacological agent on the mammary gland of animals. The aim of the presented experimental work was to study the effect of carbetocin on the mammary gland of sows in the postpartum period. The studies were performed on the main sows in the early postpartum period. According to the principle of analogues, the animals were divided into 2 groups: experimental and control. Carbetocin was parenterally administered to sows of the experimental group at a dose of 0.07 mg with an interval of 24 hours, and uterotonic agents were not used in the control group. In animals of the experimental group, the time of induced secretion of breast secretions after administration of cabetocin was recorded. The concentration of immunoglobulins in colostrum (milk) of all studied animals was determined using a Brix refractometer. It was found that after carbetocin injection, the average duration of excretion of mammary gland secretions in sows had no significant differences during 1 and 2 days after delivery and amounted to 363.00±8.40 and 355.50±8.51 minutes, respectively. Its free release in animals occurs within 4-7 hours after administration of a prolonged oxytocin analog. The use of carbetocin in sows in the postpartum period does not lead to an increase in the amount of immunoglobulins in colostrum or transitional milk, regardless of the proportion of the mammary gland. At the same time, a significant decrease in immune proteins is recorded after 24 hours to the initial level.

SAFETY, EFFICACY AND ADVANTAGES OF PROPHYLACTIC USE OF SINGLE DOSE OF INTRAVENOUS CARBETOCIN DURING CAESAREAN DELIVERY FOR PREVENTION OF PPH: AN OBSERVATIONAL STUDY AT A TERTIARY CARE HOSPITAL.

Background: Postpartum Haemorrhage is the leading cause of maternal mortality and morbidity in India with 38 % maternal deaths caused by it. Although most healthy women can cope well with blood loss after birth, some do not, and this can pose a serious risk to their health and even life. To reduce blood loss after birth, the routine administration of a drug to contract the uterus (uterotonic) has become standard practice across the world. We have developed numerous drugs which can be given prophylactically to prevent PPH and each of them have some advantages and disadvantages. The newest one is Carbetocin which is a long-acting synthetic oxytocin analogue with half-life of 40 minutes. Uterine contractions occur in less than 2 minutes after a single intravenous dose of 100microgram of Carbetocin. The present study was done to analyse safety, efcacy, and advantages of the Carbetocin, when administered to pregnant women at the time of caesarean delivery as a prophylaxis post-partum haemorrhage. Material and Methods: 200 pregnant women admitted for delivery at tertiary care hospital, who underwent caesarean section, both elective and emergency were included in the study. Inj Carbetocin, heat stable preparation ,100 mcg was diluted in 10 ml distilled water and given slow IV over 1 minute to all pregnant women at the time of caesarean section immediately after delivery of baby. Results: 84% of women had no atonic PPH and did not need any additional uterotonic drug for PPH. Remaining 16 % women who needed additional drugs for control of PPH had one or more risk factors responsible for PPH Conclusion: Single dose of 100 mcg IV Carbetocin is a safe and good drug for prophylactic use in pregnant women undergoing caesarean section for prevention of atonic PPH. Side effects are very less, advantages are many and overall results are promising.

Non-invasive method of obtaining milk from mice using carbetocin, a synthetic analogue of oxytocin

IntroductionThe mouse is an important laboratory animal in pharmacological and toxicological research. However, there is a limited ability to analyse the penetration of tested substances in mouse breastmilk, which is technically difficult to obtain in sufficient quantities. The aim of the study is to verify the use of carbetocin for this purpose. MethodsThe effect of carbetocin (20 and 40 μg per animal) was tested in nursing ICR females that had milk collected for 15 min, started 1.5 min after administration. At a higher dose, carbetocin was also tested with a 20-min collection, started 7 min after application. Oxytocin (2 IU per animal) and saline were used as positive and negative controls, respectively. ResultsMilk yield using a lower dose of carbetocin was comparable to oxytocin. However, the duration of action of carbetocin was longer than that of oxytocin. A higher doses of carbetocin resulted in significantly higher milk volumes. DiscussionThe use of carbetocin has proven to be an effective non-invasive method to obtain up to 0.89 g of milk from one mouse in 20 min.

