Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement), pp. 6S-19S PROSTAGLANDINS IN PEPTIC ULCER DISEASE Physiology and Pharmacology of Prostaglandins S.J. KONTUREK, MD, and W. PAWLIK, MD Prostaglandins (PGs) are products of polyunsaturated acid metabolism, particularly arachidonic acid (AA) released from membrane phospholipids by the action of phospholipase A2 in response to a variety of physical, chemical, and neurohormonal factors. AA is rapidly metabolized to oxygenated products by two distinct enzymatic pathways: cyclooxygenase and lipoxygenase. The intermediate cyclooxygenase products are converted to primary PGs, while the lipoxygenase products are converted to leukotrienes. The generation of various cyclooxygenase products varies from tissue to tissue. Aspirin and related antiinflammatory drugs reduce tissue biosynthesis of all cyclooxygenase products; their therapeutic effects and side effects parallel the inhibition of cyclooxygenase. Exogenous PGs exhibit a broad spectrum of effects. PGs of the E series and PGI2 are generated by the endothelium and the vessel wall to maintain the microcirculation and to counteract the vasoconstrictive and proaggregatory actions of thromboxane A2 (TXA2). Exogenous PGs of the E and I series are potent vasodilators in various vascular beds, and result in decreased systemic blood pressure and reflex stimulation of heart rate. PGEs and PGI2 increase renal blood flow and provoke diuresis and natriuresis, partly by modulating the renin-angiotensin-aldosterone system. PGFs contract the bronchial and gut muscle, while PGEs and PGI2 have opposite effects. PGEs and PGFs, but not PGI2, cause a strong contraction of the uterine muscle, hence their undesirable uterotonic effects. PGEs relax bronchial muscle, whereas PGFs cause bronchoconstriction; their imbalance may contribute to the high bronchial tone in bronchial asthma. PGs of the E and I series and TXA2 are 'generated by the gastrointes- tinal mucosa and released into the lumen upon neural or hormonal stimulation; they probably participate in the maintenance of mucosal integrity and microcirculation. Exogenous PGs of the E and I series inhibit gastric acid secretion and stimulate alkaline secretion while increasing mucosal blood flow. All PGs, including those noninhibitory for acid secretion, are cytoprotective against various ulcerogens and necrotizing agents. The classic PGs constitute only a small fraction of biologically active products of AA metabolism, and recent studies on the lipoxygenase products emphasize their biological activity and involvement in a variety of pathological conditions. Prostaglandins (PGs) constitute a family of chemi- cally related lipid acids that are among the most prevalent autacoids; they seem to modulate practi- cally every biological function in the body. They are From the Institute of Physiology, Academy of Medicine, Krakow, Poland. Address correspondence to: Professor Dr. S.J. Konturek, Institute of Physiology, Academy of Medicine, ul. Grzegorzecka 16, 31-531 Krakow, Poland. formed by a complex of microsomal enzymes, act- ing on certain 20-carbon unsaturated fatty acids, particularly eicosatetraenoic or arachidonic acid (AA). Additional products of the cellular metabo- lism of AA, differing in structure from PGs, include the thromboxanes (TX) and leukotrienes (LT), whose physiological and pathological functions are closely interrelated with those of the PGs. The existence of the PGs has been known for 6S Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement) 0163-2116/86/0200-006S$05.00/0 (cid:14)9 1986 Plenum Publishing Corporation
