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Prostaglandins

THE LANCET

ONLY ten years ago the prostaglandins were a

family of hormones in search of a function Todaytheir recognised effects are so numerous that it ishard to accept any one of these as their principalrole. The name itself-not, in retrospect, a happychoice-was coined as long ago as 1935: VON EULER 1then described a smooth-musc1e-stimulating lipidwhich was demonstrable in human seminal plasmaand whose source, he suggested, might be the pros-tate.’ Little more was heard of the substance (nowknown to be a mixture of at least 13 related com-

pounds) until 1962, when BERGSTROM and his colla-borators described the chemical structure of the firstof the series.2 Within a few years a number of pureprostaglandins became available for physiological,pharmacological, and, most recently, for clinical

study; and they proved to be extraordinarily potentin a wide variety of experimental preparations. Noless important was the discovery that the naturallyoccurring hormones are synthethised in the bodyfrom precursors which had long been familiar to

nutritionists as " essential fatty acids ", long-chainhydrocarbons with two or more double bonds.3,4 To-day well over a hundred laboratories and clinicalunits contribute regularly to the prostaglandinliterature; and, at times, from total obscurity to totalconfusion seems a short step.Chemically the prostaglandins are all derived from

a 20-carbon compound, prostanoic acid, which itselfhas no hormone-like action. The basic structure ischaracteristic and visually memorable: it consists of a5-carbon (cyclopentane) ring with two hydrocarbonchains attached to two neighbouring carbon atoms:

Beyond this, non-chemists may well feel lost in awelter of substitutions, side-chains, and mirror-

image patterns, designated by a seemingly irrationalsystem of roman letters, greek letters, numbers,subscripts, and superscripts. (In a rapidly expandingarea discoveries are not made in logical order: yetnothing can shake the delusion that serial symbols are

1. von Euler, U. S. Klin. Wschr. 1935, 14, 1182.2. Bergström, S., Ryhage, R., Samuelson, B., Sjövall, J. Acta. chem.

scand. 1962, 16, 501.3. Bergström, S., Danielsson, H., Samuelsson, B. Biochem. biophys.

Acta, 1964, 90, 207.4. van Dorp, D. A. Progr. Biochem. Pharmacol. 1967, 3, 71.

preferable to names.) At the moment, the most

important subdivision is into four series-prosta-glandins E, F, A, and B-each series correspondingto a small but functionally critical variation in the5-carbon ring:

Unlike prostanoic acid all the active prostaglandinshave at least one double bond in one of their hydro-carbon chains ; and some have two or three. The firstsubscript following the serial letter indicates the

degree of unsaturation. These double bonds can beeither of the trans or of the cis variety, the formertwisting the axis of the chain, the latter leaving it

unchanged. (Because of this the difference betweentwo prostaglandins may become apparent only whenthey are shown as three-dimensional models.) Forseveral years all naturally occurring hormones werethought to have a hydroxy group at C (carbon) 15;but a number of recently isolated natural analogueshave this apparently essential group at C 19. Thefunctional chemistry of the series is further complicat-ed by two facts. First, some inactive precursors canbe converted to active compounds in the course ofisolation even by simple exposure to atmosphericoxygen.5 Second, many of the prostaglandins are

extremely unstable; and it is often impossible to saywhether activity is due to a defined hormone or toone of its many, but still uncharacterised, fragmenta-tion products.

If the chemistry of the prostaglandins seems

complicated, the number and diversity of their

reported actions may leave the uninitiated gasping.Prostaglandin Ei from human seminal fluid, the

original source material, contracts the vasa deferentiaand the seminal vesicles of the guineapig (which, infact, has no prostaglandins in its seminal fluid) buthas the opposite effect on the corresponding organsof the rabbit (which has).6,7 Absorbed from the

vagina the prostaglandins E usually inhibit isolatedmyometrial strips, the effect being greatest on tissuesremoved at the time of ovulation ; the prostaglandinsA and B have a similar though weaker action; butthe prostaglandins F are powerful stimulants.8,9