CARBETOCIN VERSUS COMBINED OXYTOCIN AND METHERGINE FOR PREVENTION OF POSTPARTUM HEMORRHAGE AFTER VAGINAL DELIVERY IN HIGH RISK PREGNANCY

Background: Around the world, one woman every minute dies as a result of postpartum hemorrhage (PPH) and it remains the single major cause of maternal mortality and morbidity. The early identification of risk factors and effective prevention and management of PPH are critical to minimize the impact of PPH. Carbetocin, a new drug for the prevention of uterine atony, is a synthetic analogue of oxytocin with a half-life of up to 4 to 10 times longer than that of oxytocin. In comparison with oxytocin, it is used as a single-dose injection instead of an infusion and can be given intravenously or intramuscularly. Objective: To evaluate the effect of carbetocin in preventing postpartum hemorrhage after vaginal delivery in comparison with combined oxytocin and methergine. Patients and methods: This study was conducted at Al-Galaa Maternity Hospital during the period from 1 June to 1 December 2020. The study included 100 candidates between 37 to 40 weeks with a risk factor to develop PPH divided randomly into two equal groups: Group A received a single 100 mg IM dose of carbetocin (Pabal®) and Group B received 5 IU IM oxytocin (Syntocinon®) combined with 1 mL, 0.2 mg IM methylergonovine maleate (Methergine®). Results: Carbetocin was more effective, with significant difference, in reducing the time of 3rd stage of labor, reducing amount of blood loss and drop of both HB% and hematocrit levels with significant decreased incidence of side effects. Conclusion: A single 100 mg IM dose of carbetocin (Pabal®) may be more effective as compared to 5 IU IM oxytocin (Syntocinon®) combined with 1 mL, 0.2 mg IM methylergonovine maleate (Methergine®) in reducing postpartum blood loss with a smaller drop in hemoglobin levels.

Carbetocin at Elective Cesarean Section: A Sequential Allocation Trial to Determine the Minimum Effective Dose in Obese Women

(Anaesthesia. 2020;75:331–337) Uterotonics are widely used in cesarean deliveries to prevent postpartum hemorrhage, which can cause maternal death or severe morbidity. Obesity, among other factors, has been implicated as a contributing factor to the rise in atonic postpartum hemorrhage in developed countries. The use of carbetocin, a synthetic oxytocin analogue, is associated with a reduced need for uterotonics in cesarean deliveries. While previous studies found 90% effective dose (ED90) of carbetocin for women with a body mass index (BMI) <40 kg/m2, none have addressed the ED90 for obese women. This study aimed to find the ED90 of carbetocin in women with a BMI ≥40 kg/m2 undergoing elective cesarean delivery.

Discovery of peptide probes to modulate oxytocin-type receptors of insects

The oxytocin/vasopressin signalling system is conserved across the animal kingdom. In insects, the role of oxytocin-type (inotocin) neuropeptides has only been studied in locusts, beetles and ants, but their physiology continues to be poorly understood. One reason for this knowledge deficit is the lack of available research tools to complement functional genomics efforts. Consequently, ligands to probe insect inotocin receptors are essential. In this study, we sought to identify novel agonists and antagonists of the inotocin receptor from the representative model species Tribolium castaneum and Lasius niger. Drawing upon known ligands of the human receptors, we examined the pharmacology of the plant-derived cyclotide kalata B7 and the synthetic oxytocin analogue atosiban. Kalata B7 is a weak partial agonist of both inotocin receptors. This is the first reported direct interaction of cyclotides with an insect receptor, an observation that may explain their presumed role in herbivore defence. Furthermore, we discovered atosiban is an antagonist of the Tribolium receptor, which may provide a useful probe to investigate the functionality of inotocin signalling in beetles and related insect species. Our findings will enable further examination of insect inotocin receptor pharmacology and physiology, and may trigger studies to comprehend the interaction of plant cyclotides and insects.

