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·RECENT PROGRESS IN OXYTOCIN RESEARCH

·Publication Aumber 360
AMERICAN LECTURE SERIESE
A Monograph on
AMERICAV LECTURES IY BIOCHEMISTRY AND BIOPHYSICS
Fdited by
W BLADERGROEN, IR (DELFT). MA, PMD (BASLE)
Sandoz Lid, Hasle, Suitzerland

·RECENT PROGRESS
IN
OXYTOCIN RESEARCH
B. BERI)E. 1.1).
Pharmacological Laboratory
Sandoz Lut
Basle, Switzerland
PUBLISHER
CHARLES C THOMAS
Springfield Illinois
+
•
U.S.d.

·CHARLES CIHOVAS · PUBLISHER
BINNERSTON Hous
301-327 East Lawrence Avenue, Springfiekel, Illinois, USA
Published smultaneously in the British Commonwealth of Nations by
BLACHIT SCIENTIFIC PUBLICATIONS, IT!, OXFORD, EVID
Published simultaneously in Canada by
THE RIFRSO PRESS, TORONTO
I his book is protected by copyright Yo
part of it may be reproduced in any manner
without written permission from the publisher
© 1959, by CHIRLES C THOVAS. PUBLISHER
Library of Congress Catalog Card Number 59 8190
With THOMAS BOOKS careful attention is given to all details of manu
facturmg and design It is the Publishers desire to present looks that all
Satisfactory as to their physical qualities and artistic possibilities and
appropriate for their particular use THOMAS BOOKS will be true to
those lans of qualits that assured good name and good will
Posted in the United States of door

·Science is al no moment quite right,
but it is seldom quile urong.
Bertrand Russell

·CHIRIES CIHOVAS.PUBLISEIFR
BINAFRSTONL House
301-327 East Lawrence Avenue, Springfield Illinois, ('SA
Publisher simultaneously in the Britsh Commonu'enlth of Nations by
BLACHFIL SCIENTIFIC PURT ICATIONS, ITD, OYFORD, EXCI 4WD
Published simultaneously in Canada by
THE RIFRSO PRYS, TORONTO
This book is protected by copyright
part of it may be reproduced in any manner
without written permission from the publisher
© 1959, by CHARI ESC THONIS. PL'BI ISHER
Library of Congress Catalog Card Number 59 8190
With THOMAS BOOKS careful attcution is given to all details of manu
facturing and design It is the Pul>lisher's desire to present books that are
satascas cors as to their physical qualities and artistic possibilities are
appropriate for their particular uc THOMAS BOOKS will be true to
those laws of quality that assure a good name and gond all
frunted in the United States of America

·ACKNOWLEDGMENTS Fo 'OR TH}}IR generous permission to reprocluce in this bmxol tables and figures that have appeared cleulicrc, 1 am Teatly indebted to l'rol W'. Bargmam, Dr. G. 1 Risset, of R. Caldey marcia and his colleagues, Ds, R. R. Chaudhury, Dr. SI Dicker, Dr RJ Frypairich, Prof. it ilanström, Prof G. W. Ilarris, Prof. H, Ilciler, Dr. 1. I{ild, Dr H Jung, I'rof. G. Kuschunshy and his col. laborators, Dr }, Lee, Dr H. Nessadba, Prof. W CW Nixon, Dr E. W'. Page, Prof. G. Peeters and his co- Korkers, Dr. M l'ichlord and her collcagues, Dr W. 11. Sawyer, Dr C. X. Smyth, Dr II Tuppy, Dr C. Tyler, Dr. IN Walker and Dr G. Zeiler My sincere thanks are also duc to The Royal Society of Sciences, Uppsala, Sueden, and the Society for Expermental Biology and Medicine, You York, to the Editors of the Archives internatsonales de pharmacodynamic el de thérature, the British Medical Journal, the Bratrsh Jour. nal of Pharmacology and Chemotherapy, the Helvetica physiologica et pharmacologica acla, the journal of Physiology, The Lancri and Triangle, the Saudo: Journal of Medical Science, as well as to Messrs E Arnold (Pul. fishers) Lid, London, J F Bergmann Verlag, Muspich, Buttern onths Scientific Publications, London, LA Chuchu]] Ldt. London, Springer-Verlag, Herdelberg, Springer-Verlag, Vienna, C V Mosby Company, St Louis (USA), Periodica (Publishers), Copenlagen, Williams & Within Company, Baltimore I should also hhe lo express my gratuuste to Wr. J. E Smith, BSc, for the English translation and to Miss S Ebner for typing the manuscripts B BERDE, VID

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·CONTENTS
Page
I mirodluciorv tetasis
II. Chemical structure 21: biological acts.sty of oxy
rocin and relaietl polypeptules
11) The production of oxytocin in the organism
20
IV. The face of ox11OXIN
33
V Orvocin and labout
VI Oxytorm and Lactation
131 Some other actions ol oxitocin
W Kelerences
83
Index
107

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·78** *****
} htt) 2 Lay
111 yrse Orher actions of arttorin
References
Index
Sx

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·RECENT PROGRESS IN OXYTOCIN RESEARCH

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·INTRODUCTORY REMARKS Sect the turn of the century, the lsioxhemical approach has comne to acqmre an ever greater siguficame in the field of medicine flith the new techniques of buxhenistry it lias licen possible to isolate and symlesise a large member of active sillystant c's sxeurring in the living or. ganism. Morcover the presses of normal and patho. lomual metalvolim fane been analysed and the mode of action of many wlogwally actise sulestan es has been clucidated. The informatien derived from these studies has made possible a planned search for sicu <rugs Piog. ress las not, of course, been cqually rapal 11 all fiells Whule masy amnestuns can be regarded as virtually settled, It is only in the last few years that research into the biologically active polypepuues has got properly under way, mainly because it has had to awart the refined methods of modern chemistry Sticla metluxds are gradually inahing these interesting composels accessible to clic physiologists and pliarmacologists and, indeel, a les of thern are already available to the dukjans The progress that has been made in recent years in the fickel of posterior pituitary hormones, including oxytoxin, hears witness to the great impetus that can be guen to playsłognal and clinical research by a major iwleme al avance Reviewing the most important stages in Oxytocin rescarch (Table 1), we see that the effect of posterior picuitary gland extract on the uterus was discovered in 1906 3 ·4 Recent Progress in Oxytocin Research (Dale), and its mammary gland effect shortly afterwards in 1910 (Ott and Scott) Nearly twenty years went by, however, before KAMM and his co-workers (1928) succeeded in obtaining a posterior pituitary extract, Pitocin, which consisted mainly of oxytocin, i.e., was largely, but not entirely free from vasopressin. Yet another scorc ycars passed before pure oxytocin was isolated from animal pituitary glands (LIVERMORE and Du VIGNEAUD, 1949). A TIBLE I 1906 1910 1928: SOME IMPORTANT DATES IN OU TOCIN RI SI ARCH Action of posterior pituitary extracts on the uterus-11 II Dale Action of posterior pituitary extracts on the mammary gland- I Ott and ) C Scott I posterior pitutar, extract (Pitocm) containing mail) y 1001.), re, relats els free from vasopressu-O Kamel al Isolation of pure oxytocin -A H Livermore and V Du ligne and Synthesis of oxytocin-V Du ligneaud et al Process for industrial synthesis of owsoun (Syntocinon --R Boissonnas et al Synthetic analogues of oxytocin-R Boissonnas et al. J Rudinger stal 1949 1953 1955 1956 few years later its structural formula was elucidated (Du VIGNEAUD et al, 1953c, Tuppy, 1953) and, finally, oxytocin was synthesised (Du VIGNEAUD rt al., 1953h) Du l'IG FAU'?> and his colleagues thus won the distinction of having achieved the first synthesis of a polypeptide hormone-a fitting reward for years of patient rescarch For this fine achievement, rightly bailed by the British Medical Journal as "a major triumph of the biochemists," Du VIGNEAUD was honoured with the Nobel prize for cheinistry 1 1933 In that same year a method was developed for the produc. tion of oxytocin on an industrial scale (Boissossas et al, 1955), and since February 1, 1956, the synthetic hormone has been available to the clinician under tlic trade-name of Syntocinon. The first analogues of oxytocin were like ·It&tatluroky Remax!! wise symbesiseel in 1936 ( Islay et al, 1956; Kur. INGER et al., 1950), Is the follox ing cfaplers wil} shin, thic sHccessful cluidation of the chemical aspects of the axili prols. lem was of special importance is furthering the progress that has been made it this field. It will be appropriate, therefore, s dis 18 hrst some questions relating in the chemistry of oxytocit. W'e slia}} then claimine the findings that have been fortiscoming from physiological and phar. 97acological studies and deal with some questions of clinical interest. The author has sought in trace a thread of inherence tlirough the clolton of the oxyroxcin problem over the last few years, loncier, sio atteinpt kas lyceri made 10 ginc an exhaustive review of the literature.

·II CHEMICAL STRUCTURE AND BIOLOGICAL ACTIVITY OF OXYTOCIN AND RELATED POLYPEPTIDES O. xx tocin is a polypeptide amide (DU VIGNI AUD et al., 19531») which, on hydrolysis, yields a mixture of eight ammo-acids and aminonia The components are arrangeel in peptide linhage to form a 20-membocied ring of five amino-acids (a cyclic pentapeptide moiety containing cystine with one free ammo group) and a suc-cham of clirce amino-acids (Fig 1) Oxytocin isolated from liuman, bovine and porcine posterior pituitary is chemically iden. tical (Licki and Du l'IGNEAUD, 1958) The molecular weight is 1007 An important diemical property of oxytoxin is that the 20 membered ring can be reversibly opened by reduction of the SS. of the cystine residue to .SH HS, 10 to form tko cysteine residues The question naturally arises as to boss tar the ring structure contributes to the specific brological activity of oxytocin peptile amıle which represents the cyclic mocy of oxytocin (Fig 2) has been synthesised (RISSER, 1956) and found to have a measurable, though only very weak • A penta • The biological activity of Oxitekin and related compounds Net pressed in international units ( l = 1 ml = ir 4) Tus unit is the poufit exstocse actiut corresponding to that of 1 mg of the sun ternational Standard Patutan (Poderor Love) Powder 6 ·Otrain and Kelated Polypepiidrs YYROSINE $3OLLUCINE On ty CMS CYSTINE CM CH CACH-ANH- AhowC N CHCNH COCK NACO CH CO CHE PROLINE Co wity CHE ASPARAGINE COMM Arte CH, QUUTAMINE Maman Category CM CO LEUCINE NH CH, Cow 147 GLYCINANIE +2) 1 se structural formula s oxyI0C! istokuga al effect 0664, 022", or 0% that of oxyek III, depending upon the method of lyoassay employed Clearly, Chercfore, tire side-chain of the oxytocin moletutie is of ton. siderable bologu alumportance Os Tye Rex Glue / Asp Cy${ky? ile sequetke al the fifth dens sa fie disulphide ring motếty to} {}} {{x 40 ·8 Recent Progress in Orytocin Research Vasopressin, the other posterior pituitary liormone (Fig. 3), is likewise an octapeptide amide (DU VIGNEAUD TYROSINE PHENYLALANINE CH CYSTINE NH, CH CH, CH-CH--CO-NH--CH-CD NH-CH CO NH CF-C--MH-CO-CH-NH-CO- CO CH, CH PROLINE CO--NH, CM, ca ASPARAGINE CO- NH GLUTAMINE NH-C-- NH - сн,— си, Сн ΝΗ со ARGININE NH Сн, CONH GLYCINAMIDE Hug s he structural formula of vasopressin Thurs + the 'Joune type of the hormone or 'arginine vasopressure" occurring in many animals und in mani I le "porune" type of the liormone or "lysine vasopressin' ſound in the pig contains lysine instead of urgmine en the side chain el al, 1953a) with a 20-membered ring of five ammo-acids and a side-chain of three amino acids Vasopressin differs from oxytocin only in two of its amino-auds instead of ·O rytocin and Related Polypeptides iso-lcucine in the sing structure it has pliculalanine, anel instead of leucine in the side chain it has arginine (human, monkcy, ox, camel, domsliecp, rabbit, rat) or lysine (pig) (Var Diar el al., 1957). „Is miglit be expected, clicreforc, pure vasopressin possesses a certain ovyrocic activity (l'av Uterotonic Depressor Alejecting Pressor Antidiuretic (rat in vitro) ffowl in antud rabbit in situ) (rat in Bifu) (dog in situ) Oaytocin 500 500 500 7 3 Vasopressin 600 000 30 85 100 Hag 1 Diagram illustrating the biological activity of oxytocin and argimine vasopressin in different tests lhe surface areas are propor. tonal tro the potency in terms of the II sr standard per mg sub stanCC The figures are those published by l'ex Dikt o al (1997) Punk et al, 1933) and pure ou locin cierts sery slight. hut measurable vasopressor and antidiuretic cffccts (VAY Dune et al, 1955, (Eryth and FFkFre, 1955, Berde and CFRLETTI, 1936; Konzert et al., 1959). This can be seen from Figure 4 In addition to the uterotonic, ie, the true oxytocic (sce Chapter 1), to other properties are regarded as characteristic of oxytocin, namely its action on the mamnary gland (see Chapter VI) and its depressor effect on avian blood pressure (see Chapter VII). The pressor and antidiuretic activities aje typical properties of vasopressin ·10 Recent Progress in Oxytocin Research Particular interest attaches to those synthetic oxytocin analogues which differ from the natural hormone in only one amino-acid (Fig 5), since a comparison of the pharma. cological properties of such compounds gives some insight into the relationship between their chemical structure and biological activity. Synthetic oxytocin CyS-Tyr - Deu-Glu (NH,P-Asp (NH-Cys-Pro-Leu-Gly (NH) Phenylalanyl analogue Cys-Yyr-Phe Glu(NH)-Asp (NH2)-Cyş-Pro-Leu-Gly{NH) Levcyl analogue Cyş-Tyr-Leu-Glu (NH)-Asp (NH)-Cys-Pro-Lew-Gly) Valyt analogue ( valyl oxytocin ) Cyş-Tyr-Val-Glu (NH)-Asp (NH)-Cyş-Pro-Leu-Gly(NH) Glutaminyl analogue Sys-Tyr-lieu-Glu (NH2)-Glu (NH, -Cys-Pro-Leu Gly (NHJ) Isoglularrunyl analogue cys - Tyr lev- Iglu (NAL) Asp (NH) Gys Pro-Leu Gly{N) (glutande for eaglutam ne by analogy to file for moleucor Fig 3 I he sequence of amino acids in oxytocin and its analogues Pharmacological studies of these oxytocin analogues Trave shown that qute minor changes in the oxytocin mole cule can result in a loss of the specific biological activity. though this is by no mcans always the case Thus the poly peptide in which iso-glutamine replaces glutamine (RFs LER and Du l'ICVEAI'D. 1937) has none of the actions of Oxytocin and vasopressin in the consentional tests. Simi larly, the oxytou in analogue with glutamine replacing asparagine-one of a series synthesised in the Sandoz laboratories (Borssons et al. 1956-I also practically with out activity (Berdt et al. 1957) It can therefore be as. sumed that the glutaminyl and asparaginyl residues are of particular imporcance with regard to the spcufic biological activity of oxytocin ·Ovi and Related Polypeptiles Not so the iso leucyl residue in the ring if this is replacel Isy other aminoacid residues, the compounds ofitained are biologically actite, though their properties dif. fer to a greater on lesser extent from those of oxytocin (BERIE el al., 1957). For instance, the phenylalanyl ana- Joque las a less poucrful otoxic effect and a greater vaso. pressur and antitliuretic activity than oxylxm. This is not surprising, for the phenylalanyl analogue is intermedi. ate in chemical structure between orytex in and sasopressin. it is an extapeptide comprising the cyclic moicty of vasopressin and the tripeptide amide side-chain of oxytocin Quanisative «lata on this analogue are given in Talle Il. This same compuan luas also been prepared and studied in a number of biological tests by KATSOYANVIS (1957) who gave it the name "oxypressin KATSOY ANXIS (1957) Ithewise found this polypeptide to have a higher ratio of pressor fo oxytoxx activity than oxytoxun; al. thoughs. quantitatisely, fus findings differed somewhat from those published from the laboratory (BERDE et al, 1937) The substitution of leucine for iso-leucine in the ovy. tocin molecule leads to cssentially the same changes in activity as the replacement of 150-lea ine by phenylalanine thic oxytocin properties are attenuated and the vasopressin properties are enlianced On the whole, however, the lency) analogue is less active than the phenylalany) com. pound (Table II) One of the compounds synthesised by Borssonas et al. (1956) merits special attention, namely the oxytocin analogue with valme replacing iso leikine (Fig 6). This compound, "valyi oxytron," has almost negligible pressorantidiuretic acuvity, but retains high oxytocic potency; its activity in various tests can be seen in Table II The most ·12 TABLE II (.Activity 01 14 OF SOLUTIONS OF THL CYCLIC OCTAPCPTIDES IN UNITS OF INTERNATIONAL STANDARD PITUITARI (l'OSTERIOR LOBF) POWDER IN DIFFERENT TFSTS (BERPr el al, 1957) Isolated Rut l'terus Milk-ejection Chichen Pressure Blood Pressure (Rabbit Mam- Antidiuretic Activity Preshor Cat Uterus (Non-anaes. Activity in 51114 thetised (Spinal Rats) Cats) mary Gland) Synthetx toun Panalogue L-analogue - intlogue ("valulcoun") G-anikxguic 80 (22) 27 (+011) 0 25(101) 28 (+011 <00023 81 (016) 83 (+0 23) 107(*09)009 (+005) 0 07 22 (+008) 58 (+037) 2 + (03) 28 (+12) 05 033 (+101) 2 2 23(+14)015 (008) 015 32 (+008) 150 (+075) 16 7(+13)004 (+002) 0015 <002 0025 (1003) 0 0 0 (up to 1 ml (up to 1 ml / (up to 05 /kg iv) 100g sc) ml/kg. Recent Progress in Oxytocin Research P- phenylalins! L - leuc (i = glutamins ·3 Oxytocin and Related Polypeptides interesting feature of salyloxin (ruin biological point of vicu is that it possesses a more powerſul otoxic activity in viro than in ritio Oxin preparations are TYROSKE VALINE CN CYSTINE - MM CHE Ckg ČR ca - Awww ca MHW CK مها NM NH -CONNA Com CN 8.- CHE CH PAOLINE CONNIE CH, co ASPARAGINE NH GLUTAMINE CM CM CM ca LEUCINE CM7 CON OLTCINAMIDE Dag 3 he structural formula of salyloxytox1 usually standardised against International Standard Patuitary (l'osterior Lobe) Poudler, for ulxh purpose both the United States Pharmacopera (1955) and the British Pharmacopoera (1953) recoinmend an assay method based in the depression of blood pressure in the chuchen (Coor, 1939) In alternative test suggested in the Bntish Pharma- ·14 Recent Progress in Oxytocin Research coporia (1953) employs the rat uterus in vitro (HOLTON, 1918). If other methods are used to assay oxytocin-based for example on the cat uterus in situ or the milk-ejection pressure-practically the same values are obtained as with the pharmacopocia methods. However, valyl-oxytocin belaves differently than the natural hornione: its oxytocic effect measured on the cat uterus in situ or on the millejection pressure in the lactating rabbit is appreciably higher than the values found by the pharmacopoeia methods (BERDE et al., 1937) - Tug 7 Characteristic posture of a doe rabbit during delivery the anual puts its head betheen its hund legs, licks its genuals before the expulsion of the foetus, then licks the new-born offspring and cats the placent, and the membranes For this reason an attempt was made to devise a method which would make it possible to ineasure the posteny of oxytox in-like sulystances under physiological con ·Orifum and Related Polypeptides 15 ditions and on the same funtion on thich such substances rould act in man (BERDE and GHRIFTTI, 1958a). It is known that about can be induced in pregnant rabbits near eenn by administration of a posterior pituitary ex. 1130 (Kral's, 1926), or of pure ovexin (CSP), 1937). 001 33 DOS 01 02 0.33 Probit 6 83 $0 *$ 70 פחלכוחן שתיכנוסע סן סממן 60 50 40 30 75 20 002 0033 0066 01 02 0 33 Dort wirathun Witro) * Parocin Syntacion mer Vatyhytoen Fig 8 Dose respxiase cunat ol Suntokinon sinthetic Dxicon Punxcm (natural oxytocin) and talularecer asQscc by the induccon al lainut methox! In this test vallarstocin i MKC 35 ptent 26 wlien assayed in the comennonal methods for the burley.al scandardisation of oxytoxin (BERve and CARLTTI 1958a) Moreover, even in non-pregnant rabbits, orycoin exoles a behaviour partern wuch in many respects is reminiscent of labour (Faure, 1957) I method was duly developed in which induction of labous in the saltst is used in assay oxytocic substances the test substances are administered to rabbits on the 31st day of pregnancy and the time of onset of labour is recorded (Fig. 7) Like other ti! VIVO methods this new test gave a higher potency for valyl. Oxytocin ihan the pharmacopoeia methods (Fig &} ·of ex 16 Recent Progress in Oxytocin Research The phenomenon of higher activity in vivo is demonstrated to particular advantage when the uterotonic ac. tivity of valyl-oxytocin is compared in the same species both in vivo and in vitro. In the cat and in the rat tlic effect of valyl-oxytocin is some three times more powerful on the uterus in sin than on the isolated organ. In contrast, oxytocin has the same activity in both types periment. The fact that the two compounds should difſer so radically in this respect is all the more interesting which we consider that valyl-oxytocin lias only one methyl group less than oxytocin, but is otherwise identical in structure * The high in vivo oxytocic activity of valyioxytocin-which, incidentally, has recently been corrob. orated in the human female (Fig. 9) (SMITH, 1958b)us still more impressive when compared with the almost negligible pressor-antıduretic effect of this analogue And, furthermore, the ratio of the oxytocic effect to the blood pressure lowering activity in the human female (sec Chapter VII) is likewise higher (i e., clinically more favourable) for valyl-oxytocin than for oxytocin (SWYTH, 1958b). The implication of these findings is that the oxytocin molecule can be modified to gnc a substance which, from the obstetrician's view pomt, is superior to the natural hormone The valyl and leucyl analogues of oxytocin have also been synthesised by RUDINGER et al. (1956), but these Another instance has recently come to light of the way in which to placement of an amino acid residue by a sals1 residue can markcely alter the properties of a protein In sichle cell anaenua, serious blood disease, the haemoglobin in the ens throcytes differs in chenical structure from that of normal bloou! The difference toolves only one of the nearly 300 - to cell lieto toy a valy! -".