Prostaglandins Fla and F 2ex contract all segments ofthe human uterine tubes; prostaglandin Eg relaxesall segments; whereas prostaglandins El and E2contract the uterine end but relax the ovarian end.1O

5. Nugteren, D. H., Vonkeman, H., van Dorp, D. A. Rec. Trav. chim.Pays-Bas, 1967, 36, 1237.

6. Eliasson, R., Risley, P. L. Acta physiol. scand. 1966, 67, 253.7. Goldblatt, M. W. J. Physiol., Lond. 1935, 84, 208.8. Hansson, E., Samuelsson, B. Biochim. biophys. Acta, 1965, 105, 379.9. Bygdeman, M. Acta physiol. scand. 1964, suppl. 242, p. 1.

10. Sandberg, F. L., Ingelman-Sundberg, A., Ryden, G. Acta obstet.gynœc. scand. 1965, 44, 585.

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Prostaglandin El stimulates the uterus of the rat,the guineapig, and the cat as well as that of thehuman female; but it inhibits the uterus of therabbit." 12 (Two recent contributions 13,14 in thesecolumns describe the use of prostaglandins in theinduction of therapeutic abortion.) At least two

prostaglandins-prostaglandin F2« and prostaglandinE2-have been demonstrated in menstrual loss, thehormone concentration being reduced in anovularcycles and increased by progesterone administration:they could conceivably account for the increasedincidence of diarrhoea during menstruation and forsome types of dysmenorrhoea.15 Amniotic fluidcollected during labour is particularly rich in prosta-glandin El which contracts the pregnant myometrium;but some of the active material may be of fetal

origin.16,17 Human umbilical blood also contains

prostaglandins in high concentration 18; and thehormones are vasoconstrictor in the perfused matureplacenta.l9 Such a list is confusing enough; and yetthe genital tract is only one possible site-andperhaps not the most important site-of prosta-glandin activity.A mass of experimental data connect the prosta-

glandins with the central nervous system; but againno principal role has so far crystallised.2O What hasbeen established is that brain tissue is rich in prosta-glandins ; that a number of prostaglandins are

released by brain and spinal cord on stimulation; andthat several members of the series have a powerfuleffecc both on reflex activity and on generalbehaviour. 21-25 (The potency of prostaglandin F 2(J(on the chick spinal cord is of the same order as that ofstrychnine.) But the hormones seem to be no less

busy at peripheral nerve-endings. Over a hundred

years ago CLAUDE BERNARD observed that the anti-dromic stimulation of the trigeminal nerve causessustained pupillary constriction and vasodilatationwhich are resistant to atropine 26; and reinvestigationof these phenomena has led to the discovery of agroup of lipids in extracts of iris which may be

responsible for some intricate ocular responses. Oneof these compounds has now been identified as

11. Berti, F., Naimzada, M. K. Boll. Soc. ital. Biol. Sper. 1965, 41, 1324.12. Horton, E. W., Main, I. H. M. J. Physiol. Lond. 1965, 180, 514.13. Karim, S. M. M., Filshie, G. M. Lancet, Jan. 24, 1970, p. 157.14. Roth-Brandel, U., Bygdeman, M., Wiqvist, N., Bergstrom, S. ibid.

p. 190.15. Pickles, V. R., Hall, W. J., Best, F. A., Smith, G. N. J. Obstet.

Gynœc. Brit. Commonw. 1965, 72, 185.16. Karim, S. M. M. ibid. 1966, 73, 93.17. Karim, S. M. M., Devlin, J. ibid. 1967, 74, 230.18. Karim, S. M. M. Br. J. Pharmacol. Chemother. 1967, 29, 230.19. von Euler, U. S. J. Physiol. Lond. 1938, 93, 129.20. Horton, E. W. Physiol. Rev. 1969, 49, 122.21. Avanzino, G. L., Bradley, P. B., Wolstencroft, J. H. Br. J. Pharmacol.