Efficacy and Safety of Carbetocin Given as an Intravenous Bolus Compared With Short Infusion for Caesarean Section: Double-blind, Double-dummy, Randomized Controlled Noninferiority Trial

(Br J Anaesth. 2017;118(5):772–780) Uterotonic drugs, such as oxytocin, are given after cesarean section (CS) to help maintain uterine tone. It is recommended that these drugs be administered as a short, rapid infusion rather than a bolus, so as to minimize adverse side effects. However, there are no trial designs that show noninferiority of uterine tone using a slower mode of drug administration. Carbetocin is a synthetic oxytocin analogue with the same mechanism of action and side effects as oxytocin but with a longer half-life. The authors of the present study investigated the efficacy of a 100 mcg carbetocin dose on uterine contractility administered as a short, rapid infusion compared to a slow manual injection.

Carbetocin versus Oxytocin for the Prevention of Postpartum Haemorrhage

Postpartum haemorrhage is the leading cause of maternal mortality worldwide. Total 67-80% of cases are caused by uterine atony. Preventive measures include prophylactic drug use to aid uterine contraction after delivery, thus avoiding severe blood loss and reducing maternal morbidity and mortality. Carbetocin is a synthetic analogue of oxytocin with a long half-life which ensure more effective contraction and less adverse effects. It can be administered as a single dose injection either intravenously or intramuscularly rather than as an infusion over several hours as is the case with oxytocin. Carbetocin is currently indicated for prevention of uterine atony after delivery by caesarean section in spinal or epidural anaesthesia. A reduced need for additional uterotonics was observed with carbetocin vs. oxytocin in high-risk women and carbetocin was at least as effective as syntometrine in low-risk women. Carbetocin is effective treatment for the prevention of postpartum haemorrhage not only following caesarean delivery but also after vaginal delivery in high-risk women and those who suffer from hypertensive disorders in pregnancy. Further research is required to assess whether prophylactic carbetocin is superior to conventional uterotonic agents following vaginal delivery in low-risk women.Faridpur Med. Coll. J. Jul 2015;10(2): 76-83

Natriuretic properties of [2-p-ethylphenylalanine] deamino-6-carba-oxytocin (Nacartocin) in cats.

Nacartocin, a synthetic analogue of oxytocin, [2-L-p-phenylalanine]deamino-6-carba-oxytocin has a specific natriuretic effect in cats. The doses of 0.05-10 micrograms/kg b.w. (0.05-10 nmols/kg) of Nacartocin applied i.v. caused a several fold increase in the excretion of sodium, while the excretion of kalium was only slightly enhanced.

Ascending dose tolerance study of intramuscular carbetocin administered after normal vaginal birth

Objective: To determine the maximum tolerated dose (MTD) of carbetocin (a long-acting synthetic analogue of oxytocin), when administered immediately after vaginal delivery at term. Materials and methods: Carbetocin was given as an intramuscular injection immediately after the birth of the infant in 45 healthy women with normal singleton pregnancies who delivered vaginally at term. Dosage groups of 15, 30, 50, 75, 100, 125, 150, 175 or 200 μg carbetocin were assigned to blocks of three women according to the continual reassessment method (CRM). Results: All dosage groups consisted of three women, except those with 100 μg ( n=6) and 200 μg ( n=18). Recorded were dose-limiting adverse events: hyper- or hypotension (three), severe abdominal pain (0), vomiting (0) and retained placenta (four). Serious adverse events occurred in seven women: six cases with blood loss ≥1000 ml, four cases of manual placenta removal, five cases of additional oxytocics administration and five cases of blood transfusion. Maximum blood loss was greatest at the upper and lower dose levels, and lowest in the 70–125 μg dose range. Four out of six cases with blood loss ≥1000 ml occurred in the 200 μg group. The majority of additional administration of oxytocics (4/5) and blood transfusion (3/5) occurred in the dose groups of 200 μg. All retained placentae were found in the group of 200 μg. Conclusion: The MTD was calculated to be at 200 μg carbetocin.

Uterine blood flow and myometrial activity at menstruation, and the action of vasopressin and a synthetic antagonist.