·Oylucan and Related Polypeptides lorhers have not yet publishic detailed quantitatise data on the biological acuvitics of these conxunuls. G-SINTOCINON STUNTPE * VALYL OKYTOCIN IIULITRE SYNTOCINON SUAE VALYL OXYTOCIN BRUILTRE A TONIC VALY) 413 RUBRE CONTRACTIONS PER 10 MINUTES O SYNTOCINON & IUILITRE X VACY OXYTOCIN 210 LITRE SYNTOC RUTRE these time to с D 8 20 50 30 00 20 30 INFUSION AATE DROPS PEA KUTE (7 Lew Ihre activity of tug 9 Comparison of synthetic oxytocin (591001) and alysoxytocin four intra partum patients at tum both preparations 15 gren sa International Unu as determined by the pharmacopesa methods in equal concentrations salt oxytocin $5 considerably more polent that oxytocie (cune C.) Dured 8 umes {curse 1) salyloxytocin y noticeably less potent, and at times <iucson (curse Dy there is nos perceptible difference (SYTI, 1938h) Recapitulating pliarmacological studies of a number of oxytocin analogues lase revealed that if the glutaminyl or the asparaginyl residue is the orytocin molecule is replaced by some other amino-acid all oxytocic potency is ·16 Recent Progress in Orytocin Research The phenomenon of higher activity in vivo is demon. strated to particular advantage when the uterotonic activity of valyl-oxytocin is compared in the same species both in vivo and in vitro. In the cat and in the rat the effect of valyl-oxytocin is some three times more powerful on the uterus in situ than on the isolated organ. In con. trast, oxytocin hias thic same activity in both types of cxperinient. The fact that the tivo compounds should diſfer so radically in this respect is all the more interesting when we consider that valyl-oxytocin has only one methyl group less than oxytocin, but is otherwise identical in structure * The high in vivo oxytocic activity of valyl- Oxytocin-which, incidentally, las recently been corrob orated in the human female (Fig. 9) (SO TH, 1958b).is still more impressive when compared with the almost negligible pressor-antidiuretic effect of this analogile. And, furthermore, the ratio of the oxytocic effect to the blood pressure lowering activity in the human female (sec Chapter VII) is likewise higher (ie, clinically more tavourable) for valyl-oxytocin than for oxytocin (Svyill, 19581)) The implication of these findings is that the oxytocin molecule can be modified to give a substanc whic, from the obstetrician's viewpomt, is superior 10 the natural horinone The valyl and leucyl analogues of oxytoun have also been synthesised by RUDINGER et al (1936), but these • Inother instance has recently come to light of the way in which to placement of an amino acid residue us a valyi residue can markedly alter the properties of a protein In sichle cell anaemia, a serious blood disease the hacmoglobin in the erythrocytes differs in chetntcal strukture from that of norinal blood The difference insolves onls one of the nearly 500) amino acids that make up the haemoglobin molecule in sachle cell hacmio globin, a glutaminyl restdlue of the normal protein is replaced by a valyi residue (IXCRAY, 1977) ·19 Oxytocin and Relateil Polypeptides disulphide ring than oxytoxin anel vasopressin but none of their activity, inhibits the presser effect of vasopressin on the rat loloxl pressure. 1 min. 2 Foto 11 Contractions clicitut in the rolated rat uterus by syry foxin, indubited by a nonapeptide It intervals of 5 min (indicated by thic wlute spwks). 12 mili of synthetic oxytocin (Syntocinon) was introduced into the organ bath (50 ml) nluch was washed out When the contraccion had taken place du 1, 003 ml and at 2. 01 ml of nonapeptide solution has added in the bath, 30 seconds before the next close of onsterin Ilie smaker dose of nonapepude reduced the amplitude of the contraction by about 30%, while the lurger dore almost fully inhibited the contraction ·18 Herent Progress in Outer in Hesrarch Ins. On the other hand, 1 eplacement of the isoleucine boy other amino-aciels yiekls xx'tapeptiles with moxlifici lirs. Ingical activity. One of these ox tapeprides-allylovytocili --S**passes the natual hormone as an oxytoxic. Research {}}{} synthetic higher leckerkliges (il nya tox in has not yet progressed so far as the study of vytocin malogries, but nos crticless eine Imding of some impor. Line fias coresgerl. A 110»appuicle lias 1er ently 1x<!! syet thorised in the Sandoz lalutatories which contains all ciglit amino acids of the fatural lionmone ani, in addition, a X COYSK tylnyi tesiclue in the sing (lig. 10). This lama Oxytocn Gyą Tyr lieu Gunt, Aspire) Cy Mo Low Gly (11) Nannpopito Cys Tye Pyt lieu Guints I ARD (NH) CYS Pro Lou Glynne) Ilic sequence of the mouids in otton and ma *** plece laci mulut vite effects of an pepuisie has been found to have accomain whibitory eller 1313 oxytox 113 wlien given startly bclose ille facce all some (css, c.8. chicken blood pressure, rabbit and lot diferits in two (Fig ) ((-VITTMANN et al, 1957: kovin, 1977) For the MC's this is ol purely thecual interes l'ha ute mician requires is an oxytox in mhibitor with a prolonged action IN VIVO Whih could be me fui ( ex kary Step TONS of uterte moulity. Vone the less, they fonimgs stiggest that synthetk polypeptides relateel 100 fou in my sl 115 !!! (LII cildi ter sua compound, The monapeptide my inhubut the con olotoxin boy some cantine mer l?25m). It is tempting 15 px'!! lace wellier the muboty Hity of this bugher promo lagte is due to the large size of the dolpful sing this pussilality like licen Juntoil it by Russtermu Kam (1978) imo ford that the so-glutamme 1937e's my fax it (so-glutamine oxytocan"), which also be larger ·۱۰ 144 4144 : if thit 18 ( 1,114 v4 و 14 ۹ ۱۰ ۱۱ ) ۱۰۱۰ ) 144) • ۱۹۹) ) ) )1111111 111: 11 11 111 10 1411 } ر141 141 1411)، 11413 |۱۹۶۰ ۱۶۱۹] ({{11: ۱۶۰ ۱۶۱۱۶۹۴ { 1 } } {{ } ، { 4}{{ }} {{{ ۱۸۱۱۱۹) ۱۰ ۱۱ ۱۱۲ ۱۱ ۹۹{11}، ورا ۱۱ ۱۱۲ ۹۱۲۱۱۱ ۱٫۰ ۱۱٫۱ ۶۱۱۰۹ ،۱ /* | و) إال |• ۱۱۹ ۱۱۱ ۱۰ ۱۷) ۱۱ ۱۱۱ ۱۱۰ ۱۲ ۱۱۱ ۱۱۲ ۱۱۱۱ ۱۱۱ ۱۴ راز ۱. ۱۹۱۹ و ۱۱۱۹۰ دا ورا ۱ ۱۱۱۹۲ ۱۱۰ ۱۱۱ ۱۱۱ ۱۱۴ او ۱۱۱ ۱۰, ۹۶ ۱۰ ۱۱، و را جارو را اراء إ۹۱ ۱۰۱ نار {{{111 ، {11ء او از ۱۰ و از ابر را ۱۱ - ۱۶ : 14 142 141 و ۲۰ ۱۱۹۱۰ ۱۰۹) ۹۶ ۱۷۹۷ ۱۶ ۱۷ ۱۶ }} أ (4) 4 401 1111111} )) ۱۲ )۱)) « (۱۹۰ / ۱۱ /۱۷ ۱۰ ۱۱ ۱۲ ۱۱۱۱۱۱۱۱۱( (tv/ ۱۷۱۰۱۰۱۰۹۱۷۸۱۹) 11 أ، 1 أ ) 11111111 م 11 11 !!! رأء || ا ورا ۱۱ ۱۱۱۱۱۱۱۱ ۱۹۱۱/۱ ۱۶۹۰۰۹۱۴۱۱۹۰ 1۱۱۱۶۱، ! ، و ۱۱٫ ۱۱۱ ۱۱۱۰ } ۱۱۷ ۱٫۱ ۱۲ ۱۱ ۱۰ ۱،۱۷۹ (۱۱۱۱۱۱۷ ۱۱۰ / ۱۱ ۱۱۲ ۱۱۱ ۱۰ 11 1 با ۱۱۱۱ ۱۱۰ ۱۱۷ ۱۱۸ ۱۱:۱۷ ۱۱ ۱۹۱۰ و ۱۱ ۱۱۱ ۱۹۱ ۱۹۰ 44 11111111111111 ·III THE PRODUCTION OF OXYTOCIN IN THE ORGANISM Sinct. Lotwi's (1921) classical investigations on the frog lieart, it has been known that the endings of peripheral nerves release chemical mediators which transmit impulses hom the nervous system to the organs The effect of acetylcholine liberated by cholinergic ncrucs is confuech to the immediate vicinity of the nerve ending The mediators released by adrenergic nerves, on the other hand, are metabolised more slowly than acetylcholme and can therefore evokc systemic effects Noradrenaline, for example, is present in adrenergic nerves and is lilcrared at the endings of such nerves, a part of finding its way into the blood stream and affecting the function of distant organs (foi details, see vov EULER, 1956) Here, then, we have a hormone that is produced and liberated luy pero plcral nervous clements. In recent years numerous investigations into the pro duction of oxytocin and the production of posterior pitui tary horinones in general, have pursued the possibility that such hormones might likewise be product of ner sous elements, namely of neurones in the hypothalamus The production of hormones in the central nervous system is callecl neurosecretion It has been known for a long time that the lypo thalants and the potentary gland are intimately connected If the posterior pituitary is cleneriated, it atroplues aux 20 ·Trr: *!? *** PN- Toy! F12. 13 Stained histologial section through the put the most of the dry The ganglion cells contuning 14 appear dark (BARI 4 1974 ules are smaller than they appeai unker the lulet scope In the hypophysis of the al (l'11.11.1997) Erabbit (BARRI 1937). and cat (Grunn l'As Burton ·22 Recent Progress in Oxytocin Rescarch includes the infundibular stem and the meclian eininence of the tuber cinereum (see Fig 33). There is no histological evidence to suggest that any of the cellular elements of the neurohypophysis are secretory cells (gland cells) capable of producing hormones. On the other hand, the nerve endings are intimately associated with the blood vessels (BODIAN, 1951). And, indeed, there is now much evidence to support the view that oxytocin and vasopressin are actually produced in the brain, or to be more precise in tlie anterior hypothalamuis, and that thicy are merely stored in the neurolypophysis Investigations by E. and B. SCHARRER (1928, 1932, 1954a, 1954b) and by BARGMANY (1951, 1954, 1958a) have shown that in both invertebrates and vertebrates, including mammals, certain hypothalamic neurones produce granules of neurosecretory material which are transported along the axons This neurosecretory material progresses along the axons at a rate of about 3 mm. per day. BARG- MTANA (1949) made the important discovery that the neurosecretory granules are selectively stained by Gomori's chrome-haematoxylin philoxine With this staining techmique, the supraoptic and paraventricular nuclei of various animals, including mammals, can be shown to contain abundant neurosecretory material (Fig 13), and, more over, the granules can be traced along the supraopticolıypophyseal tract down to the perivascular nerve endings Indeed in one species, the giraffe, they have been obseried in the capillaries (HA USTROS, 1977), but in other anımals, e.g, the horse, no granules fiave been found in the lumen of the vessels (Kivaro and TALANTI, 1937) Be that as it may, the accumulation of neuroseu retory material in the posterior pittuitary, massed around the capillaries, has been deinonstrated in all speries insestigated Inciden tally, neurosecretory pranules liase cien been demon ·The Production of Oxytocin in the Organisin It was pointed out some years ago (eg, by Anfi. 1921) that hypothalamic and posterior pituitary extracts quissesseil similar biological actions. Wiien Juistoinical flata lengan to accumulate, this question became the olijece of systematic rescarch (1un and ZETLFR, 1951, 1932. 1933a, 1933; Van Dikk et al., 1977). Extracts of the supraoptic anı paraventricular nuclei and likenise of the tuber cinereum were found to possess oxytocic, anti. diuretic and sasopressor properties, whereas the tissues surrounding these structures were devoid of hormone. The activity (ie., Isormone content) of these brain structures was, however, less than that of the neurohypophysis. This was first demonstrated in the con buo it applies also to a number of otlier animals and to man (Tables III and TV). There is a certain correlation between the amount TIBLE ? HORMONE CONTENT OF THE IL L'OST: XIax PUT**> 1 Il fix 11011101. AL(HILD AND ZETLF1952) ---- lawypress diuretin Oty toxin 1 3 + 8 00 6 00 I TO 28 00 10 28 15 00 000 6 40 88 32 14 40 18 72 5 20 10 80 900 1 80 34 80 12 00 90) * 80 3 84 S 7 8 to Venn to 11 49 940(82) 3 SS (11 ID 18 7 13 (75) 2 83 (2977) 10 33 8 +1(824) 3 1931, = tandard deslation = standard error of the mean ·24 Recent Progress in Oxytocin Research 1955), the granules range in diameter from 50 to 200 mm; in ox hypoplıysis they show a greater variation in diameter (SCHIEBLER, 1952). Recent data published by BARGMANN (1938b) indicate a diameter of 120 to 180 mu for the granules in the cat. It is reasonable to suppose on the strength of these histological studies alone, that the so called posterior pituitary hormones might quite well be hypothalamic hormones, generated in the supraoptic and paraventricular nuclei, transported along the axons, and released into the blood vessels of the neurohypoplysis Additional evidence to support this view is forthcoming from physiological investigations TIBLF IN I ORMONI CONTENT or IHL ANTERIOR IJUMAA HIYIONALAMOS INIU PIK INDIVIDUAL (HILD IND ZITLIR, 1952) No Visopress Aduretan Oxytoc 111 1 2 0 129 0316 0 120 0 2410 0 210 0 160 208 0 520 0 128 0 183 1 5 6 7 8 0 166 0 122 0018 0 274 0 120 0 008 0 167 0 184 0 101 0 105 180 257 0 251 0 324 0 101 0031 0 120 0 600 0 120 180 - 10 Menn to 0 228 O 1095 (48) 0 0316 (154) 0 135 O 0672 (50') O 02 38 (18) 0 255 0 1810 (71) 00550 (22) o = standard des nation & stand orel error of the mus ·The Product of Orytocin in the Organism 27 solubility studies that the neurosecretary material cannot be identical with the hormones, but must ise regarded as a carrier substance (1lilo anul 281178, 1953.)). It is not yet clear whether the GOVORI-positiic carrier sulistance is identical with "neuraplysine", a biologically inert protein present in some neurolypophyseal extracts, which is said to be someliow associated with ovincin and yasopressin (Acnee, 1938), Paraventxular nucleus Ople chasma Supraoptic nucleus Sechon through the hypophyseal stalk Posterior lote Fı 14 Dagram showing what occurs when the hypophyseal stalk *5 (317 In the proximal stumps of the hbres descending froin the supraoptic nuciens and the paraventricular nuclens there is an accumulation of neurosecretory material The distal ends of the Abres are desor of granulation (BROVANY, 1958) Extracts of the supraoptic nucleus, like extracts of the paraventricular nucleus, possess both oxytocic and pressorantidiuretic properties (Van Dyke et al., 1957) Thus would seem to indicate that oxytocin and vasopressin are not produced in different, clearly defined regions of the ·26 Herent Progress in Orylocin Research ol neurosecretory material that can be demonstrated and the biological activity of the extracts (Hild and ZETLER, 1952), which implies that there is some connection be. tween liormone production and the generation of neurosecretory material. In keeping with this, it has recently been observed that chlorpromazıne in doses affecting diuresis, leads to a reduction in the amount of neutro. secretory material in the neurolypophysis (Kivalo et al., 1958) A cogent piece of evidence in support of the neurosecretory theory is available in studies on dogs whose pituitary stalks liad been sectioned (Hind and ZFtlrR, 1953a) Mechanical interruption of the hypothalamo-lypoplyseal tract leads to a thuchening of the fibres in the proximal part of the pathway and an accumulation of neurosecretory material in the thickened stumps of the fibres. In the distal part of the pathway the amount of Govori-positive material decreases Tlus would suggest that there is a flow of neurosecretory inatetial along the fibres (Fig 14) The bormone content of the hypothalenmus is markedly reduced atter a lengthy period of water deprivation When such thirsting stalk-sectione animals are supplied with water, the amount of luistologically dem onstrable neurosecretory material increases proximal to the point of sectioning, and the biological activity of Hypothalamic cxtracts rises Distal to the point where the stalk was seccioned, there is no increase in the quantity of neurosecretory material, nor is there a rise in the bio logical activity of extracts (Hip and 1,1TLER, 1953a), li might clierelore be imagined that the gramnes rei caled by the specific staining technique were the actual formones, ie, that the netirusecretory material was perhaps cenucal with the proteoliormones shown up by the Govori stall. Ilorever, it has seen demonstrated by ·The l'o-luction of Orytuent in the 01:19.3- solubility studies that the neurkey reton material (angos lje identical with the lunnones, but must lx tenda as a carrier substance (llud and 71TIR, 1953). It is it Jet clear whether the Govori-poritive cartier sulmtance is identical with "neurophysine“, a biologically inert protein present in some neurolıypophyseal curacts, which is said to be somehon associated with a stocin anıl sa prosin (ACHER, 1958). Private cuernden Optic chama Supraoptic nucleus Section brough the hyppysealtalk Poster or lobo Fig 1 Diagram stunning what (curs when the liggplıyscal stalk 15 cut In the proximal stumps of the fitores descending from the supraoptic nucleus and the parasentricular nucleus there is an accumulation of neuroscretory material. The distal ends of the fibres are desord of granulation (BRGMAN, 1958) Extracts of the supraoptic nucleus, like extracts of the paraventricular nucleus, prxsess Imth oxytocic and pressor. antidiuretic properties (l's Dyke et al., 1957) This would seem to indicate that orytíxin and saspressin are not produced in different, clearly defined regious of the ·28 Recent Progress in Orytocin Research laypothalamus. Nevertheless certain findings (OLIVICKOVA, 1957) suggest that the parasentricular nucleus is of par. ticular importance as regards the production of oxytocin, at any rate in the rat: iſ thus nucleus is destroyed, the oxytocin content of the pituitary gland decreases, whereas the vasopressin content is unchanged. The blood of such animals likenise contains less oxytocin than that of normal animals (Dulces and REED), 1958). Centrifuge studies (PardoE and WEATHFRALL, 1955) have revealed that the formones in the pituitary gland are probably bound to mitochondria and not to microsomes; moreover oxytocin and vasopressin seem to be contained in different mitochondria. This lias an important Bearing on the question of whether the l1ypothalamus produces tho different lormones with a molecular weight of about 1,000 or whether the protein with a molecular weight of about 30,000 extracted by VAN Dyxt et al (1912) is the true pre-formed hormone (1 oxytoxic unit per 61 xg) This protein possesses all the biological propcrucs of the posterior pituitary hormoncs, and if it were the true hormone, tins would mean that the oxytox in (mol st. 1,007, 1 oxytocic unit per 2 ms) and vasopressin isolated by DI VIGSFALD were merely fragments of the large molecule However, V'A Diaf's protein can be resolved into two fractions, one sith oxytoric, the other with lase. pressor-anuduretic properties, by gentle methods such as clectrophoresis and countercurrent distribution lich do not insolve hydrolysis (ICFR et al. 1936a. ICR and FROVACIOT, 1957) There is additional eudence to suggest that the pos terior pituitary hormones are dix rete entities animal species the ratio of vasopressor to oxytocit sous saries greatly from one part of the neurosectetory system 1) Sonic ·The Production of Orytorin in the Organisme to another; and, moreover, the vasopressin:oxytocin ratio in a given part of the nelitosecretory system saries from one species to the next, sometimes quite considerably (Dicker and T11R, 19531); Vas Dins el al, 1957). Tlus in the dog the ratio of vasopressin to oyyaxin is 13 in the paraventricular nucleus, 21 in tlie supraoptic nucleus, 14 in the tuber cinereuni, and 1.5 in the posterior lobe of the pituitary. This ratio in the liypothalamus is 17 for the clor. 5 for the rat, and 1.1 for the caincl. In the rat the vasopressin:oxytocin ratio shoss characteristic changes cluring the oestrous cycle (Fig 1.5) (HIFLLFR, 1957a), parturition, and lactation (DICKER and Tsitr, 1933a; ACHFR et al, 19361)) The variable ratio of vasopressor to oxytocic activity of human blool (Bisset and LFF, 1937) is addtional evidence that the octapeptides are the actual linsmones and that they are procluce«l largely independently of cach otlicr Many stimuli are known to bring about a release of oxytocin. dilatation of the cervix and body of the uterus. coitus or mechanical stimulation of the uterus and vagina, suchling or mechanical stimulation of the mamulla, certain emotional stimuli, thirst or a rise in the osmotic concen. tration of the blood, acetylcholine, nicotine, anaesthetics; electrical stimulation of the supraoptico-hypophyseal tract Apparently each stimulus that causes secretion of oxytocin elicits a simultaneouis release of vasopressin. This is true of coitus (HARRIS and PICKLES, 1933 FRIEBERG, 1953), suckling (Cross, 1931; PEETERS and COL'SSENS, 1950. Kai- LIALA and KARTOV, 1931) and milking (Cowie and For IE», 1957). thirst (Syvox, 1931) and smuik stimul (ABRAILA US and PICKFORD, 1931, HOL LAVD et al, 1958). emotional factors (Fig. 16), acetylcholine (ARRAILA US and PICAFORD, 1954), nicotine (Bissen and WALKER, 1957). anaesthetics (CHAUDIIURY and W'ALKER, 1958) and stimu ·30 Recent Progress in Orytocin Research D. Oe Di+Mt OeMt Oxytocic Pressor 2 23 P<005 5 21 <0.001 656 S0001 t 256 P<005 297 <001 552 <0 001 500 mu 100 g body weight 400 300 200 100 - Dioestrus () Oestrus (=O) Metoestrus (- M) Pressor Oxytocic Fig 15 Dressor and oxitocic activity in the pituttın glands of adult teinale rats at different stages of the oc strous (de (IFLLER, 1937a) ·The Production of Oxytocin in the Organisi 31 lation of the hypothalamus (ITARRys, 1918, 1953, INDERS- SOY, 1937) The mechanism of action of most of these stimuli is not you understooxl. It is, however, Anown that the supraoptic and parasentricular nuclei are situatcil in thar part of the Irypousalamus which is sensitive to local osmotic stimuli (L'EXVE, 1938) The mjection of eserite or disepropy: shiotopliospliare (to the supraoptic nucleus of the Urine tiow (ml/min) he 20 40 60 80 120 100 WO 10 30 50 70 90 130 150 Time (min) Frs 16 I he effect of emotion on urine flox and vietine moulit in a dry lpper record unine how Lontt record frequence of uterine contraction At vero eine 300 m) » JET by mouth During period preparations were made for an intraceroud injection which was not guien following this emotional stimulus decrease of urine secreta (release of sopressin, as well as increase of uterme mon tilltı (release of otro197) 2n be observed (AERAHA VS and Pia FUE, 1931 ·32 Recent Progress in Orytocin Research dog causes increased uterine motility, from which it can be assumed that cholinergic transmission is involied m the central mechanisms responsible for the liberation of oxytocin (ABRAHAMS and PICKFORD, 1956). Studies with nicotine and hexamethonium have showni, lionever, that this particular synaptic transmission mechanism differs from that in the peripheral autonomic ganglia (BISSET and WALKER, 1957; WALKER, 1958) Irrespective of the “logical purpose" of a given stimu. lus, the annount of oxytocin released from the neurohypophysis is always greater than the amount of vasopressin The ratio varies from 4.1 for electrical stiinulation of the hypothalamus to 100. I for suchling (Harris, 1955). For the time being this phenomenon remains an enigma If oxytocin and vasopressin were always released in constant proportions, it could be assumed that the cytochemical processes by wluch they are produced were so intimately geared that the two hormones could only be built up and released in a fixed ratio However, thus is not the case: the organism appears to be able to regul. late the production and liberation of cach liormonc separately Why then is oxytocin released along with vasopressin after an osmotic stimulus and why arc both oxytocin and vasopressin released during suchling? Could it be that some sort of interaction between the two poly peptides at the effector organs is of greater importance than we suspect?

