PROSTAGLANDJNS

THE POSSlBLE MODE OF AC'l'lON uF Y~iOsTAGWiNUINS. XPI. DIFFtinEN'I'IAL BFYLCTS OF PtiOSTAtiL&NDIN F2a IN INDUClNG YHEHiiTUiih EVACUiiTlON OF CbNCc!4’US IN THE INTACT AND CASTttA'l'EU PddiNtiNI’ tlA’P

Amar Chatterjee

Department of Physlology, Haja Peary Mohan College,Uttarpara 712258,Hooghly,W.Benqal,

Indla.

A single inJectIon of 2.0 me/kg prostaglandin F2a(PGF2a) on day 18 of pregnancy was consistent in inducing premature labor by 72 h following the injection. Conversely, castration before PGF2a on day 18 of pregnancy made the animals almost inert to PGF2a and only 20% of the treated animals showed premature evacua- tion of the conceptus. Injection of 10 ye; of estradlol cyclopen- tylproplonate (ECP) on day 18 was, however, found to be effective In emptying the gravid uteri of lOO$ castrated preqnants by 72 h. Indomethacln, a consist,ent inhibitor of prostaglandin biosynthesis and release, alonq with ECP in an identical experimentaL sltuatlon was found to be Ineffective in reversing the ACP-Induced premature parturition in castrated pregnants. The importance of intact ovary for the action of PGF2a concerning premature labor in rats has been discussed.

l The expenses of this investigation were defrayed by research grants from Indian Council of Medical tiesearch The Population Counci_1, New York (N.74.5111 World Health OrgaGation (Human Heproductlon Unit, Small Supplies Programme) and The Forr Foundation (ICM).

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PROSTAGLANDINS

The antlfertlllty effect of prosta~~,lnndln F2a (PCP'2a) in terms of 1uteolysl.c in animals (rharr1s.C; & Jynearden,lybYi Elatch- lay t Donovan.19691 L+abhsetwar,lg71I Uartke et al.,lY'/21 Chatterjee, 1972) and uterine evacuation in human (Karlm et al.,196tit1969) has been discussed by a large number of investigators. The lmpor,tance of prostaElandln in normal labor (for reference see bergstrGm,lY73) and its possible involvement In animal parturition by some direct or lndlrect experimentation (Ligcr,lns & Grleves,l971!-Chester et al., 19721 Alken,1972) have been documented. Present experimental evi- dence reveals that the PGF2a-induced premnture partiritlon which 1s consi::tent in Intact rats folnd to be very much lnconslatent in cas- trated pregnants.

MTEYIAW AND MTHODS

Laboratory bred female rats of 230 - 250 p.m bw were maintained In a controlled environment and the liqht was on for 12 h per day. The animals hnd free access to pelleted food (Hindlever,Indla) and water. Pregnancy was produced by keeplno the pOoestrus females with males of proven fertility. Evidence of sperm positive estrous smear WRS desi-noted as day 1 of pregnancy, Countin,- of fetuses and blla- tersl ovsr!sctor?y were made by laparotomy an? flank lnr:lsion, res- pectively under llqht ether anesthesia.

Prostanlandln F2a-Tromethamine salt (PGF2a) and estradlol cyclopentglpropionste (tiCP), a long acting estrogen, were m?de avnllsble through the courtesy of Dr. John E. Pike, Up.john Company, MichiFsn. Indomsthacin (l-(p-chlorobenzoyl)-5_methoxy-2-methylln- dol-j-acetic acid) was kindly donated by Rerck InstitlAte for 'Thera- peutic Research, hTew Jersey. PSP2a was dissolved in cold seline and administered sc (Table 1).

at a dose of 2.0 me/kg bw as per the schedule ECP was diluted with corn oil kind admini:;tcre,l sc as

a single injection of 10 pg In a volume of 0.2 ml of the vehicle (Table 2). Indoaeth?cin (Indocin) was 3issolVJed in corn oil and adfli?istered (0.2 ml) SC (5.0 &kg) as scheduled (Table 2).

It was observed that a single injection of PGF2a on day 18 of pregnancy initiated complete evacuation of uterine contents by day 21 in 100% of the test ani'mals, ho:uever, when the same sched,>le was tried on day 18 castrated pregnants, lr failed to precipitate cremn?ture emptyin,? of uteri In rjO$ of t'he pr?gnants rats (Table 1).