Local endometrial blood flow was measured by a thermistor technique and myometrial activity by intrauterine pressure recording in 10 women before and during menstruation. The effect of lysine vasopressin infusion (1 pmol/kg body-weight per min) and of bolus injection of a synthetic oxytocin analogue, 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin (10 nmol/kg body-weight), were studied. Spontaneous variations in blood flow were seen synchronous with clearly demarcated uterine contractions, the myometrial activity being significantly increased in early (day -1 to day +2) compared with late (day +3 to day +5) menstrual phase. The vasopressin infusion decreased blood flow, stimulated uterine activity and caused slight to moderate dysmenorrhoea-like pain. These effects were completely inhibited by the injection of the oxytocin analogue. In-vitro studies on uterine arteries confirmed that the analogue also inhibited the vasopressin-induced constriction of the uterine arteries. This antagonist was more effective than two other analogues, 1-deamino-2-D-Tyr(OEt)-4-Val-8-Orn-oxytocin and 1-deamino-2-Tyr(OEt)-oxytocin. The counteracting effect of 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin on the vasopressin-induced decrease of blood flow and increase of contractions supports the therapeutic value of the drug in primary dysmenorrhoea and preterm labour.

Inactivation of oxytocin and synthetic oxytocin analogues by hen tissues.

SUMMARY The oxytocin-inactivating activity (OIA) of liver, kidney, uterus, pancreas, spleen and duodenum homogenates of hens was studied. The first-order constant of oxytocin inactivation was higher in the liver and pancreas than in the uterus and kidney or in the duodenum and spleen. Using synthetic analogues of oxytocin (deamino-oxytocin, deamino-carba1-oxytocin and carba1-oxytocin the mechanism of enzymic inactivation of oxytocin by hen tissue was investigated. Enzymic hydrolysis by the CH2-terminal cleavage was most marked in duodenum (about 86% OIA) and kidney (54·8% OIA). Reduction of the disulphide bridge was most marked in the uterus (about 80% OIA) and pancreas (about 73% OIA). Splitting by non-specific aminopeptidases after reduction of the disulphide bridge occurred mainly in the liver (72% OIA) and in the spleen (44% OIA).

Characterization of a Proposed Oxytocin Receptor in Rat Mammary Gland

Abstract [3H]Oxytocin, incubated with mammary tissue from the lactating rat, was bound specifically to three particulate fractions obtained by homogenization and centrifugation at 1,000, 20,000, and 105,000 x g. Radioactivity in the cytosol appeared to be unbound oxytocin, as determined by gel filtration on Sephadex G-100. Oxytocin was distributed about equally among the three particulate fractions and could not be correlated with either the amount of protein or the enzymes putatively characteristic of cell membranes, mitochondria, or microsomes. [3H]Oxytocin, added directly to particles sedimenting between 1,000 and 20,000 x g, was bound with an apparent Kd of 7.6 x 10-10 m under optimal conditions; 0.28 pmole of oxytocin was bound per mg of protein. Binding was maximal in 1 hour at 20°. The affinities of synthetic analogues of oxytocin, [4-threonine]oxytocin g oxytocin g [8-valine]oxytocin g [8-lysine]vasopressin g [4-proline]oxytocin, paralleled their milk-ejecting activities in rat mammary tissue. [3H]Oxytocin did not appear to be metabolized during incubation. Binding was enhanced by Mn2+ and Co2+ g Mg2+ g Zn2+ and was absent in the presence of 1 mm ethylenediaminetetraacetate. Ca2+, 50 mm, did not affect binding nor did 100 mm NaCl, LiCl, or KCl. Binding in 50 mm Tris-maleate buffer, containing 20 mm Mn2+, was optimum at pH 7.6. Trypsin depressed binding about 30%; phospholipases A, C, and D and neuraminidase did not. Sulfhydryl reagents such as N-ethylmaleimide and iodoacetate did not inhibit binding whereas p-hydroxymercuribenzoate did. Butanedione and sodium fluoride did not affect binding. Binding was markedly depressed by 1 mm ATP but not by guanosine triphosphate, cytosine triphosphate, hypoxanthine triphosphate, or uridine triphosphate. The binding material in the 20,000 x g particles of mammary tissue presumably is part of the oxytocin-receptor system because binding specificity paralleled biological specificity, and the high affinity of the binding sites for oxytocin is commensurate with physiological levels of the hormone. The receptor must be a protein, at least in part, because of its susceptibility to trypsin and p-hydroxymercuribenzoate.

Some pharmacological properties of a synthetic oxytocin analogue [1-N-carbamoyl-hemicystine-2-O-methyltyrosine]-oxytocin (carbamoyl-methyloxytocin), an antagonist to the neurohypophysial hormones.