·IV THE FATE OF OXYTOCIN Osstoer WYTOCIN released from the neurolıypophysis is car. nied in the isloodl stream to the organs where it exercises Jis specific biological actions It is still not known with certainty in what form outin is transportel to the blockl, but there are grounds for believing that it enters into loose combination with the serum protens: in dialysis experiments (HIFLLER, 1957a) oxytocin disappears at a faster rate from KRESS-ESCI ESTOY Sohnion than from fruman plasma (Fig 17) Inulin which is not bound to the serum protens diffuses out of Ixth systems at the same rate. The estimation of oxytocin in biological fuds acquires a special importance uben se come to sindy the fate of the hormone. Quanuitame data on the oystocin content of the blood shou considerable variation and are often clifficult to interpret. This is due, in part at least, to difficulties inlierent in the assay procedure Present clay methods for determining the ovytocin content of the blood (Bisset and I'ALKER, 1954, Bisset et al, 1956) are based on measurement of that part of the uterotomc activity of blood extracts which is not due to order sulistances known to act on smooth muscle, e g potassium ions, frista. mine, 5-hydroxy-cryptamine, acetylcholine or adrenaline, and is abolished by thioglycolate This method is founded on sound biological principles, nevertheless so facis clie lugh degree of certainty that could be attained by means 33 ·32 Recent Progress in Orytocin Research dog causes increased uterine motility, from which it can be assumed that cholinergic transmission is invoked in the central mechanisms responsible for the libcration of oxytocin (ABRAHAMS and PICKFORD, 1956) Studies with nicotine and hexamethonium have shown, however, that this particular synaptic transmission mechanisın differs from that in the peripheral autonomic ganglia (Bisset and WALKER, 1957; WALKER, 1958). Irrespective of the "logical purpose" of a given stimu. lus, the amount of oxytocin released from the neurohypo. plysis is always greater than the amount of vasopressin. The ratio varies from 4 : 1 for electrical stimulation of the hypothalamus to 100 . 1 for suchling (Harris, 1955) For the time being this phenomenon remains al enigma If oxytocin and vasopressin were always released in constant proportions, it could be assumed that the cytochemical processes by which they are produced were so intimately geared that the two hormones could only be built up and released in a fixed ratio Howcı er, thus is not the case. the organism appears to be able to regu. late the production and liberation of each liornione separately. Why then is oxytocin released along with asopressin after an osmotic stimulus and why are both oxytocin and vasopressin release«l cluring suchling? Could it be that some sort of interaction between the two poly. peptides at the effector organs is of greater importance than we suspect?

