THE PosSiBLE MODB OF ACTION OF FRoSTACLANDINS: VII - FZVIDEXCBOF AN ANTIFltWl'IPTx FECT OF

PRCSTAGLANDIN El IN BATS 1$

bar chatterj ee

rbpartaent of PhyBlology, Haja may M&an College, Uttarpara, Hoogbly, W.Bengal 'fl223S,&g&

ABSTTUCT

F'rostaglandlntl (pGF1) of 5 m&g body might ns found to he ineffective to induce luteolysis in 16 of the test animals when ib jeoted either, 08 day 3, day 5 or day 7 of pregnsncy. While, converse- ly the s-e dose sahedule uas absolutely potent in the in&t&on of luteolysis and resorption of fetuses, plutentre uhen tested on day 10 or d8y 13 of pregnaucy. Progesterone alongwIth PcEl consistently pre- rented the l bortifaoient effioacy of FG?Sl. Moreover, it uas observed that ml could also suacessfully tennisate pseudopregnant state in the bilaterally hysterectmired rats between fortyeight and ninetysix hours after the iqleotioa. It uas suggested that the luteolytio or abortifacient effioaoy of FIXI ir mt the ea5lusive reflection of an l ugnented activity of uterine musoulatum.

1) This study ms supported by the grants Frau the INDIAN COUNCIL OF MEDICAL Rl%ARCH and FOPULUION COUNCIL (NEW YORK).

The author is grateful to WI0 for reaeivlng one "Speotronio 20" as a stiuu&ting gift.

Accepted May 8

PROSTAGLANDINS

JUNE 10, 1974 VOL. 6 NO. 5 413

PROSTAGLANDINS

INTHODDCTIOU

The efficacy of prostaglandine in the interruption of pregaancy in various manonalian forma has been extensively studied (1). Althcugb opinion differs on the proposed mode of antifertility effect of proeta- glandins in rats (2,3,4,5), hmveters (6,7) and even in the hrpran (8,9), pat the abortion requencea follouing prcetaglandin F2a or FQ are con- eistcnt , Recently Labhretvar (10) has reported that prostaglandia Ei is effective in hamsters, while its l n9ifertility effect is not demon- attrable in rata even after using large sublethal doses for three con- recutive daya. Ecuever, the evidence of l significant depxwaion of progesterone secretion aa the consequence of prostaglandin Ei treatment in the experimental animals of Aldrige et al (11) is rather provocative to report that a single injection of moderate dosage of prostaglandin Ei is consistently effective in inducing luteolysis and abortion in rata :.

laboratory bred adult rats of 180 - 2OC g body ueigbt were houeed under controlled lighting schedule (12h light/l2 h darkness) and bad free acce~a to food and water, Vaginal eoeara were taken daily and each had elicited an estrus aear at least thrice before experimental use ; animals with irregular cyclea were rejected. Females vere caged with the malea of proven fertility in the evening of the day of vaginal pro- estrua. Succeeaful insemination ua8 confirmed the next morning by the presence of either spermatoaoa or a vaginal plug. The day on which VG ginal spermatoaoa or vaginal plugs vere found uaa designated day 1 of pregnancy. Inaminated rats were distributed into several groups as per the treatment rcbedule (Table 1 & 2). Prcstaglandin Ei (KJEi) wae kindly donated by the Upjohn Canpany, through the courtsey of Dr.J.E. Pike. FCBl was diseolved in 95% ethanol (10 me@) and refrigerated. It was diluted with distilled water containing 0.2 mg of l@CO3 m juat immediately before use and injected ac as a single injection (0.4 ml) of 5 mg/kg body weight. Progesterone (hydroxyprogesterona caproate) wan dilutrd with sesame oil and injected ~1 at a doee level of 2.5 mg per rat per day.

The inspection for the presence and coumting of implanted blasto- cyate in the uterus was made through an aaeptie mid-ventral incision on day 8 of pregnancy under Ugbt ether aneetheeia. On sacrifice, the gra- vimetric status of the fetuses, placentae, ovaries and microdireected corpora lutea of the experimental animals was compared with the controls.