1. A synthetic oxytocin analogue, [1-N-carbamoyl-hemicystine-2-O-methyltyrosine]-oxytocin (carbamoyl-methyloxytocin), has been tested as an antagonist to the actions of oxytocin and vasopressin on the uterus, the mammary gland and blood pressure.2. The analogue inhibited the response of the isolated rat uterus to both oxytocin and vasopressin without itself stimulating the uterus to contract. The responses to equipotent doses of oxytocin and vasopressin were inhibited equally. There was little or no inhibition of the response to bradykinin. carbachol, angiotensin or 5-hydroxytryptamine with doses of the analogue up to 160 times that required to inhibit the response to oxytocin by 50%. The analogue caused a parallel displacement of the log dose-response curve for oxytocin; the pA(2) value (2 min contact) varied from 6.4 to 7.1 according to the ionic composition of the solution in the organ bath.3. The analogue inhibited the response of the rat uterus in situ to oxytocin but not to angiotensin or 5-hydroxytryptamine. It did not stimulate the uterus.4. When, in certain experimental conditions, spontaneous activity occurred in the isolated uterus or the uterus in situ, this activity was unaffected by the analogue but the increase in amplitude and frequency of contractions caused by oxytocin was inhibited. The regular rhythm of contractions induced in the quiescent uterus by the intravenous infusion of oxytocin was interrupted by intravenous injections of the analogue.5. The response of the isolated strip of rat mammary gland to the analogue depended on whether or not magnesium was present in the bath solution. In the presence of this ion, the analogue generally caused an increase in tension; in its absence, it acted as a pure antagonist. As on the isolated uterus, oxytocin and vasopressin were equally inhibited, and the analogue caused a parallel displacement of the log dose-response curve for oxytocin. With 0.9 mM Ca and 1.0 mM Mg, the mean pA(2) value (2 min contact) was 6.28 +/- 0.08 (S.E.)6. In the lactating rat, the analogue inhibited the milk-ejection response to oxytocin and vasopressin but not that to acetylcholine, bradykinin or 5-hydroxytryptamine. A milk-ejection response to the analogue itself was seen occasionally with retrograde arterial but not with intravenous injections.7. The analogue inhibited the avian depressor response to oxytocin and the rat pressor response to vasopressin.8. On all assay preparations, the degree of inhibition caused by the analogue was dependent on the dose, and the inhibition could be surmounted by increasing the dose of agonist. Recovery usually occurred within 15 min. These features, together with the parallel displacement of the dose-response curve for oxytocin on the isolated uterus and mammary strip, and the equal inhibition of the responses to oxytocin and vasopressin, suggest that carbamoyl-methyl-oxytocin acts as a specific competitive inhibitor of the neurohypophysial hormones.9. The structure-activity relationships of analogues of oxytocin having substituents in the terminal amino and phenolic hydroxyl groups, and some practical applications of the carbamoyl-methyl analogue, are discussed.

Isolation and Characterization of a Hormone-binding Polypeptide from Pig Posterior Pituitary Powder

A large polypeptide has been isolated from acetone powder of pig posterior pituitary tissue by the methods of percolation, gel filtration on Sephadex G-25 and G-50, and ion exchange chromatography on diethylaminoethyl cellulose. The purified polypeptide appears to be homogeneous by the criteria of electrophoresis on paper and starch gel, column and paper chromatography, ultracentrifugation, and amino acid analysis. It consists of 89 amino acid residues with a molecular weight of 9170. The purified peptide contains all of the usual amino acids except histidine and tryptophan. There are 14 glycyl, 13 glutamyl, 7 seryl, 7 alanyl, 7 leucyl, 6 prolyl, 6 cystinyl, 5 argininyl, 5 aspartyl, 3 phenylalanyl, and 1 or 2 of each of the other residues. Its isoelectric point is estimated to be about pH 5.8. It is devoid of pressor and oxytocic activity but has the ability to bind lysine vasopressin, oxytocin, and synthetic analogues of oxytocin. However, the performic acid-oxidized polypeptide fails to bind either lysine vasopressin or oxytocin.

Synthetic analogues of oxytocin: an approach to problems of hormone action.