·The late of Orylocuri sov, 1950) and from the fiypothalamus-Istit not the pitui. itary gland-of various animals (ROBERTSON and HAWXR, 1937). Unlike ovytocin this substance is not inactivated ly thioglycolate. Clearly, this finding still further complıcates the interprctation of data on the oxytocic activity of blood and tissue evracts. In the rat blood from the pirmtary gland drains into the external jugular icm, so that tlic blool in thus vessel would be cxpected to have a higher oxytoxm con entration than that in other cins and arteries In anacsthetised rats thic oxytocin concentration of blood from the external jugular icin ranged from ? to 7 ml' /ml (Btsser and WATER, 1931) In tlie same vem in the cou, the oxytocin concentration was 120 to 300 xU./ml. and increased after stimulation of the uterus and sagina to as high as 420 to 850 4U/ml (F117rATRICK, 1937). In man blood from the pituitary gland finds its way into the internal jugular vein "The oxytox in concentration of blood from this vein was about 12 mU/ml in anaesthetised men and women (Bisser et al, 1956) In nonanaesthetised subjects the oxytocin content of blood from this vein was lower (Table 1), while that of blood from peripheral veins was still less always below 04 mU/ml (Bisset and LFF, 1957) Other investigators (HAWKER and ROBERTSOY, 1956) have found considerably higher oxytocin concentrations in female venous blood: 02 to 78 mU/ml in non-pregnant women, o 95 to 13 inU /in1 in pregnant women, and 01 to 1.17 mU/ml during the first stage of labour If we compare the values of Bisset and LEE (1957) for son pregnant women with those of HAWKER and RORERISOY (1956), se see that the discrepancy is of the order of 1.10 Oxytocin is eliminated by inactivation or excretion. If strong uterine contractions are induced in a woman ·34 Recent Progress in Oxytocin Research of a specific chemical method of detecting ovytocin in the blood, if any such method were available. The sliortcomings of the biological method are evident from the fact tliat if a known amount of oxytocin is added to tlic blood in vitro and an oxytocin assay is carried out, the value found is invariably too low. This can be scen from the last column of Table V Moreover, it has recently becn reported that a second oxytocic substance can be ca. tracted from human female blood (HAWKER and ROBERT- 100- 90- 80 - activity remaining within dialysis bag 70- 60- X 50- X 40- 30- 20- 10 6 8 10 Dialys13 lime hours) Fis 17 Dialysis to equilibrium of synthetic oxytocin (Syntocinon) Y--x in human plasma and o--o in relys Eggleston phosphate salıne buffer Initial concentration of oxytocin in dialysis bag 100 mU/ml Nojas casing (8/82) was used as the dialysis membrane It was rotated at 200 rpm at room temperature Acuisits was estimated by means of (+ + 1) assays on the rat uterus (H/ELLER, 1957a) ·The Fate of Oryfocin 33 sox, 195f) and (rom the laypothalamus-but not the pitu. itary gland-of various amınals (ROBERTSOV and HAWAIR, 1957) Unlike oxytox in this substance is not inactivated by thioglycolate. Clearly, tliis fineling still further compli. cates the interpretation of lata on the oxytocic activity of blood and tissue extracts. In the rat blood from the pituitary gland drains into the external jugular icin, so that the blood in this vessel would be expected to leave a higher oxytocin concentration than that in other veins and artcrics. In anacsthetiscd rats the oxytocin concentration of blood from the external jugular icin ranged from 2 to 7 mU/ml. (Bisset and WALKER, 1951). In the same vein in the cow, the oxytocin concentration was 120 to 300 xU./ml anel increased after stimulation of thie uterus and vagina to as leigh as 420 to 850 „U./ml. (FITZPATRICK, 1957). In man blood from the pituitary gland finds its way into the internal jugular sein. The oxytocin concentration of blood from this vein was about 12 mU/ml. in anacsthetised men and women (Bisset et al., 1936) In nonanaesthetised subjects the oxytocin content of blood from this vein was loner (Table 1), while iliat of blood from peripheral seins was still less: always below 04 ml /in1 (Bisset and Lif, 1957) Other iniestigators (HAWLER and RobertsOY, 1936) have found considerably luglier Oxytocin concentrations in female venous blood: 02 to 78 mU/ml in non-pregnant women, 093 to 43 mU/ml in pregnant women, and 01 to 1.17 mU/ml. during the first stage of labour If we compare the values of Bisset and LEE (1957) for non-pregnant women with those of HAWKER and ROBFRTSON (1956), we see that the discrepancy is of the order of 1 10. Oxytocin is eliminated by inactivation ou excretion If strong uterine contractions are induced in a woman ·36 TABLE V EXXOGENOUS OrITOCIC AVO I TIDIL RI TIC CUTI I Cratr4L AND PTRIPHERAL BLOOD PROY CONSCIOL'S PATIEYTS AND RECOCR) OF \DDCD HORMONE (BISSCT AND Lrr, 1957) Endogenous activity in the blood Age Cive Sex Curd Central Peripheral Recovery of added hormone Source 0 Source 0 Recent Progress in Oxytocin Research 1 F 56 Cirrhosis 12 <0 003 FI 0 2 (06) <0 003 429,6 2 NI 45 Infectise hepatitisIB 03 <0 007 MCV 0 1 (0 3) <0 008 78% Cirrhosts 3 M 56 (sous londoni TIB 0 (06) <O 003 0 0 (02) <0 001 N1 M 40 Corchons with sics !!JB 01 0 023 MCV <0 3 <0 013 +3'; S F 52 Carrots Sic <0 + <0 014 VCV <05 <0 015 4496

·1
6
F
+5
Cirrhosis with
nhl derleme
06 (11)
We.tn
A 019 NCI
0 +(11)
<0 003
<0+
83,
<0 012
<03
<0 008
58:
() = (y tox tanity u terms of ori texan (ml per ml)
1 antkliuretat de tists in terms of vacipresin (ml' fxr ml)
IJU, - piernal jugular seat or bulb
VC = mexan cubital en
SVC - superior 2 CIVI
Fi-femoral artery
Rriht trium
VI. - notestimated!
The late of Orytocin

·TABLE I 30 ENDOGENOUS OXYTOCIC AND INTIDIT, RETIC ACTIVIT) NCCXTRAL AND PERIIHIER IL BLOOD FROM Consciot's PaTIFITS AND RFCOVERY OF ADDED HORMONE (BISSCT AND LFF, 1957) Endogenous activity in the blood Age Case Sex Condition Central l'eripheral Recovery of added hormone Source 0 Recent Progress in Oxytocin 1 Source 1 F 56 Cirrhosis IV 1 2 <O 003 F. 0 2 (06) <0 003 4272 2 M 45 Infective hepatitis IJB 0 3 <0 007 CV 0 1 ( 03) <0 008 781 3 M 56 Currhosis (amy loulosis) IJB 0 0(06) <0 003 RI 0 0 (02) <0 004 Research 4 M 40 Cirrhosis with ascites 1JB 01 0 023 | CV <03 <0 013 139; 5 F 52 Cirrhosts SIC <0+ <0 014 CV. <05 <0 015 1457 ·The Isle of Oxytocin 39 body is dependent upon the kidneys and organs of the splanchnic vascular area; in lactating rats the oxytocin clearance is not solely dependent on this group of viscera. At all events, cell-free extracts of kidncy, liver and intestine destroy the posterior pituitary hormones (IIELLER, 1957b). 10- . 0878 log concn onytocin, mU/ml. 8 06- o 04- o 02- 0 2 4 6 8 10 minutes after injection Fug 18 The disappearance of injected oxytocin from the blood of rabbits lle animals were anacsthetised with urethane and blood was collected from the carotid artery 200 mU/100 & Oxytocin were injected into the ear vein • normal rabbits, o rabbits whose kidney sessels had been ligated (CHIALDHURT and WALKER, 1957) A factor inactivating oxytoan can likewise be demonstrated in human placenta (HAWAER, 1956). Extracts prepared from fresh placenta with physiological salıne will inactivate considerable amounts of oxytocin when in cubated with the hormone at 37°C. The amount of lormone inactivated depends upon the concentration of the ·38 Recent Progress in Oxytocin Research ficar to term by intravenous drip infusion of oxytocin and the infusion is interrupted, the activity of the uterus falls by 50 per cent within about 15 minutes (CALDEY RO- Barcia et al., 1957b). This gives a good indication of the duration of action of oxytocin on the human uterus, but it is hardly permissible to draw any very definite conclusion concermmg the elimination of oxytocin from observa tions of this kind. The persistence of an effect does not necessarily mean that the substance wluch elicited the effect is still present in an intact form in the organ affected Indeed another investigator (MULLER, 1958b) using a different-but also indirect-technique came to the conclusion that in the pregnant woman near to term a small dose of oxytocin has a half-life of about 1 minute. Both findings suggest that oxytocin is rapidly metabolised A similar inſerence can be drawn from experiments by CHAUDHURY and Walker (1957) who administered a known amount of oxytocin to rabbits and followed its rate of disappearance from the blood 10 minutes after intravenous administration of 200 mU oxytocin per 100 g body weight. the hormone could no longer be detected in the blood The half-life was 33 minutes In this respect oxytocin resembles vasopressin which likewise disappears rapidly from the blood If the renal blood vessels are ligated, the half life of oxytocin increases to 9 7 min uites (Fig 18) Though it is known that part of the in. jected oxytocin is excreted in the urine (LARSON, 1935), most of it would appear to be inactivated in the hidney tissues, as is the case with parenterally administered vasopressin which is inactivated by the kidneys and by the organs of the splanchnic vascular area (GINSBURG and HELLER, 1953) Recently published data by GINSBURG and SMITH (1958) suggest that in male rats, as well as in female rats in oestrus, the clearance of oxytocin from the

·The Tale of Oryloci!!
11
aroused a great deal of interest Further work lias been
carried out in this field (I'Li et al., 1911, 1950, 1931,
1956, SH, 1933, 1935, 1938, PAGE, 1916, 1917) on thic
assumption that lie inactivation is due to an enzyme
("oxytoxinase") This properly of pregnant scrum to in.
O NON PREGNANT
21 DAYS PREGNANT
PLASMA
SKELETAL
MUSCLE
KIDNEY
LIVER
UTERUS
PLACENTA
200
400
600
OXYTOCINASE ACTIVITY (DILUTION)
Hug 20 Comparison of oxytocinase activity in pregnant and non
pregnant rat tissue The activity of uterine tissue is increased in
pregnancy (SAWYER, 1931)
activate oxytocin can only be demonstrated in man and
monkeys Attempts to detect any such property in the
serum of a large number of other species (the rat, guinea
pig, rabbit, dog, pig, cow and horse) during pregnancy
have failed The inactivating factor in the serum appears

·-10 Recent Progress in Oxytocin Rescarch extract (Fig. 19). All placental extracts examined in this Jaboratory showed tlus activity which was of the same order for a number of specimens. The action is 1100 strictly specific for oxytocin, since the extracts will also BO 70 age of ong nal activity CO ED 0043 ml/ml 50 x 40- 30 20 10 0025 OOS 01 ml extract/ml total volume Fig 19 Inactivation of synthetic oxytocin (Syntocinon) by a physie ological saline extract of human placenta 101 IU/ml solution of Syntocinon was incubated with various amounts of the extract at 37°C for 10 minutes, whereupon the residual activity was deter muned I ml of extract corresponded to 08 g of placental tissue, dry substance = 3%. total-N = 408 mg/ml, protein-N = 3 86 mg/ml inactivate valyl-oxytocin (BERDE and ZEHNDER, 1958). It is interesting to note that the capacity of the rat uteruis to inactivate oxytocin shows a certain increase during pregnancy (SAWYER, 1954) The same does not apply to skeletal muscle, liver and renal tissue (Fig 20) The discovery that the serum of pregnant women is able to inactivate oxytocin and that its capacity to do so increases as pregnancy advances (FEKETE, 1930, 1932), ·The fate of Dytocin 13 findings in mind, the changes in oxytox inase activity could be regarded as one of nature's protective mcasures for keeping tlic torus 11 test eluring pregnancy. The owy. tocinase would guard the uterus against ovyoxcin present in the blood and released from the neuroly poplıysis in considerable amounts in respxmise to certain stimuli. It has actually been demonstrated erat ulien «xyxxxin is in. fused for five io ton hours, the oxytocinase activity of clie plasma increases (CALDEYRO-BARCIA au POSFIRO), 1938). 600 OXYTOCINASE ACTIVITY 400 200 L.__ 7 DAYS NON PREGNANT 14 DAYS 21 DAYS PREGNANT AT TERM 1 DAY POST PARTUM Fig 21 Oxytocinase actisity of the myometrium in rats at different stages of pregnancy (SAWYER, 1931) This enzymatic mechanism would be an extra-uterine protective arrangement during pregnancy. It would be complementary to the well-known hornonal mechanısını protecting the uterus (KVAL'S, 1930), whereby uterine irri. tability is reduced, possibly as a result of suboptimal intra- ·Recent Progress in Ovytocin Nesraich to differ from the inactivating factors occurring in sarious other parts of the body, e.g. in the crythrocytes, pancreas and ovaries. The serum factor does not pass from the maternal into the foetal circulation. When pregnant serum is subjected to vertical electrophoresis, oxytocinase is found on the cathode side of the albumin stream. The large molecules of serum oxytocinase cannot be dialysed, tlic enzyme is precipitated by 33 per cent saturation with ammonium sulphate, is unaffected ultraviolet radia. tion, but is sensitive to heat. It is rapidly destroyed by boiling and is slowly inactivated by heating at 57°C. Oxulation also icads to loss of activity. The oxytocin inacti. vation curve conforms to that of a first order reaction Above 10°C the rate of the reaction increases with rising temperature The optimum pH lies between 65 and 7.5 and is rather sharply defined Cysteine and glutathione activate serum oxytocinase, but chelating agents, such as ethylencdiamine tetraacetate, inhibit the enzymatic ac. tion Managanese, cobalt and zinc ions restore the lost activity Another chelating agent, 8-hydroxyqunoline, likewise inhibits serum oxytocinase Cyanide, however, does not affect the enzymatic reaction For the time being it is difficult to say anything about the physiological significance of the oxytocin-inactis ating factor of pregnant serum This is mainly because the diflerent authors disagree as to the serum oxytocinase ac. tivity in the last weeks of pregnancy and during laboun According to DICKER and TÜLER (1956) the capacity of pregnant serum to inactivate oxytocin decreases frons the 28th week, and in most cases no such activity can be detected at term. There is a certain parallel between thus finding and the observation that the capacity of the rat uterus to inactivate oxytocin increases during gestation, but is low at term (Fig. 21) (SAWYER, 1954). With these

·The rate of Oxytocin
UNITS
900
250-
100
$0
25
DELIVERY
10
05-
0254
0
5
10
15
20
25
30
35
Fig 22 l'lasma oxytocinase levels in normal pregnancy Ordinate
units per ml plasma (values belon 01 not illustrated) Abscissa
keels of pregnancy, dating from conception (PACE, 1916).

