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A COMPARATIVE STUDY OF THE EFFECTS OF PROSTAGALNDIN F2 (F2 ALPHA) AND ITS SYNTHETIC DERIVATIVE ZK 71677 ON THE RAT UTERUS  

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A COMPARATIVE STUDY OF THE EFFECTS OF PROSTAGALNDIN F2 (F2 ALPHA) AND ITS SYNTHETIC DERIVATIVE ZK 71677 ON THE RAT UTERUS  

 

TABLE OF CONTENT

Declaration

Dedication

Acknowledgement

Chapter one

Introduction

Material and methods

Substances

Solvent

Animals

Source of tissue

Bio-instrumentation

Results and preliminary study

Effects of adrenaline on the isolated preparation of rat uterus

Effect of zk 71/677 on rat uterus

Effect PGF2 (alpha) on rat uterus

Precartions during experimentation

Discussion

Conclusion

Graphs and figure

References

ABSTRACT

Prostaglandins are products of arachidonic acid metabolism. They are group of pharmacologically active lipids not stored free in tissues but are synthesized due to membrane pertubations.

They are ubiquitous in occurrence and are among the most prevalent of the autacoids, as they are widely distributed in mammalian tissues and body fluids.

A considerable amount of evidence exists showing the implication of prostaglandins in uterine physiology. However most of these natural prostaglandins have been shown to posse a short duration of action. Due to their instability, enzymatic degradation and heat-labile nature. It has enzymatic degradation and heat-labile nature. It has therefore become necessary to synthesize more stable derivative of the parent compound.

In this investigation, the effects of postage F2 alpha and zk71677; a novel prostaglandin F2 alpha – derivative on rat uterus using the organ bath method have been studied.

It was observed that both prostaglandnis F2 alpha and ZK71677 have contractile effects on the uterine myometrium to a varying degree, ZK71677 contracting the myometrium much more than the parent compound BGF 2(alpha). Their effects are largely mediated through cholinergic and or alpha adrenergic receptors in the uterine myometum.

It is then concluded that ZK71677 being a more potent uterine contractant than its parent compound (PGF2&) has a greater degree of oborfifacient effect and hence it is clinically used in obstetric to induce labour.

CHAPTER ONE

INTRODUCTION

The biological activity of seminal fluid and prostate gland extracts has been recognised for many years. Japell, and Scafa (1906) observed a rise in the blood pressure of dog upper injecting extracts of bull and dog prostate glands. (1) A few years later, Battez and Boulet, 1913 showed a fall in the blood pressure in dogs when aqueous extracts of human prostate were injected. (2)

However, in 1930, two new York gynaecologists, Kurzrok and Lieb reported that York gynaccologists, kurzrok and Lieb reported that fresh human myometrium. (3) von Enler and Goldblatt, working in Sweden and England. Respectively, furthermore showed the presence of asodepressor and smooth muslces stimulating material in extracts of human senminal plasma and the vesicular gland of sheep (4). They successfully demonstrated the vasodepressant and stimulant activities of the human semen both hivivo and invitro. Von Euler erroneously named the active principle – ‘’prostagalndin’’ on assumption that the active substance originated from the prostate gland. He also showed that this active principle was an acidic and lipidsoluble materials. (5) however, the isolation in crystalline form of two biologically active prostaglandius – PGE1 and PGP2 (alpha) was credited to Bergstrom and jovall in 1957. (5) the isolation was made from sheep prostate gland. One of these compounds, PGE1 was a very potent vasodepressor and smooth muscle stimulant, whereas PGE1 (alpha) and only showed smooth muscle stimulating activity. More recently, additional biologically more active compound e.g. PGE2 and PGE3 were isolated, from the same source.

Furthermore, by using the slit-ejaculations technique, Eliasen, (7) was able to show that the prostaglandins are formed in the vesicular glands and apparently not in the prostate gland as erroneously assumed by VonEuler.

Nevertheless, in 1962, Bergstrom and his associates, researching in Sweden and using ultramicro-analysis and mass spectrometry unravelled the mystery that had hitherto shrouded the prostaglandins. They went on and announced the unique chemical structures of these two naturally occurring prostaglandins. (8)

Two years later, the enzymatic biosynthesis of prostaglandins from 20-cerbon essential polyunsaturated fatty acids was published simultaneously by Van Dorps (9) and Bergstroms group (10).