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`PHYSIOLOGY AND PHARMACOLOGY OF PROSTAGLANDINS over half a century. Kurzok and Lieb (1) were the first to observe, in 1930, that strips of human uterus relax or contract when exposed to human semen. In the mid-1930s, von Euler (2) in Sweden, and Goldblatt (3) in England independently extracted crude PGs from the seminal fluid of man and vascular glands of sheep, and reported their smooth-muscle-contracting and vasodepressor ac- tivities. In the late 1950s, Bergstrom and Sjovall (4) isolated PGs in a pure form and, in the early 1960s, determined the chemical structure. With the identi- fication of two unstable cyclic endoperoxides, PGGE (5) and PGHz (6), the emphasis shifted from the primary PGs (E and F series) to other biologi- cally active products of AA metabolism, resulting in the discovery of TXAz (7) and prostacyclin (PGI2) (8). In addition to the cyclooxygenase mechanism, another metabolic pathway, converting AA to hydroperoxides (HPETE and HRTE) (9, 10) and then to LTs (11) ! was identified. The impact of the PGs and other products of AA metabolism could be compared only to that of corticosteroids in the late 1940s and 1950s. CHEMICAL STRUCTURE AND BIOSYNTHESIS The natural PGs are considered analogs of pros- tanoic acid, a structure with a 20-carbon and 5- membered ring. They fall into several classes des- ignated by letters, indicating different substituents on the ring, alphabetically, in order of their discov- ery. The main classes are subdivided according to the number of double bonds on the side chain indicated by the subscript 1, 2, or 3. The common precursors of PGs, TXs, and LTs are three naturally occurring eicosapolyenoic acids: trienoic (dihomo--r acid, tetraenoic (arach- idonic) acid, and pentaenoic acid (12). In man, tetraenoic acid (AA) is by far the most common, giving rise to the PGs of the subscript-2 series. It is either derived from dietary linoleic acid or ingested as a constituent of food. After absorption from the gut, it is esterified and present ubiquitously in the body as a component of phospholipids of ceil mem- branes and of other complex lipids. The hydrolysis of esterified AA provides the first rate-controlling step in PG formation. Dihomo-~- linolenic acid, which has one less double bond than AA, gives rise to PGs of the subscript-1 series. Pentaenoic acid is very rare, derives from fatty acid with three double bonds, and is converted to PGs of the subscript-3 series. In mammalian tissues, PGs and their precursor acids occur in appreciable quantities only in semi- nal, menstrual, and amniotic fluids. The precursor acids are present as phospholipids in cell mem- branes. A wide variety of divergent physical, chem- ical, and neurohormonal factors may activate the enzyme phospholipase A2, setting free the precur- sor acids to gain access to enzyme complexes present in most tissues. Once released, fatty acids can follow two pathways: the cyclooxygenase path- way gives rise to the PGs and TXs, while the lipoxygenase pathway gives rise to the LTs and other unsaturated hydroxy acids. The metabolic pathway for AA and the structures of selected metabolites are shown in Figure 1. The specific metabolites of the AA cascade formed in vivo vary according to the tissue and species. The first product of cyclooxygenase is an unstable cyclic endoperoxide derivative, PGG2, which can proceed either spontaneously or by way of a peroxidase to PGH2. PGH2 is the common intermediate for TXA2, PGDE, PGE:, PGF2~ and PGI2. An endoperoxide isomerase can convert PGHE to either PGE2 or its isomer PGD2. The combined action of this isomerase and reductase yields PGF2~. In some tissues, a 9-keto-reductase catalyzes the interconversion of PGE2 and PGF2~. PGE2 may then undergo dehydration to PGAE and isomerization to PGB2. In the plasma of some species, an enzyme isomerizes PGAz to PGC:. PGH2 may be converted by prostacyclin synthe- tase into PGI2, first discovered in the vascular wall. PGI2 is unstable under physiological conditions, hydrolyzing to a stable compound, 6-keto-PGFl~ (12-14). The other route of PGH2 metabolism is to TXA2, yet another unstable and highly active compound formed by an enzyme complex, thromboxane syn- thetase. TXA2 is hydrolyzed nonenzymatically to the hemiacetal oxane TXB2. The details and significance of the lipoxygenase pathway are still under intensive investigation. As in the cyclooxygenase pathway, the first products formed are hydroxyperoxides (HPET), which are then converted by peroxidases to the corresponding hydroxides (HETE), giving rise to the LTs (15). (These products will not be discussed in this re- view.) The chain of events leading to the release and metabolism of AA from the membrane phospho- lipids can be initiated by a number of factors: nerve stimulation, neurotransmitters (eg, norepineph- Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement) 7S