·Recent Progress in Oxytocin Research cellular potassium ion concentration and the effect of the latter on the cell membrane (Csaro, 1956). The decline in scrun oxytocinase activity near to term would provide a convenient explanation of the increase in uterine sensitivity to ovytocin. It must, liowever, be pointed out that most investi. gators have not found a decrease in serum oxytocinase activity at the end of pregnancy, but the opposite. Ac. cording to Wrrre and SEMM (1956), oxytocinase activity can be detected with certainty in the serum from the second month of pregnancy. It remains at roughly the same level from the third to the eighth month and then begins to increase again until at birth serum oxytocinase activity is sixty times higher than at the end of the second monti According to another investigator (Pace, 1946), oxytocinase activity is a thousand times higher in the thirty cighth week than in the fourth week. He found a continuous rise in serum oxytocinase activity (Fig 22) without a plateau between the thurd and eighth month Yet another team of investigators (CAI DERO-BARCIA and Poseiro, 1958) has found oxytocinase activity to be at a inaxunun at term Hence the increasing sensitivity of the literus to oxytocin towards the end of pregnancy can hardly be explained on the basis of changes in serum oxytocinase activity According to most investigators the mactivating factor only begins to decline after delivery Tuppy and NESVADBA (1957) have recently shown that the effect of pregnant serum on the oxytocin molecule is probably to open the ring between the cystine and the tyrosine residue (Fig 23) From this it would appear that the inactivating factor is an aminopeptidase And, in fact, aminopeptidase substrates, viz. the B-naphtlıylamides of glycine, DL-alanine, L-leucine and L-cystine, were lydrolysed more rapidly by the serum of pregnant women in ·1.IBLI II HIDROLYSIS OF VINO-CID - VATITIYLAMIDLS AS THI SERA OF I'R GYNT AND NOY-TXEGNANT , Thrz MATIC ACTIVITY OF THE SER TEKND TP}} 7 AND IS GUITV IN VOB-NHNISLAVINE/100 ML, SIKU /HOLX (TLPPS AND\F514D74, 1957) Substrate - Vophthylamule of Sera Glycine DL-llanine L-leucine 1.-C, tine L-Cysteine (NLMethionine 37 to 40th week pregnant women S43 S + S 15 16 25 19 01 16 10 79 2 81 2 77 6 +7 2 19 6 50 + 6 05 5 80 5 05 000 070 0 58 2 75 3 20 2 95 The fate of Orytorin Vean (1) 17 23 793 491 5 63 0 63 2 97 15 2 0 58 S 71 Non-pregnant women s 72 S73 7 35 $ 85 448 26 1 25 6 128 13 6 0 50 040 010 0 S6 0 0 25 2 25 Jean (16) 8 97 32 2 13 9 013 0 51 28 16./.112 19 25 35 12 11 17 ·46 Recent Progress in Oxytocin Research tlic tliirty-seventh to fortieth wech than by the serum of non-pregnant women (Table VI). Since the activity of the seruin varied depending upon the enzyme substrate employed, it must be assumed that the serum contained more than one aminopeptidase. This type of investigation tales us an important step towards a solution of the "oxytocinase" problem, for it makes use of well-defined reactions permitting accurate chemical determination of the various aminopeptidases in the serumi at different stages of pregnancy. Cy8-Ty-leo-Glu (NH2)-A39 (NH2)-Crº-Pro-Leu-Gly (NH, Pregnant serum Cỹ Ty-leo-Glu (NH4)-Asp (NH, Cy8-to-vu-Gly (NH, Fig 23 The action of dalysed pregnant serum on the oxytocin molecule (Tuppi and NESVADBA, 1957) The inactivating principle acts on the peptide link between the cystine residue and the tyrosine resalue, opening the ring It is still not certain, however, that the aminopeptrclases investigated by Tuppy and NESVADBA (1957) are udentical with the so-called serum oxytocinase of other workers in the first place, the serum of non-pregnant women has been found to possess a quite appreciable minopeptidase activity, whereas earlier inuestigators were unable to detect any serum oxycocinase in non-pregnant Furthermore, the most active enzyme, that hyctrolysing L-cystine di-8-naphthylamide, shows only thir. teen times greater activity (at pH 74) in pregnant women near to term than in non-pregnant women, whereas serum oxytocinase activity has been reported to be sisty, indeed as much as a thousand times higher during pregnancy. Then again, the aminopeptidases studied by TUPPy are inhibited by cyanide and manganese ions which are withivoirien ·CABLE UT HYDROLYSIS OF THNO-ACID AMITHYLAMIDI S MI TI SIX OF I'R GYSTAD SOS-PIGNANT llovi. S INZYMATIC Activity of the SCRIMIS DI TIKVIND 4T PII 7 AND IS GISTING - MATTISTA VINI/100 VI Sext/HTOLK (1UP AND, SI ADUI 4, 1957) Substrate - Naphthstomile of: Seru Glycine DL-llanine I.-L.Cucine L-Cistine L-Cysteine Dl. Vethionine 16 25 17 to 10th wech pregnant women S #3 S 11 S 5 79 2 81 2 77 6 19 03 +7 2 196 50 + 05 5 80 5 05 no 070 0 58 2 75 3 20 2 95 The Case of Orylucan - 16 40 Mean (1) 17 23 793 191 S 63 063 2 97 Non-pregnant women S 71 S 72 S 73 13 7 7 35 5 85 448 261 25 6 15 2 12 8 136 0 50 010 010 0 58 0 $6 0 10 36 2 3 2 25 Mean (11) 8 97 32 2 139 0 43 0 31 28 1/1/2 19 25 131 12 17 ·.18 Recent Progress in Oxytocin Resrarch out effect on oxytocinase, though, both systems are inhibited by chelating agents, eg ethylenediaminc tetraacetic acid. Further research on these lines may well lead to an carly clarification of these problems and so to a better un clcrstanding of the fate of oxytocin in the organism. An inactivation of oxytocin different from that discovered by TUPPY and NESVADBA (1957) lias been de. scribed by RESSLER (1958). It involves cleavage of the intramolecular disulphide bond of oxytocin and the formation of intermolecular disulphide bonds between two or more molecules of the hormone. A less soluble dimer or other higher molecular weight forin is obtained This type of inactivation was found to occur under mildly alkaline conditions in vilro. It is not yet known whether oxytocin can undergo such changes in vivo.

·V OXYTOCIN AND LABOUR The term “oxytocic" is derived from the Greek ofis (swift) and rocos (birth). Ovytocin is therefore aptly named, for it accelerates labour luy cliciting or reinforcing contractions of the uterine sinooth muscle in many species including man 'This property finds clinical application for induction of labour and correction of uterine merria. Oxytocin has a peripheral site of action-it acts directly on receptors in the smooth muscle cells of the uterus-so that in vitro preparations can be used to demonstrate its oxytocic or uterotonic action (Fig 24) In addition to eliciting uterine contractions, oxytocin appears to enhance the sensitivity of the myometriurn to other stinuli (Csapo, 1951) From electrophysiological studies on the rat uterus (Jung, 1957), the primary action of oxytocin on uterine muscle seems to be to lower the membrane potential Thus is followed by a series of tetanic action potentials whicha, with low doses (eg., 0001 IU 1v), are attended by a inechanical contraction. The latent period before these clischarges appear depends upon the hormone concentra With increasing oxytocin doses, the amplitude of the action potentials as well as the time that elapses before the peak potential is rcached, both decrease But the most remarkable plienomenon is that the muscle remains contracted long after the action potentials have died away (Fig 25) It may be concluded from this that the protton 49 ·-18 Recent Progress in Oxytocin Rescarch out cllect on oxytocinase; though, both systems are inhib ited by chelating agents, eg. etliylenediamine tetraacetic acid. Furtlier research on thesc lines may well Icad to an carly clariſication of these problems and so to a better un. derstanding of the fate of oxytocin in the organism. An inactivation of oxytocin different from that discovered by Turry and NFSVADBA (1957) has been described by RESSLER (1958) It involves cleavage of the intramolecular disulphide bond of oxytocin and the formation of interinolecular disulphide bonds between two or more molecules of the liormone. A less soluble dimer or other higher molecular weight form is obtained Thus type of inactivation was found to occur under millly alkaline conditions in vitro. It is not yet known whether oxytocin can undergo such changes in vivo ·O vytocin and Labour 31 oxytox in levels that obtain in the sequence of cients in childbirth. This question, moreover, is of commsılerable biological interest. There is really only one finding at odds with the supposition that oxytocin may be implicated in labour, (03 mV a 1 sec. b 12 VI с d Fig 25 The action potentials and mechanical responses of a rat uterus under the influence of increasing doses of oxytocin Following large doses the tonus stays high even when the action potentials have subsided In trace "d" the action potentials are sery low and are of a different kind as can be seen even at this recording speed (Jung, 1937) ·50 Recent Progress in Oxytocin Research 2 1 2 I'ng 21 The effect of synthetic oxytocin (Syntocinon) on an 180- lated strip of human uterine muscle Caesarian section was performed on the 15th day after term At 1, 002 1 U. and at 2,001 IU of Syntocinon was added to the organ bath (50 ml) At | the bath Was washed out twice Time 1 minute The response was de pendent upon the dose tracted shortening of the uterine smooth muscle, the socalled "tetanus uteri," elicited by high doses of oxytocin, is not really tetanus in the true sense of the word, but a contracture However, recent studies (Evans et al., 1958) suggest that the action of oxytocin on uterine muscle is not exclusively mediated via changes in membrane potential: rat uteri were immersed in RINGER's solution in which sodium was replaced by potassium. Although the uterı had no measurable membrane potential they still contracted in response to a number of smooth muscle stimulants including oxytocin It seems possible, therefore, that oxytocin may activate the contractile elements without invoking the mechanism of membrane depolarısation. A question of much interest to the clinician, and especially to the obstetrician, is whether oxytocin is actually a physiological factor in the process of labour If this were the case, it would be interesting to know the physiological ·Olytocin and labout sary to administer roughly ciglit times more oxytocin 111 the 20th acck and twice as much in the 30tl iveck than at term (Post, and CALDERO-Ilakcia, 1958). The increase in sensitivity is mainly confined to the cornis (Fig 20) 1 MID FREGNANCY ARE PARTURIENT 30 Responsen Hy CA 10 025 os 2 B 025 05 10 DOMA IU Quytorm 11 26 Increase in the sensitivity to ositocin of the corpus uteru at the end of pregnancy Sunultancously recorded responses of Corpus (Co) and cerin (x) are ploted against the dose of oxytocin (*) at the stages of pregnancy At mit pregnancy (22 weeks) thic etical responses are consistently greater than those of the corpus, wist in a cou 36 hours before delivery the corpus responses are the greater (IT/PATRICA, (1157) (FITZPATRICK, 1937) whell, by its contractions, contributes to the expulsion of the loetuis during labour The sensi- Pility of the cervix does not appear to be enhanced at term Thus is in keeping with the passive role of this part of the uterus in the process of labor So pronounced is the increase in uterine sensitivity to oxytocin at term, that it ·52 Recent Progress in Oxytocin Research painely oxytocin is not found in higlier concentrations in the blood of women in labour (IIAwarr and ROBERTsox, 1956). This clearly cannot be ignoree, but it sloull be pomted out that the methods it curent trse for estimating oxytocin in the blood are beset with considerable difficulties (see Chapter IV). The results of such esti. mations are frequently contradictory and a certain cali. tion should be exercised in evaluating them, bearing in mind that transient, periodic fluctuations in the blood oxytocin level could conceivably occur and pass unnoticed Experimental evidence to be discussed belon suggests that the blood oxytocin level may well be subject to periodic fluctuations of this kind. There was formerly a great deal discussion as to wliether or not labour was retarded by hypoplysectomy or sectioning of the pituitary stalk, since the experimental findings (recently reviewed by HARRIS, 1955) were contraclictory This subject has lost some of its interest, for it is almost certain that the so-called posterior pituitary liormones are produced in the hypothalamus, and the median eminence of the tuber cinereuin is known to be as much a part of the neurolypophysis as is the posterior lobe itself The view that oxytocin plays a part in labour finds support in the complete analogy between normal, spontaneous uterine contractions and uterine moulity elicited ly oxytocin appropriately administered in correct dosage Tlus applies to the shape, intensity, frequency, duration, tonus as well as to the co-ordination of the contractions in women (CALDE) RO-BARCIA and POSEIRO, 1958) Evidence that oxytocin partcipates in the playsıological processes of normal birth is likewise furnished by the observation that uterine sensitivity to tliis hormone ific reases at term For a comparable response it is neces.

·Ovytocin and Labour 55 au le employed to predict with a ligh degree of prolbility wietlicr rupture of the membranes will incluce tour (Svyru, 1958a, 1958): il a uterine contraction clicited by intra chous administration of 0.011 U./min ytocin up to a total ol 1.03 1.U. the chances of successal surgical induction are goodi (l'ag. 27): if the uterus re. ronds only to greater announts of oxytocin, the immediate hances of successful surgical induction are slight. Table 'It shons that the ovrocin sensitivity of Ilie uterus is also useful guide to the probable date of spontaneous unset f labour (Nr\os and Swits, 1958) The response of the terus to oxytocin is, furtlier, a tselul indication as to hether medical induction of labour is likely to be suic. essful (MULLER, 1938). TIBLE WIT TIF SCALF OF SENSITIVITIES IPFLICABLE FOR ISSISSING TUF PRODABLE O SET OF LADOL OK Falsr LAHOLK (NIV AND SHYT1958) = Sensitivity-total units ory toxin Probable days to onset 001 0 02 0 03 00+ 0 00 0 08 0 10 Sime das same day or next day next da 2 days 3 to + June S to 6 dan a week An observation by GUNTUFR (1948) has a close bear: ng on the question of oxytocin secretion during labour he noted in a lactating womnan in labour that each uterine ontraction was accompanied by a spontaneous ejection of milk The phenomenon of milk ejection is now known

·54
Recent Progress in Oxytocin Rescarch
Primipara -
Muitspara = x
300-
200
***
*
100
TIME FROM INDUCTION TO ONSET OF LABOUR (hours)
50-
..
х
10
05-
01 -
..
.
001
002 003
OXYTOCIN SENSITIVITY (units)
Fig 27
Relation between oxytocin sensitivity and onset of labour
after amniotomy in patients sensitive to less than 001 IU oxytocin
The correlation is significant at 200 I probability (Syst, 1958a)

·Lactating cats (+) 2 750 2,269 3 - 108 +32 3 1+2 +1+ 3 629 Normal dog (8) 12,313 5,218 2, 140 =7229 7,050 *+20 0.6:00 +1.830 6,600 +1.480 90 30 1 6+ * 16 180 1.020 +122 1 6,950 +505 3 500 + 1,021 1.220 203 +5 2 38 +18 + 138 01 03 #14 7 65 193 1+ 500 5911 28 0 113 + - Female dos Deliser (3) Female dogs, Lactating (4) 12,000 S350 13 23 5 41 +139 131 *244 Data for dogs are taken from a paper bs DICKFR and Tux (1953) Number of asumals in parentheses Orytocin and Labour ·+ 450 | +99 FABLE VIII 56 RULATION BETWIIN VASOLKI SSOR (1) AND OXYTOCIC (O) ACTIVITILS OF THI PITUITAKY GLAND AND BODY TIGHT AND Rope SuktacI, AND TIN EUCE O DUTIVE KY AND LACTATION, IN ADULT RATS, GUINE A-PIGS, CATS AND Dogs (DICKER AND Tyrr, 1953h) ml' /gland ml' /100g Isods ut mU/100 cm Bodyt Surface (cm') Iverage 1o. of V/O littermales 0 0 V O Lault rits (18) 230 325 150 100 1 14 350 + 100 330 # 51 + 186) 288 1 73 9 216 314 Recent Progress in Oxytocin Research 240 1 85 10 320 190 * 249 1 30 + 238 240 70 4 460 187 2 129 Female rats, Delivery (5) Femile rath Llitating (6) Idule gunned pigs (10) I'mule guline.l- Deiner () Female guine pigs, Luting (2) Mormlats (4) 130 96 105 +150 71 #21 8 61 +12 7 79 +20 6 19 411 181 +29 5 131 +50 5 145 #808 135 +28 3 69 101 95 + 9 3 07 * 8 9 15 +11 8 54 +15 9 81 +22 2 21 +56 6 600 #122 0 770 *13+ 2 470 116 +18 3 85 * 27 3 128 +23 7 135 +29 4 76 2 13 538 514 1 88 682 620 3 64 3 3140 2 302 3,870 *262 0 3,250 + 160 3 126 +10 3 108 + 10 9 1 19 168 + 96 141 +18 3 .