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fable 1 alearly ahoum that m of S r&g body veight den i, jrckd&r~sl~e~~tien~thero~&~S,~~Ser~~7,~gusy iuratr rarinedummffeeted. Thm gmuthrate of fetuwr or plaoeutu mdwig# &the omqmdoorpora luteawre notrignifioautl~diffc rent frm oontrolr. Howter, l&loathe sme proat@audinngiaeulaa shIfted on day lo of pregnamy, corplete rewrptlea of f&user U wll as of plwentae wr* evideut 08 d&y& A riguifleantnd&ioniB omriu wi t (P 0.001) aswll aI theueuwight efiBdiuidaaloolc poralutea P o.OOl)wre recorded caparedte aoutrolr. Similarly, ? uhen the iujeotion of FGEl no mhsduled 08 day 18 of pregmmy, it ~8 observed that the mean wi&t of fetxues, placentae, ovuirr.and indi- ridu~lcorporaluteawe ~~igniflcantl~lowredon da718 of ~gaamy, while on day 20, rerorption of fetueee and plaoentae ua8 eomistent and there wr a further reduction iomean ovarian and luteal wight. Tb regrerrion of corpora lutea wa arroeiated uith wight lorr kl hiatole- Rical luteolmir. Cono~it8ut~inidrationof lmWe8teroue rifh ml!1 &nteiued &wth aud developneut of the fetuses,-pl&entae and luteal- timue aa good as that observed in oont~~la (Table 2).

Emed en the proposed BeOhUIhI of a&ion of proetaglaadin I5 ca~pounds (12) It uould possibly be justified to amme thet the lute81 dmise in our experimental auiuals uight be the remlt of fetal death aa the consequence ef au augmented activity of uterine uuaeulature. %uoe iu hm~ #iBi aud PCiGe are l pproaimatel~temfold greater in potee cy tbrn PWg8 iu tome of oauaiug contra&ion of tho uterine mumml~ture (for reference we 15) aud progs6terone ratheruaker the uterine uuecu- lature to acme l utent refractory to pro.staglandin0 etimulatio~ (14), Haukins et al (15) have confirmed that in ovuieofcrised aud adreualee- tcmised rate utorur ooutraetr in rerpouee to all prostrglandine. To ve- rify this auaspicioue mediation of ration of lX%i in the indu&ion of la- teolpie, bilaterally hgsterectouited rats wre ude peudoprewt b fertile mating and on day 10 of p8eudopreguanay RXi we ideated aacor- din&. In tbe vehiclctrerted oontrole the daration of peeudopregmuey we 18tl daya. RX& eu day 10 eonsiatently reducod the length of puo- dopreg&cytolSti dnys. The individualoorponluteaof the l xperiue8- tal rats ns fad smaller in Might aud histological luteolpir use also evident campared to controls of day 14 of peeudopregnrm~ (Table 5).

Present evideme of the &mtifacieut l ffiomy of FGgi in rata and it8 reversal by concaaitaut 8dninirtrrtion of progesterone are oontradic- tory to that reported by Lbhsetuar (10) uhere ho has wed even larpr and repeated doeeo of #;Ei. The feilure of Iabhwtvir in induoing ooupleto luteolynis aud resorption of fetuses and plaaentae aay be due to hie drug wheduling at the refrmtorp phare of prepu~ to poke ae dommented in the present utndy. blthouc the em& rea~~h of tbi6 iuertl~~~ to RI

9 stimlationis not zetknoawn, howver, the dualluteotrophic oontriht on of the pituit8ry and trophoblmts at least upto 1387 10 Of pregmucpuy be an aamomiate exulmatiou. It ir evident that the pituitary gUad could be d&&able u&r day i6 of pregueacyi~ r&m (18). Iorbi&ga and AW (17) have alao repowd that early eoneeptus bt rats poaseosos lutwtropbic influeuee.