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`KONTUREK AND PAWLIK L~poxygenase OH OOH~ 12-HPETE CH HEIE I ESSENTIAL FATIY ACIDS IN DIET] ESTRIFIED ACID IN CELL LIPIDS e.g. Ph0sphollpids I Various / Activation of Stimuli ~ Phospholipase A2 Chemical & Mechanical Ara(:hid0nic Acid Fatty Acid Cyclooxygenase "---..._ Fa,s.Cubs,',at.. i * LO-O ~-=,r'v'-'-j j 5 B111/,.., Antiinflar~atory [Drugs eg ~0~ OOH] Eic0satetraynoic Aspirin and Ac id Indomet hac in - (?OH P~2 HOOC~'-I~ . , 0"~, Proslacyclin ~COOH Thromboxane ~f1~f~COOH = S, nth.ase OH ~ PGH 2 , (~H TXA 2 OH ~, 6H Pot2 /1\~ ?H i oHO,~COOH / I \ ~ r"'f"~--/'~/~COOH /I \ Q / /"t H.T O. O. OH OH PGD2 OH OH PGF2 PGF2w Fig 1. Biosynthesis of the products of arachidonic acid. rine), neuropeptides (eg, somatostatin), various hu- moral agents (eg, bradykinin), hyperosmolar solu- tions, and even mechanical strain. Indeed, almost any deformation of cell membrane, such as stretch- ing a blood vessel, inflation of the lung or contrac= tion of the intestine, may lead to increased PG formation under physiological conditions (i6-21). Numerous pathological conditions may increase PG or TX synthesi s. Any damage of tissue, apart from frank trauma, increases the generation of cyclooxy- genase products (22). Acute cardiac ischemia favors the synthesis of vasoconstrictor products over nor- mal vaSodilator metabolites of AA. Tissue injury from an anaphylactic reaction or edema may aug- ment PG formation (eg, in the lungs) and may contribute to increased vascular permeability. Acute hypoxia or exposure to tobacco smoke in the lungs also increases PG synthesis. Thus, many kinds of tissue injury may lead to increased generation of PGs and LT products (23). Breakdown of lysosomes will release, among other enzymes, phospholipases, which may hydrolyze AA from the membrane phospholipids. Not all metabolites are formed in every tissue when AA is released; it depends on the most active enzymes in the tissue involved. All cells contain phospholipids and at least some Cyclooxygenease and iipoxygenase. Most tissues seem able to syn- thesize PG endoperoxides from free AA, but the factors controlling their further steps have not been defined. Certain tissues (such as lung, spleen, gas- trointestinal tract, thyroid, and adrenals) are able to synthesize the whole range of products, whereas other tissues predominantly produce PGD2 (mast cells), PGE2 (seminal vesicles), PGI2 (vessel wall), or TXA2 (platelets). Antiinflammatory steroids appear to reduce PG biosynthesis by lowering the availability of the substrate acid to the cyclooxygenase or by blocking the effiux of PGs from their biosynthetic site (Figure 2). They seem to act by inducing the synthesis and release of proteins (lipomodulin) that possess 8S Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement)
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`PHYSIOLOGY AND PHARMACOLOGY OF PROSTAGLANDINS Cell Membrane Phospholipids J PBPAB t ~+ mepacrine -.~ Phospholipase A2 Corticosteroids , macrocortin Incl~ Arachidonic Acid I Indomethacin Benoxaprofen ~ ~ I Benoxaprofen BW755C ~ ~ 1 BW7550 ETYA ~ Lipoxygenase Cyclooxygenase--~. ~ I ETYA 5HPETE 5HETE LiA4~ LTB4 \ LTC4 ~,.. ~ 1 FPL 7121 LTD4 ~'~" 1 " "1 Indomethacin I LTE4 I I-Benzylimidazole [ P~G2 Imidazole |'~ ! ~--" Thromboxane A2 PGIz PGE2 PGF2 o, PGD2 Thromboxan e B2 6-KETO-PGFI~ PGA2 PGB2 ~- PGCz Fig 2. Cascade of arachidonic acid, showing blockade at different steps of metabolism. antiphospholipasr properties. Aspirin and related nonsteroidal antiinflammatory drugs (NSAIDs) are very potent inhibitors of PG biosynthesis; they work by preventing the production of PG endoper- oxides. Vane (24) proposed that the inhibition