Chemother. 1966, 27, 157.22. Duda, P., Horton, E. W., McPherson, A. J. Physiol., Lond. 1968,

196, 151.23. Phillis, J. B., Tebecis, A. K. Nature, Lond. 1968, 217, 1076.24. Holmes, S. W., Horton, E. W. J. Physiol. Lond. 1968, 195, 731.25. Kataoka, K., Ramwell, P. W., Shaw, J. E. Science, N.Y. 1967, 157,

1187.

26. Bernard, C. Leçons sur la Physiologie et la Pathologie du SystèmeNerveux; vol. n, p. 205. Paris, 1858.

prostaglandin F2et.21,27-30 Nor are the " irins " theonly active " principles " which were known to

physiologists before the prostaglandins’ rise to fameand which are now being gathered into the prosta-glandin fold.

" Darmstoff " was described by VoGTin 1949: it is a product of the intestine and affectsperistaltic motility.31,32

" Medullin " has beenextracted from the inner zone of the kidney and is apowerful hypotensive agent.33,34

As might be expected, the reciprocal relations

reported between the various prostaglandins andother metabolic regulators-insulin, glucagon, thesteroids, the catecholamines, and a host of drugs-have become labyrinthine. In the isolated rat

epidydymal fat-pad, prostaglandin El is a stronginhibitor of lipolysis 35-37; and the prostaglandinswhich are released by adipose tissue on nervousstimulation or in response to catecholamines couldact as a link in a negative feedback mechanism.2oThe in-vivo changes, however, are more complex:both in dog and man, for example, prostaglandin Elactually induces lipolysis.38-41 Prostaglandin El alsoinhibits vasopressin when tested on the isolated toadbladder; and it has been suggested that the antag-onism could explain the diuretic and natriureticaction of the prostaglandins in the whole organism 42The thyroid is rich in prostaglandins; and prosta-glandins have been recovered from the blood ofpatients with medullary carcinoma of the gland 43Prostaglandin E2 potentiates the formation of dihydro-progesterone in response to gonadotrophins.44 Prosta-glandin El given by mouth inhibits gastric secretionin the rat; and subcutaneous injection into the dogdiminishes both the volume and the acid and pepsincontent of gastric juice.45,46 Directly or indirectlyseveral prostaglandins affect the active transfer ofcalcium ions across interfaces; and an increased rateof calcium uptake by the isolated heart of the frog orguineapig (but not of the cat or chicken) could berelated to the digitalis-like cardiotonic action of

prostaglandin E1 in some species.47 Prostaglandin27. Ambache, N. J. Physiol. Lond. 1955, 129, 65p.28. Ambache, N. ibid. 1957, 135, 114.29. Ambache, N. ibid. 1959, 146, 255.30. Ambache, N., Brummer, H. C., Rose, J. G., Whiting, J. ibid. 1966,

185, 77P.31. Vogt, W. Arch. exp. Path. Pharmak. 1949, 206, 1.32. Vogt, W. J. Physiol., Lond. 1957, 137, 154.33. Lee, J. B., Covino, B. G., Takman, B. H., Smith, E. R. Circulation

Res. 1965, 17, 57.34. Muirhead, E. E., Leach, B. E., Brown, G. B., Daniels, E. G.,

Hinman, J. W. J. Lab. clin. Med. 1967, 70, 987.35. Berti, F., Usardi, M. M. Giorn. Arterioscler. 1964, 2, 261.36. Steinberg, D. Ann. N.Y. Acad. Sci. 1967, 139, 897.37. Vaughan, M. Pharmacol. Rev. 1966, 18, 215.38. Bergström, S., Carlson, L. A., Ekelund, L., Orö, L. Acta. physiol.

scand. 1965, 64, 332.39. Bergström, S., Carlson, L. A., Orö, L. ibid. 1966, 67, 142.40. Bergström, S., Carlson, L. A., Orö, L. ibid. p. 185.41. Bergström, S., Carlson, L. A., Weeks, J. R. Pharmacol. Rev. 1968,