Synthetic organic chemistry has in recent years become a recognized participant in the study of hormone action. Although the synthetic approach is capable of yielding copious information about the relation between chemical structure and biological activity and thereby, in principle, it can aid in exploring the molecular basis of hormone action, the results obtained by this approach are by no means unambiguous. For one thing, the great conformational flexibility of peptide chains makes it difficult to estimate the overall effect of a change in chemical structure on the topochemistry of the molecule in that conformation which it adopts in its interaction with a particular receptor site. Furthermore, the complexity of biological systems capable of showing a response to the hormones or their analogues is such that this response cannot, as yet, be confidently interpreted in terms of molecular interactions. A generalized scheme of hormonal regulation in the intact organism is shown in figure 5; an exogenously introduced hormonal peptide will bypass the stages of biosynthesis and release (though it might conceivably operate feedback mechanisms where these exist), but its behaviour in each subsequent stage of the system will be affected by its chemical and physical properties. Any change in the structure of the peptide is therefore likely to modify its interactions at several or all of these stages and the change in overt response will represent the complex results of these modified interactions. To some extent the effect on the individual stages can be distinguished by working with biological preparations of varying complexity, from the whole organism to isolated tissues; but even the simplest tissue preparations are still biochemically very complicated systems in which the receptor molecules have yet to be identified. On the other hand, any stage of the whole process of hormonal regulation is a fair target for attempts to achieve modified biological properties by structural variations, and this paper will be concerned with illustrating these possibilities, using examples from our work on neurohypophysial hormone analogues.

The action of oxytocin and synthetic analogues on the isolated mammary-gland myoepithelium of the lactating rat; effect of some ions.

SUMMARY The contractile response of mammary-gland strips from lactating rats to oxytocin varied with the concentration of calcium ions in the organ bath; calcium could be partially substituted by strontium but not by magnesium. High concentrations of potassium did not substantially affect the response to oxytocin. In these and several other respects the mammary gland myoepithelium resembles uterine smooth muscle, notwithstanding the differences in morphology and embryonal origin. The effects of 12 synthetic analogues of oxytocin modified in sequence positions 1, 2, and 3 of the peptide chain on the rat mammary-gland strip were examined. None of the analogues showed a higher potency than oxytocin. However, the mammary-gland strip was less sensitive to the structural changes represented in this series of analogues than the rat uterus in vitro. The action of some of the analogues on the mammary-gland strip differs from that of oxytocin in the time-course of the response.

The antagonism of disulphide polypeptides by thiols.