of PG biosynthesis by NSAIDs may account for their therapeutic effects, and this has been confirmed by direct measurements of PGs in various tissues and fluids in animals and humans treated with conven- tional NSAIDs. The sensitivity of cyclooxygenase to NSAIDs varies from tissue to tissue (25). Unlike in other tissues, the biosynthesis of PG endoper- oxides in platelets can be suppressed by low doses of aspirin, resulting in the reduction of TXA2 for- mation, which may be useful in reducing TX bio- synthesis in platelets without affecting PGI produc- tion by the vessel wall. Products of lipoxygenase are direct inhibitors of the cyclooxygenase path- way, suggesting the existence of a negative feed- back relationship between these two pathways. Similarly, the inhibition of TX biosynthesis (eg, by imidazole derivatives) leads to increased formation of primary PGs (26). Several efficient mechanisms catabolize and inac- tivate biologically active metabolites of AA. The PG intermediates, PGG2 and PGH2, are highly unstable, apparently existing only momentarily in vivo. PGs are rapidly inactivated, the first step being the oxidation of the C-15 hydroxyl group by 15-hydroxy-PG-dehydrogenase (PGDH). This en- zyme is widely distributed in many tissues, espe- cially the lungs; consequently, about 95% of PGs of the E and F series, but not D or I, are metabolized during a single passage through the lungs. The 15-keto compound is then reduced by a A 3 reduc- tase (PGRI ~ s the 13,14-dihydro A 3 derivatives. Subsequen{ b~ta-oxidation and omega-oxidation of the side chains cau.ses further degradation, giving rise to the dicarboxylic acids in the urine. Both PGDH and PGR are intracellular soluble enzymes, so that the substrate must pass through the cell membrane before degradation can proceed. Natural PGEz and PGF2~ pass through the membrane and are quickly inactivated. In contrast, methylated PGs (eg, 16,16-dimethyl PGE2) also cross the mem- brane but are not the substrate for PGDH; there- fore, they are taken up by lung tissue and then slowly released unchanged into the circulation. This results in prolonged biological activity. PGI2, which is the substrate for PGDH in vitro but not for transfer into lung cells, can pass unchanged from the venous to the arterial blood. Such selectivity in PG inactivation is not seen in the gastrointestinal mucosa or in the liver, where all natural PGs are inactivated on passage through the portal circula- tion. However, methylated PGs can escape inacti- Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement) 9S
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`KONTUREK AND PAWLIK vation, being resistant to the mucosal or hepatic PGDH; they are active orally and, in part, act from the gastric lumen directly on the gastric glands. PGD2 and TXA2 are not degraded by PGD2, al- though they possess a 15-hydroxyl group. TXA2 is very unstable and spontaneously converts to TXB2, which follows the catabolic route of other PGs. PGI2 is also hydrolyzed spontaneously to inactive 6-keto-PGFl~. PHYSIOLOGICAL FUNCTIONS AND PHARMACOLOGICAL PROPERTIES The biological actions of PGs comprise a wide spectrum of effects. Some have directly opposing actions in many systems, and prostanoid-mediated control of cellular, tissue, or organ functions re- flects the interactions between different PGs, TXs, and LTs. Cardiovascular System and Platelets. The major cyclooxygenase product in the wall of all arteries and veins so far examined, and also in the microcirculation, is prostacyclin (27). The generat- ing capacity for PGI2 was found to be greatest in the endothelium, progressively decreasing toward the adventitia (28). In vitro, the endothelial cells are the most active producers of PGI2 (29). Because of its resistance to inactivation in the pulmonary circula- tion, investigators have proposed that PGI2 may function as a circulating hormone, but its biological instability suggests that it is most likely a local factor (30). Various data indicate that the vessel wall can synthesize PGI2 not only from its endoge- nous precursors