Two years later, the enzymatic biosynthesis of prostaglandins from 20 –cerbon essential polyunsaturated fatty acids was published simultaneously by Van Dorps (9) and Bergstroms group (10).

Two years later, the enzymatic biosynthesis of prostaglandins from 20-cerbon essential polyunsaturated fatty acids was published simultaneously by Van Dorps (9) and Bergstroms group (10).

The prostaglandins are derivatives of a patent 20-Carbon carboxylic acid called prostanoic acid. They contain in a cyclopentane ring and differ from one another in the number and location of double bonds bydroxyl groups and keeto groups. (ii)

Prestalglandins of the E-type contain 9-keto and 11-alpha – hydroxyl groups on the 5-membered ring. This structure  is readily dehydrated to the 10, 11, unsatunated ketone by weak acid (PGA – type). In prostagalndins of the E-type, the 9-keto group of PGE is reduced to a hydroxyl function. Only the F group of PGE is reduced to a bydroxyll function. Only the F alpha isomer occurs naturally but on sodium boro hydride reduction of the parent E-prostaglandin, both isomers (F alpha & F Beta) are formed. All the primary prostaglandins contain a 13, 14—transdouble bond and a 15-hydroxyl group in the 15-s configuration.

The subscript numerical after the letter in the abbreviated names of the prostaglandius indicates the degree of unsaturation of thee side chains. The prostaglandins, a family of biologically active lipids are not stored free in tissues but are synthesised the novo as a result of membrane mertubations that cause the release of free fatty acids from esterified lipid sources. (12) phospholipase A2 has been recognised as an important enzyme in the release of the precursor fatty acids. Of the three substrate fatty acids, Cis – 5,8,11, 14-eicosatetraenoic acid (arachidonic acid); Cis- 8, 11, 14-eicosatrienoic acid, and Cis-3, 8, 11, 14 17-eicosapentaenoic acid, the first, arachidonic acid is the most relevant to prostaglandins synthesis and physiology, as it is the only one that is converted enzymatically to an active thromboxane and prostacyclin. (13)

Essentially, the free arachidonix acid reacts with a complex group of enzymes given the generic mane ‘’prostaglandin synthetawse’’. However, cyclooxygenase is the first enzyme of the prostaglandium biosynthetic sequence. This enzyme oxygenates arachidonic acid to the endoperxide intermediate, PGG2 which is further converted to a variety of biologically active products. (Prostaglandius, E,F, 12 and Thromoboxanes).

Prostaglandins are autacloids. (14) They have beenwdetected in almost every tissue and body fluids. In fact their production increases in response to astonishingly diverge stimuli. They produce in minute amounts, a remarkably broad spectrum of effects that embrace practically every biological function (15). Furthermore, prostaglandius F2 and F2 & are present in human menstrual fluid and in endometrial curetthings obtained during the proliferative and secretory phase of the menstrual cycle. PGF2 has also been identified in lungs from guinea pigs, monley and man.

No other autacoids show more numerous and diverse effects than do prostaglandins and other metabolites of arachidomic acid. P[rostaglandins and other metabolites of arachidonic acid. Prostaglandins have a myriad of physiological effects and these lie in their ability to provoke contraction and relaxation of smooth muscles in various sites in the body. By this action, they exert a profound influence on the function of the digestive tract, the respiratory tract, reproductive tract and in the blood vascular system. E-type prostaglandius are said to be potent bronchodilators, while the F-type have been shown to be potent brocho-constrictors. (16)

In humans and monkeys, during early pregnancy, administration of PGF2 causes a decrease in plasma progesterone level. The increase in steroid level is associated with the onset of veginal bleeding. it is debatable whether this drop in progesterone level reflects a direct affect of PGF2 on the corpus Luteum or whether it is the result of an indirect luterolytic effect, brought about by the removal of the possible luterotrphic support of the conceptus, the latter being dislodged by the direct uterine stimulant effect of prostaglandins (17). Some synthetic analogs of prostaglandins ar albe to produce sustained contractions of the uterus – a property which is essential for the prevention of post partum haemorrhage. Also, prostaglandins anlog-particualry 15-methyl PGE2 or 15 metthyl PGF2 given as a single extra-amniotic dose on few hours prior to uterine evacualtion has been found to be effective in dilating the corvix. Independent of the phase of the menstrual cycle, PGES cause a centration of the proximal. Qurter of the fallopian tube and a relaxation of the strips from the distal is of the tube, whereas PGF compounds produced contraction of all segments. Investigations in lower animals have suggested that prostaglandins Amy be involved in gonadotropin secretion at the pituitary and hypothalamic levels (18).