20, 1.42. Orloff, J., Handler, J. S., Bergström, S. Nature, Lond. 1965, 205, 397.43. Williams, E. D., Karim, S. M. M., Sandler, M. Lancet, 1968, i, 22.44. Bedwani, J. R., Horton, E. W. Life Sci. 1968, 7, 389.45. Shaw, J. E., Ramwell, P. R. J. Physiol., Lond. 1968, 195, 34.46. Robert, A., Nezamis, J. E., Phillips, J. P. Am. J. dig. Dis. 1967, 12,

1073.47. Arienti, S., Piccini, F., Pomarelli, P. Boll. Soc. ital. Biol. Sper. 1966,

43, 521.

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El also restores coagulation-time lengthened by areduced calcium-ion concentration; and it alters

platelet mobility and aggregation.4° Both prosta-glandins El and A,7-but not prostaglandin F1&agr;—stimulate epidermal proliferation and keratinisationin the chick embryo.49 Spontaneous ureteric peris-talsis is inhibited by prostaglandin El in the dog.50A number of prostaglandins are released in differentparts of the gastrointestinal tract on vagal or humoralstimulation; and the effect of the hormones on theisolated intestine provides a means for bioassay.51,52(The assay is influenced by many factors, especiallyby the ionic composition of the milieu.3) Prosta-

glandin El increases transit-rate through the smallintestine and colon of healthy volunteers.54 Humanbronchial muscle is relaxed by prostaglandins El andE2 but contracted by prostaglandins F2o:.53,55,56 Inmost vascular beds the prostaglandins E and A arepotent vasodilators; and a precipitous fall in systemicblood-pressure can follow intravenous injection of thehormones. 57-59 ’But prostaglandin El constricts thearterioles not only of the placenta but also of thenasal mucosa; and in some animals the prostaglandinsF are general vasoconstrictors. 60 Prostaglandin-likeactivity in certain kinds of exudate and the influenceof prostaglandins on capillary permeability point toa role in inflammatory reactions; and prostaglandinE2 has been shown to benefit adjuvant arthritis (alaboratory model for chronic joint inflammation)in the rat. 61-63

What, one may reasonably ask, does all this mean ?It does not, of course, mean that all the actionsmentioned are physiological functions: almost cer-tainly they are not. But even if most current experi-mental systems should prove to be no more than

ingenious laboratory confections-and some un-

doubtedly are-the prostaglandins are going to

emerge as an exciting new molecular species. Theyare exciting because of their extreme potency:effective concentrations are of the order of nano-

grammes per 100 ml. But it is the newness of the

species that needs emphasis, for too strenuous

48. Emmons, P. R., Hampton, J. R., Harrison, M. J. G., Honour, A. J.,Mitchell, J. R. A. Br. med. J. 1967, ii, 472.

49. Kischer, C. W. Develop. Biol. 1967, 16, 203.50. Boyarski, S., Labay, P., Gerber, C. Invest. Urol. 1966, 4, 9.51. Coceani, F., Pace-Asciak, K., Volta, F., Wolfe, L. S. Am. J. Physiol.

1967, 213, 1056.52. Bennett, A., Murray, J. G., Wyllie, J. H. Nature, Lond. 1967, 216,

873.53. Coceani, F., Wolfe, L. S. Can. J. Physiol. Pharmacol. 1965, 45,

445.54. Misiewicz, J. J., Waller, S. L., Kiley, N., Horton, E. W. Lancet,

1969, i. 648.55. Sheard, P. J. Pharm. Pharmacol. 1968, 20, 232.56. Sweatman, W. J. F., Collier, H. O. J. Nature, Lond. 1968, 217,

69.57. Strong, C. G., Bohr, D. F. Am. J. Physiol. 1967, 213, 725.58. Bergström, S., Carlson, L. A., Ekelund, E., Orö, L. Acta physiol.

scand. 1965, 64, 332.59. Nakano, J., Perry, M., Denton, D. Clin. Res. 1968, 16, 110.60. Jackson, R. T., Stovall, R. in Worcester Symposium on Prostaglan-

dins; p. 329. New York, 1968.61. Willoughby, D. A. J. Path. Bac. 1968, 96, 381.62. Willis, A. L. J. Pharm. Pharmcol. 1969, 21, 126.63. Aspinall, R. L., Cammarata, P. S. Nature, Lond. 1969, 224,

1320.

attempts to fit them into an established mould mayseriously hinder progress.