but also from PG endoperoxides released by the platelets, suggesting a biochemical cooperation between the platelets and the vessel wall. PGI2 produced by the vessel is a strong vasodilator and also the most potent known inhibi- tor of platelet aggregation known (31) (Figure 3). On the other hand, the major product of AA metabolism in platelets is TXA2. It appears that when platelets are activated and the endogenous AA cascade is triggered, the PG endoperoxides thus generated are converted predominantly to TXA2, the most potent stimulant of platelet aggregation known and a very strong vasoconstrictor. PGI2 and TXA2 show opposite effects on cyclic AMP concen- trations in their target cells, thereby giving a bal- anced control mechanism affecting both the plate- lets and the vessels. PGI2 is not only the most potent inhibitor of platelet aggregation among the naturally occurring ARACHIDONIC ACID I (non steroidal anti- inflammatory drugs) PG GH .. 0 cAMP\ AGPLAETELTEI T N VASODILATATION ~ (cid:127)~ rNHIBITION OF PLATELET AGGREGATION I FA- OOH (LDL) (cid:127) ~ PGI2v (cAMP{) PLATELET ( VASOCONSTRI CTION AGGREGATIONI ~, FIBRINOLYSIS ) I ~- ~ DEVELOPMENT OF ATHEROSCLEROSIs Fig 3. The interaction of TXA2 and PGI2 on platelet aggregation, vessel diameter, and fibrynolysis. PGs, but also the most potent endogenous antiag- gregating agent described. Since it is generated in large amounts by the endothelial cells, its likely physiological role is to inhibit platelet adhesion to the endothelium and the formation of thrombus. It can also inhibit the mobilization of fibrinogen-bind- ing sites on human platelets in vitro, and thus may limit the extent of fibrinogen-platelet interaction. Furthermore, it may enhance fibrinolytic activity in the lung (31-33). PGI2 is a potent vasodilator in the mesenteric vascular bed, the gastric mucosal circulation (34), and in pulmonary (35), coronary (36), and renal (37) vessels. It is also active in the microcirculation and causes pronounced vasodilation of both large and small arteries. Because of the potent vasodilator activity in many microvascular beds, PGI2 genera- tion may be involved in the modulation of local blood flow and in the functional hyperemic re- sponses of the tissues (38). Since TXA2 is highly unstable, studies of its vascular effects are difficult. TXA2 causes an imme- diate and brief vasoconstriction in various vascular beds, such as the mesenteric and femoral vessels. As with platelet function, the directly opposing vasoactive properties of TXA2 and PGI2 may play an important role in the regulation of vascular tone and tissue blood perfusion under physiological and pathological conditions. Several diseases have been related to imbalance between PGI2 and TXA2 sys- tems. In general, in thrombotic diseases (eg, arterial or venous thrombosis, or myocardial infarction), TXA2 production is increased or PGI2 generation is 10S Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement)
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`PHYSIOLOGY AND PHARMACOLOGY OF PROSTAGLANDINS 1 Medullary blood flow 2 Osmotic gradient 3 8locking water reabsorption (ADH) Stimuli Angiotensin "ff Vasopressin Bradykinin Sympathetic Activity 1 -- PGF2a~ ( i n !eGs!i i ~~ Ps~iui' a r, ,[{ ~i~ / ~ Cortical'~lood flow ~~ I'1._~ Rry~ihnopoietin _J----" release in urine Fig 4. Role of prostaglandins in renal physiology. reduced, or both. The opposite findings were re- ported in diseases associated with bleeding. A de- ficiency of PGI2 formation and an imbalance be- tween PGI2 and TXA2 may be important factors in arteriosclerotic and thromboembolic diseases (39, 40). Pharmacological properties of PGs of the E and I series include potent vasodilation in most vascular beds, including coronary, renal, and mesenteric. Vasodilation in response to PGs occurs in the arterioles, precapillary sphincters, and postcapil- lary venules, resulting in a fall in arterial blood pressure. Particularly, PGI2 causes prominent hy- potension due to dilation of various vascular beds (38). Cardiac output is generally increased