·Ovytorin and Labour 59 tinuously recorded and calculated in Montevideo umus (amplitude of contractions in mm. Hg x frequency of contraccions per ten minuie interval). There was found to be it clearly dcfined relationship beticen the amount of ory. cocin infused and the resultant uterine activity (Fig. 28) Iudeocl, it uiterme activity and otocin close are plotted on a stable scale, a rectilinear relationship is obtained TONUS conteCHONS VERINE ACTITY NTENIMFNEOUENCY mm Hgmm Hg per mon WONTEWOO UNT mm Hg 12.30 Moura 0 الجالياتافه 7 32 2 54 13 3 rourt 7 23 94 14,30 hours Ett a 27 15 30 hours 80 40 S8 29 709 OXYTOCIN INFUSION RATE mU) minut O 18.30 hours 8 en 10 69 32 218 0 n 30 hours 19 30 hours 13 75 38 270 1930 hours 14 77 42 323 minutee Fig 28 Seven sections from a record of uterine contraculty obtained in a full term pregnant women Section Ostions the spontaneous contractility The subscquent sections show the contractility produced by the infusion of orstocist at the rates of 1, 2, 4, 8, 10 and 32 mU/min The average salues of the tonus, intensity, frequency and uterine altity are indicated for each section In section 16 the recording has been temporarily interrupted (CALDE1 BO-BARCIA et al, 1937b) ·58 Recent Progress in Oxytocin Research to be due to the release of oxytocin from the neurohypoplıysis (see Chapter VI). This observation would therefore imply that there is a periodic rise in oxytocin secretion during labour which coincides with the uterine confractions. A similar observation has recently been made in rabbits (Cross, 1958b): it lias been estimated from the mill-ejection pressure that some tnenty mV. of oxytocin may be released during expulsion of a ſoetus. Another important finding in this connection is that electrical stimulation of the supraoptico-hypophyseal tract in anaesthetised pregnant rabbits at term can induce labour in the same way as intravenous administration of 50 to 200 mU. of oxytocin (Cross, 1958b) In conclusion it should be mentioned that the orytocin content of the hypoplysis decreases during labour (Table VIII) in both rats (Dicker and Tyler, 1953b, ACHER and FROMAGEOT, 1957) and dogs (DICKER and Tyler, 1953a) There is a certain parallel between this finding and the observation that the oxytocic activity of the urine of pregnant komen is higher than that of the urine of men and non-pregnant women (COCKRILL et al., 1934). There is thus quite a considerable body of evidence to support the view that oxytocin may well be one of the physiological regulators of uterine activity during labour it oxytocin actually were a physiological factor in the process of birth it would be of considerable importance for the obstetrician to know the amount of oxytocin-se. creted during labour For this reason the direct tocometric investigations of CAI DE) RO-Barcia et al (1997a, *T67), 1958) in women shortly belore delnery are highly inter. esting These investigators administered synthetic oxytocin (Syntocinon) by intravenous drip infusion in various doses, each dose for one hour l'terine activity was con- ·Oxytocin and Labour mnotility at the end of the first stage and in the second stage can lie simulateci by giung alsout & mU/min.; and the must powerful contractions occurring during the second stage can be unitated by administering about 16 mV./min. This latter infusion rate may ixcrasionally clicnt uterine comtractions more pouerful than those oc. curring in spontaneous la jour. From these findings CAIDE DRO-BARCIS his co-hothers conclude that the plıysiological secretory activity of the steurolypophysis using the different stages of lafuur is probably within this range hypothalamus oxytocin cervical dilatatron Fig 30 Diagram of the IRCLSON Teller Dilatation of the ceryxx and less consistenth dilaldian of the corpus augments uterme mouility by reflex release of oritocin (CALPFYRO-B4034 dl al, 1957a) "These are average salues pertainmg to physologscal conditions in pathological states the imatulty of the uterus may be different Thus 161 toxacmia of pregnancy sensitivity to ortocin is enhanced, while in polyhydramnios and vxoedema, and in elderly phimigravadac, 45 lowered (CALDEYRO BARCHA and POSEIRO, 1958) ·60 Recent Progress in Oxytocin Research (Fig. 29). Uterine activity at the commencement of labour (cervix 2 cm) can be simulated by giving an intravenous drip infusion of 1 to 2 mU./min of oxytocin; uterine AUA 250 - Amar UA-237 Montevideo Units 2001 INCREASE OF UTERINE ACTIVITY (Montevideo Units) 150 AUA-113 91 R-21 100 50 (Rint)-o -047992 050000 1. Rint) 18942 034295 056829 081363 096526 inf-1 inf-2 inf-4 inf-8 inf-16 Fig 29 The exponential relationship between the oxytocin in fusion rate and the increase of uterine activity in full term preg nant women The increase of uterine activity (AUA) is plotted against (1 e Rinl) The values of infusion rate (inf) are indicated below the corresponding value on the abscissa The straight line represents the theoretical function Black circles show the experi mental average values of the 8 records The white urce is the baricentre of the straight line correspondıng to the mean value of both coordinates The black squire corresponds to abscissa equal to one and ordinate equal to (Am.U4) (CALDEYRO BARCIA et al, 1957b) ·Oxyform and Labour this reller also operates during labour.* It is conceivable that a sort of chain reaction could occur as labour prog. resses: dilatation of the cervix lezcling to release of oxy. tocin, increased secretion of oxytocin eloling contraction of the corpus and fundus, and this in (im causing further Bilatation of she cervix, and so on. It is instructiic to compare the levels of "physiological secretion" of oystoxin in the human ſemnale, as estimatel by CALSESRO-BAXCIA, with the oxytocin doses recommended by obstetricians for induction of labour or correction of uterinc inertia THEOBALD, the origmator of oxytocin therapy by imras enous drp infusion (1918), recently recommended an initial infusion rate of 07 10 1,8 mU/min for induction (1957), i e. a dosage almost identical with CALDEYRO-B 48CiA'S "physiological" level at the commencement of the first stage in spontancous labour. The last few years, in fact, have witnessed quite a general trenct in the literature (sec Table IX) inwards Oxytocin infusion rates of the order of the "physiological levels indicated abose. There would this appear to be a valid case for regarding sell condutted intrasenous infusion of ovytocin as physiological subscrution therapy raclier than pharmacological intervennon, She HERCESOIN seller cannot ik demosstrate non pregnant and nals (CROSS, 19582) ·62 Recent Progress in Oxytocin Research The rise in oxytocin secretion as labour proceeds is explained by the FERGUSON reflex (1911). Dilatation of the uterus, but more especially of the cervix, acts as a secretory stimulus on the neurohypophysis (Fig 30) FERGUSON made his observations on postpartal animals, but it has recently been demonstrated (Cross, 1958b) that TABLE IX DRIP INFUSION RATES FOR THIC INTRASENOUS ADMINISTR 4TION OF OXITUCI IN WOMEN (CALDES RO-BARCIA et al, 1957a) Infusion rate ml/min Author 05 - 2 1 25 - 25 2 2 5 - 5-10 - 8 9 4-15 4 - 25 5 - 20 6 - 16 7 - 10 Greenhill (1955) Nixon and Smyth (1957) Carey (1951) Faris and Kahlenberg (1951) Theobald (1948) Bishop (1955) Ilhite (1955) Holland (1955) Ratzan and Shulman (1955) Labate and Barbaro (1951) Lizana Farías and Fernández Popelaire (1953) Bosch and Kaser (1956) Bunbridge, Nixon, Schild and Smyth (1956) Engstrom and Ohlson (1956) Varangot and Côte (1955) Richon and Braye (1955) Parker and Roberts (1954) Cazzola (1955) Mathew (1956) Savı (1956) Fuster, Queralt and Varela (1951) Williams and McMahon (1956) Moore and D'Esopo (1955) MacKenzie (1954) Hellman (1919) Hellman, Harris and Reynolds (1950) Tisné (1955) Pigeaud (1952) Cantarow (1951) Hukull (1955) Piton (1952) Kaufman (1953) Dexeus and Segur (1955) Creze and Rouchy (1957) Molina Yañez (1955) 7 - 15 7 - 21 7 - 25 10 - 20 15 - 25 30 10 - 40 30 - 40 30 - 60 ·O fociu and Lactation lerous elucts and sinuses, Lin bir drann out by the me chanical action of suchling or kung The greater part of the milk, however, is in the alcoli and finer ducts which cannot be chciated by suckling at making alone, but only with the aid of the contractile system of the mam. mary gland. The milk munst be forced into the large ducts comerging on the apple. Tlus pexess is 1105 as milk ejection or let dou ni The contractile system responsille for the milk ejet tion reachon consists of special myocpithelial cells (basket cells) of ectodermal ongin, not, is might be imagined, of smooth suscle cells (RICIJAKEYSOY, 1949). Bashet cells can be demonstrated throughout the whole mammary gland, they are present in large numbers, thimmately associated with the aiseols and fine cats, and are therefore able to cxercise the necessary {v}}{rie ule forze The imik-ejection FCILLION Whil is accompanied by a measurable rise in pressure in the mammary glanl, results from the dnech action of oxytocin on the rivepithelial cells (L.IZFIL. 1955) The rise in pressure in the ducts comerging on the nipple in response to oxytocin is so characteristic that in suitable tests it can be employed to detect sinali amounts Oxytocm (Cross and HARRIS, 1951/52, VAN Dire et al, 1955, BERDE and CERLET), 1957). and for the broassay of oxytocin preparations figure 31 slows part of the traying from an experiment in with a synthetic oxytocin preparation (Syntoxinon) was compared with Internatronal Standard Prtuitary (Posterior Lobe) Powder on the mammary gland of a lactating doe rabbu, using Sciw's (1942) four-pom assa; design It should, hokerer, be added that the milk let-down reaction is not entirely speuhc for oxytocin the myoepithelial cells show a realer or lesser response wsth other allied polypeptides ·VI OXYTOCIN AND LACTATION As "S FAR AS clinical medicine is concerned oxytocin is still primarily an oxytocic However, its action on the uterus is by no means its only important biological prop. erty Oxytocin is also mainly responsible for the effect of the neurolypophysis on the lactating mammary gland This eff is just as specific as the action on the uterus, and, seen from a biological viewpoint, it is just as important There is a coherent body of convincing data to indicate that a reflex liberation of oxytocin occurs whenever a mother takes her child to the breast, whenever a young animal suckles or a cow is milhed A neurohor monal reflex involving oxytocin would seem to be essential for complete emptying of the mammary gland So specific is this action of oxytocin that a response can be detected in the mammary gland of a lactating woman with 001IU in a single intravenous injection (Beller et al, 1958) and with as little as 0 1 10 0 2 mU/min iv (THEO BALD, 1958) Similarly in the lactating rabbit 0 0005 I U of oxytocin iv (Van Dyke et al, 1955, BERDE and CER- LETTI, 1957) may elicit a measurable response The rôle of oxytocin in lactation has been thoroughly investigated in recent years (see for example PETERSEN, 1914, Cross and HARRIS, 1951/52, Cross, 1955a, FOI LFY, 1956, Cowie and FOLLEY, 1957, LABOUCHE, 1957) We now know that only a part of the mill present in the mammary gland, namely the milk contained in the large lacui- 64 ·Owlocis and Lactalon 07 which can be regarded as the reflca centre, 3nd results in a release of oxytocin by the sicurohypoplysis The lormone is carried to the manumany gland in the bloxxl streamı and constitutes the efferent lummoral) arc of the neuro hormonal relles. Afferent arc (nervous) Efferent arc (humoral) oxytocin Fig 32 Schemasc representation of the mulhejection reflex de chanical stimulation of the mammulla actssales the afferent (nerious) reflex are Oxytocin is then seleased from the neurohy poplyses to forss the efferent are of the neurolormonal reflex The presence of a humoral factor in the blood, in- Solved in milk ejection, has been demonstrated to par ticularly good effect in experiments on the isolated cow udder (PEETERS et al, 1917) Blood talen from a cow Prior to application of the milling simulus and perfusex?