Clearly, the prostaglandins are not hormones inthe generally accepted sense. They are distributedand released far more widely: indeed it is possiblethat they are invariable constituents of all cells.

Moreover, though one may loosely speak of pros-taglandin target organs or target tissues, these

targets are so far-flung, so relative, and so variedfor different members of the series that the termbecomes almost meaningless. And even if pros-taglandins do circulate in blood locally or system-ically, it is unlikely that this is how they operate.(The analogy may be with serum-enzymes whose" function " is confined to their usefulness inclinical laboratory diagnosis.) Up to a point theprostaglandins conduct themselves more like vita-mins-but only up to a point. Like vitamins theyare derived from a group of essential food ingredients,the unsaturated long-chain fatty acids; and theycould play a vitamin-like part in a multiplicity ofbiochemical transformations. On the other hand,almost by definition vitamins are trace substanceswhose deficiency causes characteristic clinical syn-dromes-such as scurvy, beri-beri, and perniciousanxmia-and, if such a syndrome accompaniesprostaglandin deficiency, it has yet to be recog-nised. Several more-or-less inspired attempts havebeen made to fit the prostaglandins into a purelyenzymic context: in particular it has been suggestedthat their primary action is to inhibit adenylcyclase.2o,64 This enzyme catalyses the formationof cyclic adenosine monophosphate, a versatile

regulator of energy transfer; and the reaction couldlink circulating prostaglandins (and other hormones)to intracellular metabolic pathways. Against suchconcepts it must be said that to many biochemists

enzyme actions have become like the actions ofinvisible spirits to the believer in invisible spirits:any biochemical change observed is ipso-factoevidence of enzymic activity. (The proposition isoften as difficult to prove as to disprove.) The

prostaglandins also show similarities to such humoraltransmitters as acetylcholine and the catecholamines:in particular their impact on the central nervous

system and their role in mediating antidromalreflexes points to an influence on synaptic trans-mission. Yet a number of prostaglandin effectsare difficult or impossible to explain on this basis.One of the most remarkable chemical facts about

prostaglandins is their solubility both in water andin fat solvents (a property noted by VON EuLER);and it is not unreasonable to speculate on the

possible significance of this. Such compoundscould be essential structural constituents of lipid-water interfaces, their role being physical-forexample, preservative-like or detergent-like-rather

64. Pickles, V. R. ibid. 1969, 224, 221.

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than biochemical. Unfortunately, very little isknown about the factors which govern the physicalbehaviour of biological structures.

Reverting to the question of what the prosta-glandins mean in broad biological terms, the answertherefore is that we still do not know. What isneeded most is more information about the mole-cular dynamics of prostaglandins in action. Livingprocesses are regulated not by substances but bythe transformation of substances; and static formulas,however impressive they are as analytical achieve-ments, often mislead biologists into taking too

static a view. Whatever a prostaglandin may do, itis not prostaglandin X which does it but the con-version of prostaglandin X into something else orof something else into prostaglandin X. Whichof the two is the key event ? And is the step reversible(as in enzymic catalysis) or irreversible (as in

preservatives) ? The facts may already be available:the answers still elude us.