by PGs because of direct inotropic effects (E and F series) and increased heart rate (I series), reflex responses from the fall in total peripheral resistance (41). Kidney and Urinary Formation. A great deal of effort has been invested in determining the role of arachidonate metabolism in renal function. The renal medulla of several species, including man, has a high capacity to form PGE2, PGF2~, PGD2, and PGI2 from AA infused into the renal artery or released endogenously by bradykinin in the kidney (42-45). These PGs originate mainly from the inter- stitial cells and renal tubules. The renal cortex has a somewhat lower capacity to generate primary PGs, but forms substantial amounts of PGI2 from the cortical;vascular endothelium. Since circulating E and F~series PGs are almost completely cleared upon 15assage through the pulmonary circulation, their amounts in the urine represent a reliable index of their biosynthesis in the kidneys. It was reported that total daily endogenous production of the E series is in the range 16-297 Ixg, and of the F series, 48-369 ~g (13, 22). PGE2 and PGI2 are potent renal vasodilators when infused into the renal artery; they cause a marked but transient reduction in renal vascular resistance and an increase in renal blood flow (46, 47). It has been suggested that PGs are responsible for reactive hyperemia and modulation of renal blood flow. The well-known antihypertensive prop- erty of the normally functioning kidney has been attributed to the synthesis of PGs and their release either locally or into the blood stream. On the other hand, the fact that aspirin-like agents, which inhibit PG biosynthesis, fail to affect renal blood flow may mean that endogenous PGs do not contribute to the physiological regulation of renal circulation. They seem, however, to protect the kidney against pow- erful vasoconstrictors, such as angiotensin II and norepinephrine (Figure 4). PG-induced increase in renal blood flow is ac- companied by diuresis, natriuresis, and kaliuresis, probably as a result of a direct action of PGs on tubular transport processes and redistribution of renal blood flow (37, 48). In addition, renal PGs seem to be involved in the release of renin from the renal cortex. This is supported by the finding that NSAIDs inhibit the release of renin (49, 50). PGs may affect renin release by modulating renal baroreceptor activity and the receptors of the macula densa. E series PGs inhibit water reabsorp- tion in the collecting ducts, probably by inhibiting cyclic AMP formation or by redistributing renal Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement) l 1S
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`KONTUREK AND PAWLIK STIMULI MECHANICAL ACh STRAIN CCK PGI2 \ \ 1PGF2 PGE2 \ PGs ] Fig 5. Role of prostaglandins in changes in muscle activity in response to mechanical and neurohormonal stimuli. blood flow. PGs may increase the production of erythropoietin, and this effect can be blocked by inhibitors of cyclooxygenase (51). No definitive conclusions have been reached regarding the role of PGs in the pathogenesis of various kidney diseases. Smooth Muscle. PGs contract or relax many smooth muscles besides those of the vasculature and may contribute to the regulation of muscle contractions. Since PGs are generated during in- creased muscle contractions, they have been con- sidered as local feedback controllers of contractile activity. In general, F series PGs contract various types of smooth muscle, including those of the bronchiopul- monary system (52, 53), gastrointestinal tract (54-56), and uterus (57). E series PGs relax bron- chial muscle but, like F series PGs, produce strong contractions of uterine muscle. The response of the uterus (whether pregnant or not) to these PGs is prompt and dose-dependent. PGs cause a sharp rise in uterine contractions, and these uterotonic effects of primary PGs are antagonized by PGI2. PGI2 also relaxes bronchial and intestinal muscle (Figure 5). In the intestines, PGs of both the E and F series contract the longitudinal muscle layer from the stomach