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Thl? rer;ult In ?:ons!sten% with the findInTs #of Ll%glns et al. (1972) that PGF2a Itself Is not oxytoclc in ths pregnant sheep, rn?her helps ta sensltlze the uterus to the stltnulatlon of oxy- tqaln. Hnwevgr, It is well recognized th4t parturltlon 1s a conplex r,rocess lnvololnrr interplay of sever41 endocrine factors. In the rat, It Is known that secretion of progecterone drops (Hsshlmoto et 41.,1968$ Wlest et a1.,196Ar and that of estrogen (IRahInagn et sl., 1969: Yhalkh,l971) and LH (Llnkle & Nlswender, 19721 Uast R mie~py,1972) rise prior to parturltlon. These ob- ssrvatlonv 4nd our experlmsntal success of PCF2a lq the intact and its failure in castrated pregnants to lnltlate prem4ture ev4- cu?%Ion of the conceptus collectively tempting us to believe that the ovarian folllcular apparatus, the primary source of’ estrogen, my be very much ennsntl41 for the action of PGF2a. The question of lut?olysis does not arise here, alnce on day 18 of pregnancy the funct?onal actIvlt% ?f luteal elements normally declines (L4bLisetwar & Watson,1974). Conversely, the estradlel levels slo;nlf?c?ntly elevated on day 19 snd the highest value obtalned 4t psrturltlon (ShRIkh, 1971). Moreover, studies conducted.by a nurllbsr of Investioators also reveal that the olasma level of es- trogen Is elevated following PCF2a in cattle {Hlxon et al.,19731 HIxon & Hansn1,197'+), sheep (Baretta et a1..1971). hamster (Lsbh- setwar.1973) and probably in rats (behrman &-a1;;1971). Ai ln- tra-ovarian injection of PCF2a also results in sn increase stlmu- l4tIon of estrogen probably of folllcular orinin (Hlxon et al.. 1973) and concomlta&. use bf antlestrogen con&rr&tly wlth P(;i2a has been found to elImin4te the abortlfaclent efficac.v of PCFga (Chatterjes.1976). Therefore, the primary Involvement of est;ogen In prsmsture evacuation of conceptus as expeoted from our preceding experinsnts was experlsentallu verified in the urennant rats after bilateral ovarlectomy 4s perfbrmed at 1300 h on-day 18 of pregnancy. It was confirmed that a single Injection of 10 URECP evacuated the gravid uteri In 100% of the-castrated pregnant; Gy 72 h (Table 2). However, as the uterus is capable to synthesize prostaglandln on estrogen stimulation (Caldwell et 41 .,19721 Saksena & Lau,1973) and prostaglandln Is known to involve In parturltlon (Challls et al., 1972: AIken,1972) lndocin at its effective dose level as the InhIbItor of prost4glandIn blosynthesls was added with ECP reglmen In the Identical experimental situation to confirm whether the ECP-lqduced pre?l?ture D4rturItIon in the castrated pregnants 1s the conse~Juence of prostaqlandln stimulation. It was, however, recorded that addition of lndocln did not affect the ECP-induced evacuation of the conceptus in any of the test anlmals, all of the anlmsls rsther delivered lamature fetuses by day 21 4s identically found folloMIna ECP (Table 2). This finding 1s In good agreement with the recent coqnent made by Dr. Csapo (1976) that theonset of labor 1s not trlqgered by 4n increase in uterine prostaglsndlns (PCs) levels, since a corllpsrlson of the levels of PCs In the human myo- metrium before and during active clinical 14bor failed to demonstrate 4 si3nlficant difference (WIllman & Collins.1976).

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ACKNOulLiiDGMPN'l'S

The stimulating cooperation of Dr. (Mrs.) S. Tejuja, Dr. S. J. Segal, Dr. R. T. Mahoney, Dr. A. Bartke and Dr. J. H. Spieler is gratefully acknowledged.

Sincere cooperation of Mr. B. S. Paul and Dr. K. V. Josh1 (Glaxo Laboratories, India) is'highly appreciated.

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