Long-term Anticoagulants after AcuteMyocardial Infarction

IN 1947 NICHOL and FASSETT 1 suggested that thelong-term administration of anticoagulants mightimprove prognosis in patients who had survived acardiac infarction. In the twenty-three years whichhave elapsed, the profession and their patients havebeen awaiting a definitive answer to this deceptivelysimple proposition. The first paper in this week’sissue is by an international review group and it drawstogether the results of many of the controlled trialsof long-term anticoagulant therapy after cardiacinfarction. Its authors, however, could reach no

agreed conclusion from the information obtained, andthey were forced to suggest that to answer the questionsquarely yet another " specially designed trial wouldbe required ". Why is the anticoagulant dilemma stillunresolved, despite large investments of money andmanpower in these trials ? First, there are the prob-lems of any very lengthy investigation in which thepatients and their disease may outlive the interest andavailability of individual investigators. This situation,then, dictates a multi-centre and a multi-participantapproach which demands rigid adherence to pre-determined selection criteria and methods. This mayitself severely limit the number of patients availablefor entry to the study, it may make the problem ofsubsequent withdrawals a considerable one, and itmay produce results which cannot be applied withcertainty to the total group of patients with the disease.Second, no drug is yet available which confers

immortality; if the condition which doctors are tryingto treat is the principal cause of death in a particular1. Nichol, E. S. Fassett, D. W. Sth. med. J., Bgham, Ala, 1947,40, 631.

group, then a therapeutic effect becomes more readilyapparent than it does when other events, not in-fluenced by the treatment under test, are the majorkillers. In the second situation, a very significanteffect on a single disease will not appreciably alter lifeexpectancy, and the survival curves for a treated andan untreated group will rapidly approximate. Theassessment of an effect in this situation requires ameasure of the natural history of the individualdisease, and its recurrence-rate, rather than a measureof simple survival.

How have these general problems interfered withassessment of the value of anticoagulant treatment incardiac infarction, and how do they bear upon the taskwhich the international review group set themselves ?The multi-centre approach means that, in theircollaborative analysis, each of the trialists used differ-ent criteria, so that in some series diabetics were

excluded, in others, hypertensives, in others the sub-jects were all U.S. Army veterans, and so on.

Moreover, different anticoagulants were used, and itshould not be assumed that because a group of agentsdepress various clotting factors to a certain degree,they are, in all other respects, equal: no-one assumesthat insulin and the sulphonylureas are identical, orrefers to them as anti-hyperglycsemics. Again, whenthese trials began, it was believed that the prognosisfor a patient with cardiac infarction was poor becauseof recurrent cardiac infarction. The hope was thatanticoagulants would prevent the further episodes ofcoronary thrombosis which caused these reinfarc-tions. But it must now be acknowledged that, in thearterial tree, anticoagulants have no a-priori claim tobe antithrombotic 2 ; that the very poor overall

prognosis in cardiac infarction is largely due to deathswithin the first few hours,3,4 the prognosis for thesurvivors being only a little worse than that ofhitherto unaffected members of the same age-group;and that sudden death and death due to arrhythmia orpump failure after cardiac infarction may be un-related to new thrombotic occlusions and reinfarc-tion.5 Reinfarction-rate ought, therefore, to be deter-mined in addition to simple survival, and it was thedifficulty of assessment of reinfarction which wasrightly emphasised by McMICHAEL and PARRY. 6 It isalmost impossible to do a double-blind trial of anti-coagulants ; and the criteria for reinfarction are moresubjective than some of the trialists would initiallyadmit. In the living, the trialists were dependent onfurther electrocardiographic changes in patientswhose entry to the study had been conditional onabnormal E.c.G. patterns. After death a post-mortemexamination will readily reveal what a patient diedwith, but what he died of is often a matter for con-

2. Mitchell, J. R. A. Abstr. Wld Med. 1969, 43, 249.3. Honey, G. E., Truelove, S. C. Lancet, 1957, i, 1155, 1209.4. McNeilly, R. H., Pemberton, J. Br. med. J. 1968, iii, 139.5. Lovell, R. R. H. Med. J. Aust. 1969, ii, 425.6. McMichael, J., Parry, E. H. O. Lancet, 1960, ii, 991.