to the colon, while circular muscle relaxes to E series and contracts to F series PGs. Natural E and F PGs, and their methylated analogs, shorten intestinal transit time and may cause diarrhea, cramps, and vomiting. PGE2, PGF2, and PGI2 have been detected in smooth muscle, and increase dur- ing contractions. Since aspirin-like agents increase motility, it has been suggested that the predominant effect of endogenous PGs is the inhibition of con- tractile activity (53). Exogenous PGE2 was tried as an alternative to isoproterenol in bronchial asthma, but was found to be of limited value because of its irritant effect on the bronchial mucosa (52). Both PGE2 and PGF2 are widely used as abortifacients. The hope that PGs given in early pregnancy could provide a simple and convenient means of abortion has not materialized because of distressing side effects, such as vomiting and diar- rhea. They appear to be of value in missed abortion and for inducing midtrimester abortion (58). Reproductive and Endocrine Systems. The repro- ductive system has long been recognized as the major source of PGs. It was the high concentration of PGs in the seminal fluid that originally led to their discovery. Indeed, PGs are present in human semen in concentrations of several hundred micrograms per milliliter, at least a million times the PG levels in other biological fluids. This high content of PGs in semen, and the significant absorption of PGs from the vagina, led to the speculation that PGs depos- ited during coitus may facilitate the transport of semen in the uterus and fallopian tubes and the fertilization of the ovum (59). A deficiency of PGs in the semen has been claimed to result in male infertility. Increased PG synthesis in the endometrium has been implicated in the pathogenesis of dysmenor- rhea, since treatment with cyclooxygenase inhibi- tors is known to reduce the pain of this condition. PG levels in the blood and amniotic fluid of pregnant women tend to increase during labor and have therefore been associated with the initiation and maintenance of uterine contractions in labor. This finding is supported by evidence that aspirin treatment in the last two trimesters of pregnancy may delay the onset of labor and increase the length of spontaneous labor. All of these findings strongly suggest the important role of PGs in the female and male reproductive systems (60). Gastrointestinal Tract. PGs of the E, F, and I series are synthesized in substantial amounts in tissues throughout the gastrointestinal tract (61-64). There are marked species differences in the gener- ation of various types of PGs. Quantitatively, the predominant form of PGs in human, feline, and canine gastric mucosa seems to be PGE2 (54), whereas it is PGI2 in the rat mucosa (62). PGs are released under various conditions, such as neurohormonal stimulation of digestive gland 12S Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement)
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`PHYSIOLOGY AND PHARMACOLOGY OF PROSTAGLANDINS T E .~E ~ 200 n-n," LIJD v- t/') n~tt3 <LU L.) tr" ~o_ 100 l,ij r~ ~--o ~q mm 3.0 m.E ] ZE ~ to "~- LU 300 c 200 E L~ § T mo E HISTAMINE 80,ug/kg-hr i.v. ~ PGE 2 (pg/kg-hr) i.a. 0.001 ~, 0.01 ~ 0.1 ~, 1.0 f~ ~. ~ RATIO CLEARANCE -3.0 ]> E -2.o ~ 5~ -1.0 m 0 2 /, 6 8 10 12 15min PERIODS Fig 6. Effects of graded doses of PGE2, administered into the gastric artery, on systemic blood pressure, mucosal blood flow, and gastric acid secretion in response to histamine in dogs with fundic flap preparation; *P < 0.05. From Walus et al, 1980 (68); reproduced by permission of Proc Soc Exp Biol Med. secretion, mechanical strain on the gut wall, action of various humorals (acetylcholine, norepinephrine, angiotensin, bradykinin, histamine, etc), and the presence of hyperosmolar solutions or other irri- tants in the gut lumen (65). Effects on Secretions. PGs of the E and I series inhibit basal and stimulated gastric acid secretion both in vitro and in vivo. In the dog, either PGE2 or PGI2 inhibits gastric acid secretion stimulated by food, histamine, pentagastrin, 