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Dhout et al (1974) and Vanderheyden et al, (1974) shovel that PGE2 and PGF2 enhanced constisol secretion and burren growth bormane but did not alter Li, FSK, prolactin or TSE in postmenypausal women (19) among the many biological actions of prostagalndins, special interest hs been devoted on their influence on the female reproductive system. Following ceitus, germinal prostagalndins act both locally and through the circulation after absorption from the vagina to effect the smooth muscle tone of the myometrium and fallopian tubes. A major possible advantage of prostaglandin would be their effectiveness in patients who were refractory to oxytocin in the induction of labour.

It has also been reported that the inhibition of prostaglandins synthesis delays labour (20). Furthermore, the use of prostaglandins synthesis inhibitors, s indomethacins. For instance, the mutually – occurring prostaglandins are proudly inactivated but when modified at C15, the resulting analogs resisted enzymatic degradation. Also, prostagalnedius are hear-labile and very unstable compounds. Also, propstaglandins are synthesised de-nevo and are not stored in the body. (24.25.26.27)

Prostaglandins occur naturally, however, synthetic analogs have been derived from the parent mutually occurring prostaglandins. (28. 29. 30)

The synthetic prostaglandius include a novel derivative of PGF2 which was synthesised accordingly to skulballa et al (31) this synthetic prostaglandins has been code-owned ZK71677.

However, its full chemical name is:

(5Z, 13e) – (8R-9S, 11R)-9, 11-Dihydroxy-15, 15-ethylenedioxy – 16- phenoxy – 17, 18, 19,20 tyetranor – prostadienoic acid, s tries hydroxymethyl aminomethane salt.

The aim of this investigation is a comparative study of the effect of PGF2 and ZK71677 on rat uterus.

MATERIALS AND METHODS

SUBSTANCES:

(5Z, 13E) – (8R-9s, 11R,)-9, 11-Dihydroxy-15, 15 ethylenedioxy 16-phenoxy -17, 18, 19, 20-tetranor-prostadienoic acid as trishydroxymethyl aminmethanme salt. ZK71677 was synthesised according to skuballa et al.

PGF2 was obtained from Fuju, JAPAN – stilboestoric (5mg/ml) was obtained from Alter – chemiee, P.M.B. 1925 Kambung, Germany.

  • Propranolol (m.wt. 295.8) Adrenaline (M.wt. 183.2) and Actylcholine, Ach (m.wt. 181.7. 99% pure) were all obtained from sigma chemie company st. Louis U.S.A
  • Limethyl sulphoxide (m.w.t.78.13) was from BDH chemicals, Ltd. England.
  • Phenotholamine, Indomethacin, Acetyl-salicylic acid were obtained from Merch, sharp and Dorme Rahway, NJ. U.S.A
  • Atropine sulphate (ampoule of 1mg/m1 from laboratory Aguetant, France.
  • Sodium chloride (m.wt. 58-44) purity not less than 99.5% and (max.impurities 0.44%), potassium chloride, glucose D, nonohydrate were all purchased from BDF chemicals Ltd, poole, England.
  • Calcium chloride, gestchmolzen granulent was provided courtesy of Meerch, sharp and Dohme, Rahway N.J. U.S.A.
  • Sodium hydrogen carbonate from may and Bakaer ltd. Da genham, England.
  • A physiological solution (Le-Jallons) was compounded with the followings salts.
  • De Jalon solution (g/litre)

Nacl 9,0     )

Kcl 0.42      )        obtained from BDF

NazHco3o.5        )        chemicals Ltd

cacL 0.027         )        poole, England.

Glucose 0.5        )        poolee, England.

Other substances used include, protease and trypsin from may & Baker, England.

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Account Number: 0046579864

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Account Number: 3139283609

Bank: FIRST BANK

 

 

 

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