416 JUNE 10, 1974 VOL. 6 NO. 5

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The eont r ibu tory ro le of prostaglandins a t the u t e r ine l eve l for inducing preesture de l ivery of fe tuses in r a t s has been evaluated. E ~ - genous ~lactln ~ieh has been reported to reverse the adverse effect of prostaglandine at even aid-pregnancy by stimulating ovarian proges- terone ssere t ion (3) , found to be e ~ p l e t e l y iae i~ac t ive a f t e r day 15 oi' ges ta t ion (18). However, rege~ding the mode of ac t ion, we are very mush inc l ined to bel ieve that p a r t i c u l a r l y i n r a t s I~E I does not e~vlu- s i ve ly act by s t imula t ing u te r ine musculature. Beeanse i t could cons is - t e n t l y induce lu t eo lys i e i n the b i l a t e r a l l y hystereetcmized pseudopreg- nant r a t e . F r ~ his experimental experience in h ~ s t e ~ Labhset~ar(10) also bel ieved i n the seBe d i rec t ion . The LH re leas ing property of the c e n t r a l l y administered POE 1 i s evident (19). A mmber of experimental explanations are in favour of the suggestion that an e~ess I~ causes luteolysie and thus increasing t~e ratio of the inactive metabelite of progesterone, 20a-dihydroprogesterone to progesterons (4,20). Further, experiments are in progress to unvail the enipa on the mode of action of I~F~ as antifertility compound.

The e~eouraglng cooperation of Dr. (Mrs.) S. TeJ~Ja, Dr.~eldon J.Segal, Dr.Riehard T.Mahoney, Dr.J.M.Spieler and Dr.A.Bartke is grate- fully acknowledged.

The sincere cooperation of Hr.B.S.Paul and Mrs.A.ChatterJee in preparing the manuscript is highly appreciated.

J U N E 10, 1974 VOL. 6 NO. 5 419

PROSTAGLANDINS

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Dumeaa,G.D. and Pbarrlu,B.B.r Fod.Proc. t9rl959(197G).

P~~IT~~~,B.B.s P6r8prct.Bi0mOd. is14s4(1970).

Ch8ttOrjO0,A.r F+rO8taglmdin8. srles(l97s).

L&h8&nr,A.P.r J.Rqmd.Fsrt. 95~rl55(187G).

Beh~u,H.B.,HmDomld,G.J. and Greop,R.G.t Upida. bc'Fgl(l9‘7l).

L&hrotnr,A.P.t Fllldocrl~loltj. 9mG6(1!375).

John&on,J.O. and &mter,K.K.t%friel0gi6t. 15rtS5(1B70).

La HJre,W.J. and Shaplrr,A.G.r Proataglaadi~. lrOSQ(lQ'/f?).

Lelmnn,F., Petrra,F., Bmehmlctt,H. and Bottondorf,G.r hehglu%ulM. llP6!+(1979).

tbhootmr,A.P.r Blol.Beprad. 8tlG5(1975].

A.ldrigo,R.R., Barrett,S,, Emwn,J.B., Godimg,J.R., Kattenbeeh, C.C. and Wolo,B.J.t J.~prod.Fert. 21r56!3(1970).

I&hutru,A.P.r Ma ondomiael.(kbh). !%ppl.170, 7lrl(l979).

Bohx%a,E.K. and Anderaom,G.G.t Areh.Idern.bd. 18Sr77(1974).

Rwter,b. and Ebhm8a,H.B.t K&we. l?5Bs6M(l971).

lkukina,R.A., Jomp,R. md Fiavell,P.W.~ wperilla, Worceeter Foundation for l@&mental Biology, fntersciem8, vi18y,K.k Ed8.BmuOll,Pc% aad -w,J.K. p.li(lQ68).

Penchars,R.I. and Lmg,J.A.r her.J.but. 55r117(1958).

bahl~rp,K. and Adam,C.t.r J.~qxod.Fort. 15s&5(1967).

&atterjea,A.r thpblirhsd.

Spber,E.G., Noman,K.L. and Campbel1,K.C.t Fad.Roa. 59~959(1975).

Wirrt,W.G., KidM.l,W.B.. ud BdoB,Jr.,K.r Eadoorinology. a?tau(lfm).

420 JUNE 10, 1974 VOL. 6 NO. 5