2-deoxyglucose, car- bachol, or reserpine (66, 67). PGI2 was found to be several times more potent than PGE2 in inhibiting acid secretion when given intravenously (68). With direct intraarterial administration, PGE2 is a more potent inhibitor than PGI2 and, in contrast to PGI2, causes a reduction in mucosal blood flow (69) (Figure 6). Methyl analogs of PGE2 were found to be many times more potent than native PGE2 in inhibiting gastric acid secretion in animals and in humans. The gastric inhibitory effect of natural PGs and their methylated analogs has been confirmed in humans. PGE1 and PGE2 are reportedly inactive when given orally and are capable of inhibiting histamine-, histalog-, and pentagastrin-induced acid secretion only when infused intravenously (70, 71). Most recently, PGE2 was reported to cause a mod- erate inhibition of gastric secretion when given orally in large doses (72). In contrast, methyl PGE2 analogs were found to be active gastric inhibitors after either intravenous or oral administration (73-75). Their prolonged inhibitory effects on basal \ . . . and pentagastrm- or meal-sttmulated gastric secre- tion were observed in healthy subjects, in peptic ulcer patients, and in patients with Zollinger-Ellison syndrome. The mechanism by which natural PGs and their analogs inhibit gastric acid secretion is still un- known. The possibility of direct inhibition of parietal cells by methyl PGE2 analogs acting from the gastric lumen is supported by the finding that these agents are capable of inhibiting acid formation in isolated parietal cells, in gastric glands, and in isolated gastric mucosa (76). Further evidence for the direct inhibitory action of this analog on oxyntic glands came from studies in dogs with stomach separated from duodenum or with two denervated fundic pouches (75, 76) and from topical application of PGE2 analog to the mucosa of the whole stomach or to only one of the gastric pouches. Likewise, in humans, the PGE2 analog was more effective after intragastric than intraduodenal or jejunal adminis- tration (77). The antisecretory PGs probably operate via spe- cial membrane receptors to reduce the formation of cyclic AMP in the parietal cells. They decrease histamine-stimulated accumulation of cyclic AMP in the parietal cells as well as the secretory activity of these cells. They appear to block the stimulatory action of histamine on cyclic AMP synthesis, thus removing the major pathway for the excitation of parietal cells by histamine and other interacting secretagogues such as acetylcholine or gastrin (78, 79). Another mechanism through which PGs might affect gastric secretion is suppression of gastrin release. Natural PGE2 given intravenously failed to affect the postprandial release of gastrin, but methyl PGE2 analogs given orally in dogs (Figure 7) and humans caused a marked suppression of gastrin response to a meal (74, 75). More direct evidence for the suppression of gastrin release by PGE2 was Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement) 13S
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`KONTUREK AND PAWLIK 350- SOl> 250. _z~. <O 150 100' LIVER EXTRACT IN STOMACH,pH 7 PG S CONTROL S,ugYkg ~ / ~../t.I'T;;~S IN [)UODENUI~t--'--! /.////F" , L .*~-""""- I PG-S IN STOMACH SO' i 15 .E 10' E g-. "I- {s 0 CONTROL PG-S " " ] ~ I 5pglkg /- I/ J<- ..... / :"'"I~I M "~ < .//~bG'S IN OUODENU /, (cid:127) / / ./ / ( .I,." ~ ____~-''g6-S IN STOMACH BASAL i 2 3 ~ ~ I~ 30 rain PERIODS Fig 7. Effects of intragastric or intraduodenal administration of 15-methyl-POE2 (PG-S) on serum gastrin and gastric acid re- sponses to a liver extract meal kept in the stomach by intragas- tric titration at pH 7; *P < 0.05. From Konturek et ah Digestion 1978 (75); reproduced by permission of S. Karger, A. G. Basel. obtained from studies on the isolated and vascularly perfused rat stomach: PGE2 added to the perfusion fluid reduced basal gastrin release from this prepa- ration while increasing the release of somatostatin (80). PGs, and particularly their methyl analogs, when applied topically to the ga