·06 Recent Progress in Orytocin Research Vasopressin, for example, has a weak, but measurable effect (Fig. 4) (Vav Dyke et al., 1955), and all the oxytocin analogues we have so far investigated in the milk-ejection test have been found 10 produce a greater or lesser response (Bernr. et al., 1957) (Table II). A B с mm Hg 140 100 cm 120 6 60- 5 3 2 1 CATE 1 0 Fig 31 The action of oxytown on the pressure in a duct of the mammary gland of a lactaung rabbit under urethane anaesthesia Above blood pressure, bclou milk ejection pressure Time 30 Sec The is injections were made at intervals of 3 min A = 0001 IV and C = DOUS IV of International Standard Pituitary (Pos terior Love) Powder, which contains natural oxytocin B = 0.000083 ml and D = 0 000166 ml of a Syntociron (synthetic ox! tocin) solution Taken from a four point assay. The release of oxytocin during suchImg or lactation is trought about by the milk-ejection reflex mechanical stimulation of the mamilla is the physiological stimulus actuating the afferent (nervous) arc of the reflex (Fig 32) Tlie stimulus is conducted to the hypothalamus, ·Oxytocin and Lactation 07 which can be regarded as the reflex centre, and results in a release of oxytocin by the neurolypoplysis. The lor. mone is carried to the mammary gland in the blood strcam and constitutes the efferent (luumoral) arc of the neuroliorinonal reflex. Afferent arc (nervous) Efferent arc (humoral) oxytocin Fig 32 Schematic representation of the milk ejection reller Me. chanical stimulation of the mammilla activates the afferent (nervous) reflex arc Oxytocin is then released from the neurohypophysis ta form the efferent are of the neurohormonal reflex The presence of a humoral factor in the blood, involved in milk ejection, has been demonstrated to particularly good effect in experiments on the isolated cow udder (PEETERS et al, 1917) Blood taken from a cow prior to application of the milking stimulus and perfused ·08 Recent Progress in Oxytocin Research through an isolated udder liad a inuch weaker milk let. down effect than blood taken from the same cow following such a stimulus (Table X). Although measurements of the blood oxytocin level in women lase not revealed any increase during lactation (HAW.FR, 1958), there is evidence to suggest that a humoral factor similar to ory. tocin is present in human feniale blood during suchling or after stimulation of the mamilla. Thus milk ejection occurs in both breasts even if only one nipple is stimulated (Newtox and NEWTON, 1948) and stimulation of the nip ple at the end of pregnancy, during labour or in the puerperium, results in heightened uterine nioulity (LORAND and ASBOT, 1952) PABLE X E PULSION OF MILK FROM THE TWO HALTES OF A BOUıl UDDLR, PERFUSED WITH BLOOD FROM THE SAME Cow BEFORE AND AFTER \PPLICATION OF THE MILKING STIMULUS (PECTERS et al, 1947) Amount of milk expelled from the udder Experiment No Left halt perfused with blood taken before muling stimulus applied ml Right half perfused with blood taken after mulhing stimulus applied ml 300 2 3 160 270 215 390 520 345 500 + The reflex nature of the milk-ejection reaction can be seen from the latent period of the response in the rabbit which amounts to 7 to 15 seconds following intravenons injection of oxytocin, 13 to 25 seconds following electrical ·Orytocin and lactation 69 strinulation of the supraoptico-lypoplyserl (:301, and 30 to 90 seconds after commenceinent of suckling (Table XI) (Harris, 1955). Tlie nervous component of the reflex appears to involve botlı acisenergic and cholinergic synap. ses (GROSVENOR and TURVER, 19571). Tlie reflex can be conditioned both in animals and the Imman female (WALLFR, 1938) and is abolished by anaesthesia, though oxyroxin encits al ejection even in anacstrictiseci anı. mals (Gailes, 1913; Cross, 19551, COWiF and FOLI E), 1937; GROSVENOR an TURVER, 1937a, 1938a). Emotional influences can adversely affect the mid-ejechon reflex hoch in animals (F.1.x anci l'£lkRSON, 1911. Cross, 1952/53a) and in the human female (NEWTON and NEWTON, 1948) Such mluvitory effects would appear to insolve the sympa. thico-actrenal system (Cross, 1932/33!), 1935.) DIBLE XI T24 FACTORS IN TI Vila-El CTION RAIN THE RARRIT (lakkis, 1955) =====----== ===-=-- Milk-ejection proces observed after Stimulation of the supraoptico-hipophy 11 trait Sormal sucking Latent period 13-25 set 30-90 er Duration of response 2- 7 min 2-51 mm In line wuh the increased liberation of oxytocin, the hormone content of the hypophysis is depleted during lactation This lias been observed in the rat (Dicker and TYLER, 1953b, Acher and FROMAGFOT, 1957), in the dog ·70 Recent Progress in Oxytocin Research (Dicker and TYLER, 1953a; Van Dyke et al., 1957), in the guinea pig and in the cat (Dicker and Tyler, 1953b) (Table VIII). However no decrease in hypoplyseal hormone content has been observed in the lactating goat (FOLLEY, 1956). In addition to promoting the withdrawal of milk (galactokinetic effect), oxytocin appears to participate in. directly in the actual secretion of milk (galactopoietic effect). Certain experimental findings (Bexson and FOLLEY, 1956a) indicate that oxytocin acts as a stimulus to the secretion of prolactin and/or other anterior-lobe lormones responsible for milk production. Involution of the mammary gland such as is observed when a lactating animal is deprived of its young can be retarded by oxytocin injections No such effect can be demonstrated in hypoplıysectomised animals (Benson and FOLLEY, 1956b, 1957). This view finds support in the observation (DESCLIN, 1956a, 1956b) that a clear-cut luteotrophic activity can be demonstrated in non-pregnant rats several days after a single injection of oxytocin The luteotrophic hormone (LTH) is, however, identical with prolactın. Oxytocin is assumed to bring about the release of prolactin by acting clirectly on the adenolıypophysis.* Direct anatomical communication between the neurolıypophysis and the adenolıypophysis is actually provided in the portal circulation of the hypophysis (Popa and FIELDING, 1930, WISLOCKI, 1938; GREEN and HARRIS, 1916/48) small arteries from the internal carotid and the * Apparently, this mechanism is not unique Another example of a hypothalamic hormone stimulating the anterior pituitary is the corticotrophın releasing factor or CRF This polypeptide, which chemically seems to be related to vasopressin, is found in the hypothalamus and acts on the adenohypophysis enhancing the secretion of ACTH (SAFFRAY, 1938, GUILLEMIN et al, 1957) ·O vytocih and Location 71 Jxosterior communicating arıcry supply the pars tuberalis of the alenolypoplıysis Thcir capillaries extend 2110 the median eminence (neurolypophysis). The blood from this primary plexus collects in portal ruhs and then passes w a second capillary bel (tie simusoids) of the pars distalis which is a part of the allenary papłzsis. The vascular system is thus a circuit containing twn capillary cals, so that any neurolypophyseal factors could act di. rectly on the adenolypophysis (Fig. 33). Opoc chats Marmary body Hypothalamua Porubarake Modianominence Pars itarmedia und triar som Novrutypophy Pudimas Infundibular proces rig 33 The purtat circulation of the fly poplaysys s the rallit blond in artery first circulates through a part of the neuroly po pl}$15 The blood from the capillaries then collects in portal trunks and is distributed through a second capillary network, so that it als circulates through a part of the adenohypophysis before leaving ific gland lyser B 1 his diagram is based on two ]}ustral tions in a book by HARRIS (1955) The view that oxytocin might exercise a prolactinreleasing effect has not gone incontested (GROSVENOR and TURNER, 1958b), but the idea is none the less an attractue one. It would mean that the organism was very thriſty with its oxytocin. for the latter on being released into the blood stream in response to the suckling stimulus would have two different actions on the mammary gland. One ·72 Recent Progress in Oxytocin Research would be a direct effect: contraction of the myoepithelial cells and let down of stored milk. The other would be an indirect effect mediated via the anterior pituitary and operating to maintain milk secretion While the uterotonic action of oxytocin is widely employed in obstetrics, the clinical application of its effect on the mammary gland has been ratlier neglected in spite of the fact that milk let down can be promptly clicited in lactating women If oxytocin is administered by the intravenous route the latent period is only 22 to 37 seconds (NICKERSON et al, 1954). The latter years have seen an increase in the number of clinical publications reporting successful therapeutic application of this property tocin, especially in postpartal engorgement of the breast and in other cases in which the mother seems unable to nurse the baby adequately (e.g. NEWTON and NEWTON, 1951, HAEGER and JACOBSOHN, 1953, Varangor and YBERT, 1955, PARDI, 1956, MASSANO, 1956, DOUGLAS et al, 1957, COLACURCI, 1957, STEWART and SLEZAK, 1958, HOL- LENBACH, 1958) Since oxytocin is effective in such cases when administered intranasally (NEWTON and Eoli, 1958, BAUMGARTEN and Watzek, 1959, WENNER, 1959) thus therapy will probably gain greater popularity. of oxy ·VII SOME OTHER ACTIONS OF OXYTOCIN It was es siost 11 in passing in (trapler !!! thae copula. tion is one of the stuult larch lead to release of ovyt0411). As soon as the con catches sight of the bull, its litering mouslicy increases (VAS DE VARA and Hars, 1952), and When the vagina andł merus of the cou are summulated the blood oxytocin concentration rises frem 120-100 kl/m lo 120-850 pll/ml (l'Ir2PATRICA, 1417) I'm the aid of the mul-coctron react1011, it can be demonstrated that Oxytocin is also relejsed on the iman female during contus (HARRIS and I'CHES, 1953), the amount of hormone liberated being greater if an orgasın is attained (CAUTRELI and PFSEN, 1959) Flowest omal studies have recalezl that me re mechanical stumutation of the uterus, agma or subsa, kithet axtual presence of the male, will Cause a simular reaction The findings from a number of S13 studies are summariser in Table XII It is assumed that ons toxin released during collus. re the uterine notility eke ned by the hormone, accelerates the ascent of the spermatomas in the female repro ductae tract (VA Descarx and Hass 1952. Cross, 1975) This assumpuon seems justified, sine e in many species the ascent of the spermatozoa is far more rapid than can be accounted for by the inherent moulity of the spermato703 13 ·74 Recent Progress in Oxytocin Rescarch TABLE XII OXYTOCIN-LIKE RESPONSES DCE TO COITUS OR MECIIANICAL STIMULATION OF THL, UICKUS, THC VAGINA OR THF VULYA (FITZPATRICK, 1957) Species Stirnulus Response Author Mating Nating Mare Mating Milk ejection Hammond, 1936 Man Mating Milk ejection Pichles, 1953 Man Mating Milk ejection Harris & Pickles, 1953 Man Mating Milk ejection Campbell & Petersen, 1953 Cow Milk ejection Hays & Van Demarh, 1953 Cow Milk ejection Campbell & Petersen, 1953 Cow Mating Uterine motility VanDemark & Hays, 1952, 1953 Bitch Mating Uterine motility Evans, 1933 Goat Manual cervis Mulk ejection Andersson, 1951 Cow Manual cervix Milk ejection Hays & Van Demark, 1951 Cow Manual uterus Milk ejection Tgetgel, 1926 Cow Manual uterus Mlk ejection Piana & Curto, 1950 Cow Manual uterus Milk ejection Usuelli et al, 1952 Cow Manual uterus/cervix Milk ejection Hays & Van Demark, 1953 Cow Manual vulya/cervix Uterine motility Van Demark & Havs, 1951, 1954 Rabbit Stretching cervix Uterine motility Ferguson, 1941 Rabbit Manual vulva I terine motility Krehbrel & Carstens, 1939 Rabbit Increased intrauterine [terine motility Reynolds, 1930 pressure Cat Increased intrauterine C'terine motility Schubel & Gehlen, pressure 1933 ·Some Other actions of Oxytocin 75 themselves. Morcoser, immobile spermatozoa and spermfree liquids are also transported along the reproductive tract. For example, transport of methylene blue, jartus green 13 and ioclochlorot has been oliseried in oestrous rabbits after artificial stimulation of the vulta (KRFIRIFI. and CARSTENS, 1939): the dyes reached the tulval end of the uterine horns tno in five minutes after commencernent of stimulation. At the present time it is not known wheller oxyacan plays a physiological role in menstruation, and for this reason it is difficult to interpret the therapeutic effect of ile hormone in dysmenorrhoca ("VOODBURY, 1950). It has been reported that oxytocin will abolish the signs and symptoms of dysmenorrhoea provoked by vasopressin As yet it is unpossibile to say whether thus is an effect isased on some physiological interplay berneen the tho hormnones, or whether the action of the oxytocin is purely pharmacological On the whole we liave good grounds for assuming that oxytocin participates in a number of reproductive functions in the female oxytocin released during coitus accelerates the ascent of spermatozoa in the reprocluchise system; oxytocin secretion resulting from dilatation of the cervix and body of the uterus increases the contractile activity of that organ during labour, and the release of oxytocin in response to stimulation of the mamilla facil cates the emptying of the mammary gland during lactation, simultaneously promoting the postpartum inuolution of the uterus Oxytocin may even be involved in menstruatron. But what is the biological role of this formone in the male? What functions does it perform in the female other than those mentioned abovet Oxytocin lias been This question has recently been series suy rich ·76 Recent Progress in Oxytocin Research IU. Pıtressin/100 g rat 000025 00005 0001 0002 0004 0008 2016 180- 170 - 160 B 150 140 1 130 120 Time of maximal rate of urine excretion (min) 110- 100 90- BO- 70 60- 016 00312 00625 0125 025 05 TU Pitocin or Syntocinon/100 g rat Fig 34 Comparison of the antılıuretic ditivity of vasopressin (Putressin), natural oxytocin (Pitocin) and synthetic oxytocin (Syn tocinon) in unanaesthetised rats 7 he antidiuretic activity of oxy tocin is about 15% of its oxytocic actutt (BERDF and CARLITTL, 1936) ·Some other actions of Oylacın found in the blixul of men and non-parturient and trottlactating nenen (1315r el al., 1936; Bisset and LFF, 1957). Moreen or the pituitary glands of male animais contain considerable amounts of stokin (Hakfx and TYLER, 1933). The first iliing that springs to inund in scching an answer in these questions is the influence of oxytociti oni renal function. It has been demonsirated (VAN DIE et al., 1933, Kovt.IT, et al, 1936, BERD} and CurlFrTI, 1950) that oxytocin las an ancidiuretic effec in high doses (Fig. 3). This is not surprising as ostakin and vasopressin are rather similar in structure (sec Chapter 11) The antidiuretx sutivity of oxytoxin is actually so slight. amounting to learely one per cent of its oxytocic activity, eliat it should perhaps le regarded as a pharmacological rather than plysiologit al property Another action of oxyrexin, and one of some biological significance, is that in die rat it caurses in reascd ex. cretion of water, sodium, potassium and chorale (FRASER, 1937, 1912, Kusculis and BUNOSCRIVII, 1999. SCHAU- MAYY, 1919, BERDE SIX CFRLFM11, 1956, CRUSATTO et al, 1956. BRUNNER et al, 193f), 1977) The stimulant effect of Oxytocin on druresis was first described by TRASFR (1937, 1912) wlio employce Burt's method (1931) in waterloaded rats These experiments have since been repeated (BERDE and CEKLITTI, 1936) with synthetic oxytocin (Syria toxinon) The results obtained brore om FRASER's obser13- tions, proving that the diuretic effect is due to oxytocin itself and not to some other factor that might be present in posterior-lobe extracts. The dmuretic effect is brought out more clearly in thursting rats (BRUNSER et al, 1956) and in rats loaded with physiological saline Under these conditions a clear dose effect relationship can be obtained (fig. 35) ·78 Recent Progress in Oxytocin Research Oxytocin has no diuretic effect in lypophysectomiset animals. However, if such animals are given NaCl anı desoxycorticosterone, they will give a diurctic response oxytocin (CrOxatto and ZAMORANO, 1957). In a certain dose range oxytocin will antagonise the antidiuretic el fect of vasopressin (FRASER, 1937; BRUNNER et al., 1956 ti 600 500- 400 - Urine excretion as 's age of the control group value 300 200- Control group value 100 0 O 0125 005 02 Da 32 Syntocinon IU /100g C Fig 35 The diuretic action of oxytocin Male rats recenved 25 ml/100 g of 09% NaCl solution at body temperature orally, and were then given the test quantity of synthetic oxytocin (Syntocinon) sc Each oxytocin dose was administered to a group of 20 animals The urine excretion was measured for 5 hours, and the urine output of the control group was taken as 100% The mean values () and standard errors are shown CROYATTO and ZANIORANO, 1957) This is a particularly interesting observation, since the two hormones are always released together, though in different proportions depending upon the nature of the stimulus (see Chapter 111) It should be added that the diuretic effect of oxytocin has not so far been demonstrated in man (CHALMERS et al, Lowlit 10 tot connect ·Soine Other Actions of Oxytocin 19 solely to ili rat. Thus if oxytocin is administered to a don during a period ol los urine flos (Fig. 36), it causes an increase mainly of sodium but also of potassium c. coction (Brooks and PicoFORD, 1957). Vo diurctic effect can lie detected in water loader clogs (Harrow and Wessov, 1933; l'Av Daf et al., 1933; Brooks and Pick- FORD, 1937), TIILE X111 Tuc.ICTION OF XATURAL Oxitoci (OKASIHTY) AND SINTH TIC OLITIKIN (SITOCINON) DILRTSIS AND WASOGENOLS CREATININ CLEARANCE IS THIRSTING RATS (BREUVR al, 1957) Dsuresis Treatment Dere ml" /rat SC Endog creatinine clearance ml /rat/mun Xo of animals Ter group Controls 1 22 +0 09 100 + 106 12 63 1 250 06 253 7 23 + 13 Orasthin 1 250 1 33 0 13 260 2 + 35 6 11 62 5 1 290 14 183 3 * 22 6 13 Syntocinon 250 1 33 * 0 12 241 5+ 38 2 The mechanism of the diuretic effect of oxytocin 35 not yet fully understood in rats the creatinine clearance (Table XIII) was found to be unchanged following administration of oxytocin (BRUNNER et al. 1937) In con scious dogs, however, both the creatinine clearance, ic, the glomerular filtration rate (41.1, 1978), and the diodone Clearance, ie the elfective renal plasma flow (Brooks and L'ACKFORD, 1957), were increased by oxytocin Both effects were antagonised by vasopressin (Brooks and! PICKFORD, ·80 Recent Progress in Oxytocin Research WW 10 Urine flow 08 06- 044 02 60- Sodium μΜΙπιιη 50 - 40 - 30 20 10 14 Potassium PM imin 10 6 4- 60 80 40 100 Tune in minutes Fig 36 The effect of oxytocin (50 mU intravenously at x) on urine flow and Na and K excretion at a lox rate of urine flow in a dog The increase of sodium excretion is especially markeel (Brooks and PICKFORD, 1957) ·Some Other doirons of Oxylocan 81 1957, Au, 1958). In the rat increased sextium and chloride excretion due to oustocin is reinforced by mersaly) (Saiyr. gan) (SCHAUVAT and SCHVIDT, 1918), and oxytocin cr. hances cxcrction of water, sodium anti potassium even when carbonic anhydr.se in Liley tissite is fully inhibited by acetazolamide (CROVATIO and LABARCA, 1958). St is still not altogether clear 03 wliat extent the diuretic effect of oxytoxın is clue in its action on the renal circulation or to liat extent a direct influence of the hormone on the renal tubuli is responsible. Some insight into this problem was secently obtamed by Brooxs and PACKFORD (1958) in experiments on (ings the action on renal blonul flos secilys to be independent of the action on clectrolyte escrecion The mfluence of oxycocin on renal clearances appears to be periplıcral in origin, whereas its action on elctrolyte excretion is mediated via an un. Inoun central site. Certain effects of oxytocin only occur 111 the presence of vasopressin shich suggests that the two lormones, acting together, play a part in the regulation of electrolyte excretion Another open question is shetlier the effects of oxytocin on the circulatiou, urch sincer certain conditions can be detected in animals and in man are of biological significance or merely pharmacological effects of lugh doses It has long been known that birds react to intravenously administered oxycocin with a steep fall in blood pressure (GADDUN, 1928) Thuis effect is due to peripheral tasodilatation (Patos and Waisov, 1912) and is so characterisesc that Coox (1939) deseloped it as a method of bioassay li las since been adopted for this purpose in the United States Pharmacopera (1935) and the British Phar. macopoeia (1953), Oxytocin analogues, eg valyl-oxyto cin, have a similar depressor action on assan blood pressure.