British Journal of Pharmacology and ChemotherapyVolume 25, Issue 2 p. 418-431 Free Access THE ANTAGONISM OF DISULPHIDE POLYPEPTIDES BY THIOLS P. J. MARTIN, P. J. MARTIN Department of Pharmacology, University College, LondonSearch for more papers by this authorH. O. SCHILD, H. O. SCHILD Department of Pharmacology, University College, LondonSearch for more papers by this author P. J. MARTIN, P. J. MARTIN Department of Pharmacology, University College, LondonSearch for more papers by this authorH. O. SCHILD, H. O. SCHILD Department of Pharmacology, University College, LondonSearch for more papers by this author First published: October 1965 https://doi.org/10.1111/j.1476-5381.1965.tb02061.xCitations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL REFERENCES Boyer, P. D. (1958). Sulphydryl and disulphide groups of enzymes. In The Enzymes, vol. 1, p. 511. New York: Academic Press. Dyke, H. B. van, Chow, B. P., Greep, R. O. & Rothen, A. (1942). The isolation of a protein from the pars neuralis of the ox pituitary with constant oxytocic pressor and diuresis-inhibiting activity. J. Pharmacol. exp. Ther., 74, 190– 209. Edman, K. A. P. & Schild, H. O. (1962). The need for calcium in the contractile responses induced by acetylcholine and potassium in the rat uterus. J. Physiol. (Lond.), 161, 424– 441. Eldjarn, L. & Pihl, A. (1957). On the mode of action of x-ray protective agents. II. Interaction between biologically important thiols and disulphides. J. biol. Chem., 225, 499– 510. Evans, D. H. L., Schild, H. O. & Thesleff, S. (1958). Effects of drugs on depolarized plain muscle. J. Physiol. (Lond.), 143, 474– 485. Fastier, F. N. & Smirk, F. H. (1942). The circulatory effects of some iso-thiourea derivatives with special reference to the sensitization of animals to the pressor action of adrenaline. J. Physiol. (Lond.), 101, 379– 388. Foss, O. (1961). Ionic Scission of the Sulfur-Sulfur Bond, vol. 1. Oxford: Pergamon Press. Guttman, S., Jaquenoud, P. A. & Boissonas, H. A. (1957). Ein Nonapeptid mit oxytocin hemmenden Eigenschaften. Naturwissenschaften, 44, 632– 633. Kolthoff, I. M. & Harris, W. K. (1946). Amperometric titration of mercaptans with silver nitrate. Ind. Eng. Chem. Anal. Ed., 18, 161– 169. Martin, P. J. & Schild, H. O. (1962). Effects of thiols on oxytocin and vasopressin receptors. Nature (Lond.), 196, 382– 383. Martin, P. J. & Schild, H. O. (1964). Pharmacological antagonism between SH compounds and S-S polypeptides. Proc. 2nd Int. Pharmacol. Meeting. Prague, 10, 109– 116. Rudinger, J. & Jost, K. (1964). A biologically active analogue of oxytocin not containing a disulfide group. Experientia (Basel), 20, 570– 571. Rudinger, J. & Krejci, I. (1962). Dose-response relations for some synthetic analogues of oxytocin, and the mode of action of oxytocin on the isolated uterus. Experientia (Basel), 18, 585– 588. Sanger, F. (1953). A disulphide interchange reaction. Nature (Lond.), 171, 1025– 1026. Schild, H. O. (1942). A method of conducting a biological assay on a preparation giving repeated graded responses illustrated by the estimation of histamine. J. Physiol. (Lond.), 101, 115– 130. Schwartz, I. L., Rasmussen, H., Schoessler, M. A., Silver, L. & Fong, C. T. O. (1960). Relation of chemical attachment to physiological action of vasopressin. Proc. nat. Acad. Sci. (Wash.), 46, 1288– 1298. Smith, M. W. (1961). Some properties of rat mammary tissue. Nature (Lond.), 190, 541– 542. Citing Literature Volume25, Issue2October 1965Pages 418-431 ReferencesRelatedInformation

Active neurohypophysial principles from a cyclostome ( Petromyzon marinus) and two cartilaginous fishes ( Squalus acanthias and Hydrolagus collei)

Fractions containing oxytocic activity have been separated by ion-exchange column chromatography from pituitary extracts from marine lampreys, spiny dogfish, and ratfish. The biological properties of the isolated components indicate that arginine vasotocin occurs in all three species. No other principle could be detected in the lamprey extract. The dogfish extract contained a neutral oxytocin-like principle (EOP I). This differs pharmacologically from all natural principles of known structure and from all the synthetic analogues of oxytocin to which it could be compared. The ratfish extract contains a principle with properties indistinguishable from those of oxytocin. An attempt is made to relate the apparent phyletic distribution of active neurohypophysial peptides in fishes to their evolutionary history.

Effects of the estrous cycle on the sensitivity of rat uterus to oxytocin and desamino-oxytocin.

The sensitivity of the isolated rat uterus to oxytocin and the USP Standard has been found to undergo a cyclic change according to the estrous cycle. The sensitivity of the tissue is lowest at metestrus, and from there it increases progressively during the successive stages of the estrous cycle, reaching the peak at estrus. When desaminooxytocin, a synthetic analogue of oxytocin, is tested on the rat uterus, a similar cyclic change is observed. However, the increase in sensitivity as the uterus approaches estrus is greater to oxytocin and the USP Standard than to desamino-oxytocin. This difference in sensitivity markedly affects the oxytocic potency values obtained for desamino-oxytocin when it is assayed against either oxytocin or the USP Standard on uteri at different stages of estrus. The calculated values for units per mg of oxytocic activity of desaminooxytocin on the basis of the USP Standard are: 771 ±36 at diestrus, 564 +17 at proestrus, 551 ±17 at estrus and 899 ±24 at metestrus.