·82 Recent Progress in Oxytocin Research In the luuman ſemale, synthetic oxytocin (Syntocinon) administered by intravenous drip infusion during labour in amounts having a pronounced effect on the uterus, cloes not influence the blood pressure (Busch and Kåser, 1956a; CalDFY RO-BARCIA et al., 1957a). However, rapid intravenous injection of high doses of oxytocin causes a transient and occasionally a rather steep fall in blood pressure (SCHILD et al., 1931; WOODBURY et al., 1914, MAYcs and SHEARMAN, 1956, CALDEY RO-BARCIA et al., 1957a) The drop in blood pressure may be accompanied by changes in the ECG, particularly when the dose exceeds 2 IU (MAIS and Shearman, 1956, CALDEYRO- Barcia el al, 1957a) Animal experiments have not, how. ever, revealed any involvement of the coronary circulation which could be held responsible for the ECG changes (WOODBURI and ABREU, 1944). The depressor effect of oxytocin in mammals shows considerable species differences (Woodbury and ADREU, 1911) and is not so readily explamed as in birds Observa. tions on chloralose-anaesthetised dogs (BFRDE and Cer- LEITI, 19581) suggest that the mechanism is probably a complex one: the fall in blood pressure that occurs in some of the animals with both synthetic and natural oxytocin, is not strictly dependent upon the dose. Thus 05 IU/g intravenously may sometimes provohe just as great a fall in blood pressure (Fig 37) as a ten times higher dose Moreover, after a dose of 5 1 UAg., bradycardia is always observed, whereas 05 IU/g usually results in tachycardia These alterations in lieart rate are not sec ondary to the fall in blood pressure Tlie investigations of WOODBURY and co-workers (1944) suggested that the effect of oxytocin on the blood pressure could not be due solely to vasodilatation and that a cardiac component was involvedl It was assumed that ·Some Other Actions of Oxytoci oxytocin reduce the contractile force of the licart. It is thus particularly interesting that oyixin has recently been reported to cart in opposite effect on the heart (LOCKETT, 1937): the pressor respx113ses elicited by adrenafine, noradrenalıc or splanchinic stimulation were po tentiated by oustocin in spinal cats. This is a cardiac action as in the heart lung preparation oxytocin Immered the ilireshold for the action of adrenaline and oradrena. line on heart size and force of contraction witliout indiu. cncing lieart rate, oxygen uptake or coronary blood flow 70 O 100 w the Jum..................... Rytren we Fig 37 lhe transient fall in blool pressure after 05 IU/kg Syntocinon is. (ac !) that is sometimes observed in dogs anaes thetised by chloralose, under aruficial respiration This effect is accompanied by slight tachycardia All these observations in animals and man merely show that lugh doses of oxytocin may affect cardiovascular function; they do not rel! 115 whether this hormone has any influence on the circulation under plıysiological condı. tions. Honeser, certain other findings hint at the pos sibility that oxyacin may in some way be involved in vas. cular phenomena. For example, in small amounts ir causes vasodilatation in the pregnant canoe uterus (Avil- QUIST and WOODBUR), 1917) and can increase renal blood ·84 Recent Progress in Oxytocin Research flow in the dog by as much as 100 per cent (Brooks and PICKFORD, 1957). But the most striking findings are those of DEMUNBRUN et al. (1954): glomerular filtration rate, renal plasma flow and tubular maxima are markedly reduced in dogs after neurohypoplysectomy. In sucli ani. mals renal haemodynamics can be restored to preoperative levels by the administration of oxytocin. Vasopressin las no such action. In view of this, these authors regard the regulation of Kidney haemodynamics as one of the physiological functions of oxytocin This could explain why the hormone is found in both males and females Tlus short review males no claim to completeness, but it will have served to show that much progress las been made in oxytocin research during latter years This progress whether in physiology, pharmacology or Jinical medicine owes more than is sometimes realised to the cliemist The isolation and synthesis of the hormone and the preparation of some of its analogues have brought about a "renaissance" in biological and clinical research Many problems have been elucidated, many more await an answer The most challenging of them all is the rôle of oxytocin in the male into oxytocin ·VIII REFERENCES AREL, ) ): Physiological, chemical and clinical studies on pituitary principles Bull Jolins Hoplins Hosp 35, 305, 1921 ARRARAUS, Y C. 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BROOKS, FP AND PICKFORD, M Conditions under wluch pos terior pituitary hormones increase sodium and potassium excretion by the kuney In "The Neurohypophysis," p 141, Butterworth, London, 1957 BROOKS, FP AND PICAFORD, M The effect of posterior pituitary hormones on the excretion of electrolytes, in dogs J Physiol 142, 468, 1958 BRUNNER, H, KUSCHIWAY, G, M VCHOW, O AND PFTIRS, (, Der Einfluss von naturlichem und sinthetischem Oxytocin auf endogene Kreatinin-Clearance, Salsausscheidung und Saureausscheidungsſahigkeit der Ratte und auf the Diurese des Menschen Arch exper Path Pharmakol 230 80, 1957 BRYNIR, H, LUSCHIASKI, GALO PETERS, G Der Einfluss von Oxytocin auf die renale Wasser- und Saltausscheidung der Ratte Arch esper Path Pharmakol 228, 157, 1956 ·References 89 BURY, J. HI.. Estimation of the antiduretic potency of pitt itary (posterior lobe) extract Quart. I. Pharmacy 4, 517, 1931. CALPFYRO-BAXCIA, R. 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·92 Recent Progress in Oxytocin Research DEXEUS TRIAS DE BFs, J. M. AND SEGUR FERRER, J M: La asociación largactil-dolantina-pituitrina en la conducción del parto Rev. españ obstetr. 14, 132, 1955 DICKER, S E AND TYLER, C. Estimation of the antidiuretic, vasopressor and oxytocic hormones in the pituitary gland of dogs and puppies J Physiol. 120, 141, 1953a DICHER, S E AND TYLER, C.. Vasopressor and oxytocic activities of the pituitary glands of rats, guinea pigs and cats and of human foetuses J Physiol 121, 206, 1953b DICKER, S E AND TYLER, C.: Inactivation of oxytocin and vasopressin by blood plasma of pregnant woinen J Obstetr. Gynaec Brit Empire 63, 690, 1956 Douchas, R G, KRAMER, E E AND BONSNES, R W Oxytocin, newer knowledge and present clinical usage Amer. J Obstetr Gynec 73, 1206, 1957 DUGGAN, AW AND REED, G TV Hypothalamus and oxy. tocin Nature 181, 1278, 1958 VAN DYKE, H B , ADAMSONS, K. JR AND ENGEL, S L Aspects of the biochemistry and physiology of the neurohypophyseal hormones Recent Progr Hormone Res, NY 11, 1, 1955 VAN DYKE, H B AVAMSONS, K JR AND ENGEL, S L The storage and liberation of neurohypophysal hormonjes In "The Neurohypophysis," p 65. Butterworth, London, 1957 VAN DYKE, H B , Chow, B F, GRICP, RO AND ROTHEN, A. The isolation of a protein from the pars neuralis of the ox pituitary with constant oxytocic, pressor and druresisinhibiting activities | Pharmacol Exper Therap 74. 190, 1912 ELY, F AND PETERSEN, WE Factors involved in the ejection of mulk J Dairy Sci 34, 21), 1911 ENGSTROV, L AND OHLSON, L. The value of intravenous oxytocin drip in obstetric cases Acta obstetr gynec Scand 35, 414, 1956 von EULER, U S. Noradrenaline Thomas, Springfield, 1956 EVANS, EI The transport of spermatozoa in the dog Amer J Physiol 105, 287, 1933 ·References 93 Evans, DHI, SC, H. O AND THEst frr, S Effects of drugs on depolarired plain muscle J. Physiol. 143, 471, 1958. FARIS, I BAVI KAN VRERG, B Intravenous Pitocin by the drop methodl in the induction of labour J. Obstetr. Gynaec. Brit. Empire 61, H1, 1951. FAURF, J. De l'influence de l'ocytocine sur le noyau amysdalien (portion cortico midiane) et sur la corne d'Ammon, J. phystol 19, 151, 1957. Frafte, K: Beitrage zur Physiologie der Gruiditat Endohrinologie 7, 361, 1930 FENFTE, K Gibt es wahrend ler Schwangerschaft ein aktives Hypoplysen-Hinterlappenhormon im Blute? Endokri. nologie 10, 16, 1932 FERGUSOV, J K W A study of the motility of tlie intact uterus at term Surg Gyn Obstetr 73, 359, 1911 FISHER, C AND IS GRAV, W R The ellect of interruption of the supraoptico-hypophyseal tracts on the antidiuretic, pressor and oxytocic activity of the posterior lobe of the lypo physis Endocrinology 20,762, 1936 FITZPATRICK, RJ. On oxytocin and uterme function In "The Neurohypophysis", p203, Butterworth, London, 1957 FOLLEY, S J The Physiology and Biochemistry of Lactation Oliver and Boyd, Edinburgh, 1956 FRASER, AM The diuretic action of the oxytocic hormone of the pituitary gland and its effect on the assay of pituitary extracts J Pharmacol Exper Therap 60, 89, 1937 FRASFR, AM The action of the oxytocic hormone of the pituitary gland on urine secretion | Physiol 101, 236, 1942 FRIBFRG, O The antidiuretic effect of contus in human subjects Acta endocr 12, 193, 1953 FUSTER, R, QUERALT, J A AND VARELA, A La inducción del parto con infusión de pituitrina registrada mediante la tocogratia intraovular Toko ginec pract 13, 571, 1954 ·92 Recent Progress in Oxytocin Research DFXEUS Trias De Bes, J. M. AVD SEGUR FFRRER, J. V. La asociación largactil-colantina-pituitrina en la conducción del parto. Rey, españ obstetr. 14, 132, 1955 DICKER, S. E. AND TYLFR, C.: Estimation of the antidiuretic, vasopressor and oxytocic hormones in the pituitary gland of dogs and puppies. J. Physiol. 120, 141, 19532 DICKER, S E AND Tyler, C: Vasopressor and oxytocic activi. ties of the pituitary glands of rats, guinea-pigs and cats and of human foetuses J. Physiol 121, 206, 1953b DICKER, S E AND TYLER, CInactivation of oxytocin and vasopressin by blood plasma of pregnant women J. Obstetr. Gynaec Brit Empire 63, 690, 1956 Douglas, R. G, Kraurr, E E, AND BONsnes, R 1 Oxytocin, newer knowledge and present clinical usage. Amer J Obscetr Gynec 73, 1206, 1957 DIRGAN, A " AND RrFD, GW.. Hypothalamus and oxya tocin Nature 181, 1278, 1958 VAN DYKE, H B , ADANSONS, K JR. ANI) ENGFI, S L. Aspects of the biochemistry and physiology of the neurolypophyseal hormones Recent Progr Hormone Res, NY. 11, 1, 1955 VAN DYKC, H BAD WAISONS, K JR AND ENGIL, S I The storage and liberation of neurohypophysial hormones in "The Neurohypophysis," p 65, Butterworth. 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The use of post-pituitary extract in physiological amounts in obstetrics A preliminary report Brit Med J 11. 123, 1948 TISNE, L AND ANSELMO, J : Inducción del parto en el embarazo prolongado. 6° Congr. y 20º Aniver. de la Soc Chilena de Obst y Gin, Oct 1955 (quoted in CALDEYRO-BARCIA et al 1957a) TUPPY, H The amino-acid sequence in oxytocin Biochim. Biophys Acta 11, 149, 1953 TUPPY, H AND NESVADBA, H. Ueber die Aminopeptidase. aktivitat des Schwangerenserums und ihre Beziehung zu dessen Vermogen, Oxytocin zu inaktivieren. Mhefte Chem 88,977, 1957 United States Pharmacopeia, 15th Rev Mack Printing Co, Easton, Pa, 1955 USUELLI, F, PIANA, G, AND CURTO, GM Sui momenti secretori e sulle modalità d'azione dell'ossitocina durante il parto Boll Soc ital biol sper 28. 1677, 1952 VANDEMARK, N L AND HAYS, RL The effect of oxitocin, adrenalın, breeding techniques and milking on uterine mo tility in the cow J Anim Sci 10. 1083, 1951 VANDEVARK, N L AND HAS, RI. Uterine motility responses to mating Amer J Physio) 170.518, 1952 VANDFMARK, N L AND HAIS, RI. Rapid sperm transport in the cow Fertility & steril 5, 131, 1954 VARANGOT, J AND CÔTF, Etudes el'hystérograpluie interne au cours du travail Gynet et obstétr 54. 149, 1955 VABANCOT, ) AND YBERT, P Le traitement de l'engorgement mammaire par l'oxytocine post-hypophysaire Sem hộp Paris 31, 1026, 1955 VERNFY, E B The regulation of water excretion Triangle 3, 307, 1958 ·INDEX Iretarolamide, B1 Icetylcholine, Action potendals, 19 Adenohypophysis, 71 Aminopeptidase in pregnant wilm, +1 Inaesthetics, 29 Analogues of ousto11, 10.6 glutamany), 10 iso glutaminyl, 10 leucyl, 11 phenylalanyl, 11 2) Dewry corticosterone. 78 Dusopropyl fluorophophale, 31 Dilatation of the cerur, 29 of the artcrus, 19 Diodonc clearance, 7" Disulphule ring moety, 6 Duress, 27 Duration of action, 38 1 ,1 راد۱ Annduurosis, 9.77 Irglane vasspressans, IS Basket cells, 63 Blocal levels 33. et seq Blood pressure avan, 13,81 caninc, 82 human, 82 Breast, engorgement of 72 British Pharmacopoeia, 13, 81 E Flectrical stumulation, hypothal amic, 50, 58 Electron microscope studies (neuro secrelory granules). 23 Flimination of oxytocin, 35. ct 4 of vasopressin. 38 motional stimuli, 30 Fresne, 31 Fxcrction of chloride, 77 of oxytocin, 38 of potassium, 77, 79 of sochum, 77, 79 of water, 77 F Terguson s reflex, 6% с Carbonic anhydrase, 81 Cardiac effects, 82, 83 Chelating agents, 42, 48 Chlorpromazine, 26 Circulation, 81 Cobalt 100, 2 Coitus, 99, 73 Contracture of the uterus, 50 Copulation, 73 Creatinine clearance, 79 Cyanide, 42, 46 Galactokinetic effect, 70 Catactopoietic effect, 70 Glomerular filtration rate, 79, 81 Glutamunyi analogue of oxytocin, 10 Comori's staining chaue 22 11 Half life, 38 Heart, 82, 83 rate, 82 107 ·106 Recent Progress in Oxytocin Research WISLOCKI, G. B.: The vascular supply of the hypophysis cere. bri of the Rhesus monkey and man. Res, Publ. Ass. Nery Ment. Dis. 17, 18, 1938 WOODBURY, R A.: The physiology and pliarmacology of the myometrium. In E. T. ENGLE: Menstruation and its disorders, p. 290, Thomas, Springfield, 1950. Il'OODBURY, R. A. AND ABREU, B. L.: Influence of oxytocin (pitocin) upon the heart and blood pressure of the chicken, rabbit, cat, dog and turtle Amer. J. Physiol. 112, 114, 1944, WOODBURY, R. A, HAMILION, W'. F., VOLPITTO, P. P., ABREU, B E. AND HARPFR, H T. JR: Cardiac and blood pressure effects of pitocin (oxytocin) in man, J. Pharmacol. Exper. Therap 81, 95, 1914 ·Indre 109 Oestrous acle, 29 Orgasm, 75 Osmotic stimull, 29 Oxypresen. 11 (xytoxin Secretion during labour (human). 58 vensitivity test, 55 Oxytocin inhibiting nonapeptide, 18 Oxytocinase in pregnant serum, +1 Structural formula of oxytocin. 7 of tall otytoxin, olacion, Suchling 29,65 Supraoptico hypophy cal tract. 21 Supraoptic nucleus, 21, 37 Synthetic analogues of oxytocin 10, et van fuigher homologue, 18 olyfoxin, et T Paraventricular nucleus, 2.27 Pharmacopoeia mcthocks, 13, 81 Thenylalami analogue of anita 1 Ictantis literi, 50 Thioglycolate, 33 Thirst, 50 Tact hypothalamo hypophy xal. 21 supraoptico-hypophyscal 21 Tubular marima R1 cin. 11 Tortat circulation of the hypo physis 705 Postpartal engorgement of the brcast, 72 Totasun excretion, 77, 79 Pressor activity, 9 Prolactin. 70 releasing circct. 71 R Release of oxytocin, 29, 17 of vasopressin. 30 Renal function, 77, et se plasma flow, 79, 84 Reproductive functions, 73 5 Secretory stimuli, 29 Section of the pituitary Serum proteins binding of oxytocin to, 39 Site of action 19 Sodium excretion 77. 79 Spermatozoa. 73 Standardisation methods, 13, 81 11 i'nit International, Wonieskie 19 T'harmacopeia, 13. AI l'tcrine inertia, 19, 63 letus cat IN 31/1, human an intro, 50 human, Walyl oxitocin, 16 on solution of, 75 mechanical stimulation of, 73 rabbit in situ, 18 rat in sifu, 16 rat in lpiro, 14 sensitivt to Oxytocin 44 52 1 agina mechanical stimulation of Valyi analogue of oxytocin, 11 Valyi orytocin, 11 action on the human werus, 16 Van Dyke 3 protein, 28 ·108 Jſexamethonium, 92 Systory,l, et seg Homologue of oxytocin, JB Hypothalamic extracts, 23 Thormones, 21 stimulation, electrical, 30, 58 Hypothalano-hypophyseal tract, 21 Hypothalamis, 20 1 Ipactation of oxytocin, 33, et seq by abdorninal organs, 38 by erythrocyles, 42 ly forinauon of intermolecular sulphude bonds, 48 by intestine, 39 wy kidney, 38, et see by Diser, 39. et seq by ovaries, 43 by pancreas, 49 by placenta, 39 by pregnant serum, 40 by sheletal muscle, 40. 41 Induction of labour, 49, 63 test (rabbit), 1; Infundibular process, 21 tash. 21 stem, 22 Inhabition of oxytocin elleuts, 18 Incerta crortal unit, 6 Juaranasal administration 72 Intravenous rip infusion 3 Iso glutamyl analogue uf urito 235/h ejection during, 55 Oxytocin blood levels during, 52 orytocin content of the hypo physis and, 58 oxylo in secretion during, 58, et SCR rôle of oxytocin in, 50, et seg second stage of, 61 Lactationt, hormone content of the hypophysis during. 69 let down of inalk, 65 In the hunan, 7 Leucy? analogue of oxyrocin, 11 Lysítse sasopressini, 8 M Mfangahese ton, 4%, 41 Median eminence, frembrane potential, 49 Menstritation, 75 Versall, 82 Methods of standardisation, 13.81 Microsomes, 28 Milk ejection, 65 during coutus, 73 during labour, 53 Vilk-ejection reflex, ho and snacsthesia. 69 conditioning of, 69 emouonal influences, 04 Milk secretion, 70 Viking, 29 Vitochondria. 28 Molecular weight, 6 Montevideo unit. 79 Vocpithelial cells, N Neurohormonal reflex, 61 eurons pophysis, \europhysine, 27 Scurosectetson, 20. et seq curosccretory material bv, et seg Vicoline Vinapeptide inhory, 18 CH, 10 L Labour after hypoplasectomy, 52 alier sectioning of the pitutas stath, 52 commencement of, Gi) first stage of, 61 Induction of, 19, 63

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·110
Index
TY
Water cxcretion, 77
Vasodilatation, 81, et set
Vasopressin, 8
Vasopressin'oxytocin ratio
hypothalamnus, 29
pituitary, 29
7
Zinc ton, 42

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