Potentiation of bradykinin-induced vascular permeability increase by prostaglandin E2 and arachidonic acid in rabbit skin.

The activity of prostaglandins (PG) in producing vascular permeability was quantitated by dye extraction method in skin of anaesthetized rabbits. PGE1 and PGE2 (0.01-10 mug) produced increase in vascular permeability. Activity was approximately equal to that of histamine (Hist) and 1/20 of that of bradykinin (BK) on a weight basis. The activity of PGF1alpha and PGF2alpha was only 1/20 of that of PGE1 or PGE2. In spite of the relatively low potency of PGE1 and PGE2 in the rabbit, near threshold doses (0.1 or 1 mug) of PGE2 could potentiate permeability responses to bradykinin (0.1 mug) by 10 or 100-fold, respectively. Equivalent doses (0.1 or 1 mug) of histamine could not potentiate the bradykinin responses. Arachidonic acid (AA) at 1 mug, produced a 10-fold potentiation in the permeability response to bradykinin (0.1 mug). Pretreatment of the rabbits with indomethacin (20 mg/kg, i.p.) reduced the responses of BK (0.1 mug) + AA (1 mug) down to a similar magnitude of those seen with bradykinin alone. However, indomethacin did not block responses to either, BK alone, BK + PGE2, or BK + Hist. Various doses (1, 10, 100 and 300 mug) of arachidonic acid alone also produced increase in cutaneous vascular permeability, although its potency was only 1/3-1/8 of that of PGE2. This activity of arachidonic acid was attributed in part to its bioconversion to PGE2, since its activity was significantly reduced by the prostaglandin antagonist, diphloretin phosphate (DPP) (60 mg/kg, i.v.) and by indomethacin (20 mg/kg, i.p.), which blocks conversion of arachidonic acid to prostaglandins. Arachidonic acid may owe some of its permeability increasing effects to histamine release, since its effects were also reduced by the anti-histamine, pyrilamine (2.5 mg/kg, i.v.).     

Receptors and signaling pathway underlying relaxations to isoprostanes in canine and porcine airway smooth muscle

Using muscle bath techniques, we examined the inhibitory activities of several E- and F-ring isoprostanes in canine and porcine airway smooth muscle. 8-Isoprostaglandin E1 and 8-isoprostaglandin E2 (8-iso PGE2) reversed cholinergic tone in a concentration-dependent manner, whereas the F-ring isoprostanes were ineffective. Desensitization with 8-iso-PGE2 and PGE2 implicated isoprostane activity at the PGE2 receptor (EP). We found that the inhibitory E-ring isoprostane responses were significantly augmented by rolipram (a type IV phosphodiesterase inhibitor), while 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (a guanylate cyclase inhibitor) had no effect, suggesting a role for cAMP in isoprostane-mediated relaxations. 8-Iso-PGE2 did not reverse KCl tone, suggesting that voltage-dependent Ca2+ influx and myosin light chain kinase are not suppressed by isoprostanes. Patch-clamp studies showed marked suppression of K+ currents by 8-iso-PGE2. We conclude that E-ring isoprostanes exert PGE2 receptor-directed, cAMP-dependent relaxations in canine and porcine airway smooth muscle. This activity is not dependent on K+ channel activation or the direct inhibition of voltage-operated Ca2+ influx or myosin light chain kinase.     

Effect of combined histamine H1 and H3 receptor blockade on cutaneous microvascular permeability elicited by compound 48/80

The pharmacological consequences of combining a histamine H1 receptor antagonist with a H3 antagonist on cutaneous microvascular permeability due to intradermal (i.d.) injections of compound 48/80, a mast cell liberator of histamine, was studied in the anesthetized guinea pig. Compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) induced permeability responses were attenuated, as determined by Evans blue extravasation, in animals pretreated with the H1 antagonist, chlorpheniramine (CTM; 1.0 mg/kg, i.v.) by 17 +/- 4, 31 +/- 4, 32 +/- 4 and 37 +/- 4%, respectively. Combination treatment with an H1 and H3 antagonist displayed greater inhibitory efficacy against the effects elicited by compound 48/80. Specifically, combined treatment with CTM (1.0 mg/kg, i.v.) and the H3 antagonist, thioperamide (THIO 1.0 mg/kg,i.v.) inhibited the skin responses of i.d. compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) by 36 +/- 4, 45 +/- 4, 49 +/- 4 and 54 +/- 4%. A second H3 antagonist, clobenpropit (CLOB; 0.3 mg/kg, i.v.) plus CTM (1.0 mg/kg, i.v.) also inhibited Evans blue extravasation. Treatment with THIO (1.0 mg/kg, i.v.) and CLOB (0.3 mg/kg, i.v.) administered alone had no effect on compound 48/80-induced skin responses. We conclude that combination administration of a H1 and a H3 histamine receptor antagonist produces greater inhibitory effect on cutaneous microvascular permeability produced by released mast cell-derived histamine than either a H1 or H3 antagonist administered separately. In addition, the antiallergy activity of combining a H3 antihistamine with a H3 antagonist activity might provide a novel approach for the treatment of allergic skin diseases such as urticaria.     

Role of COX-1 and COX-2 on skin PGs biosynthesis by mechanical scratching in mice

We examined the involvement of cyclooxygenase (COX)-1 and COX-2 on mechanical scratching-induced prostaglandins (PGs) production in the skin of mice. The dorsal regions of mice were scratched using a stainless brush. COXs expressions in the skin were analyzed using real-time PCR and Western blotting. The effect of acetylsalicylic acid (ASA) on the ability of PGs production were determined based on skin PGs level induced by arachidonic acid (AA) application. Mechanical scratching increased PGD2, PGE2, PGI2 and PGF(2 alpha). COX-1 was constitutively expressed and COX-2 expression was enhanced by scratching. Intravenous administration of ASA inhibited PGs biosynthesis in the normal skin. PGs levels of the skin 6h after ASA administration (ASA 6 h) were almost equal to those of the skin 10 min after ASA administration (ASA 10 min). In the scratched skin, AA-induced PGE2 and PGI2 of ASA 6 h were significantly higher than those of ASA 10 min. The skin PGD2 and PGF(2 alpha) of ASA 10 min were almost same to those of ASA 6 h. In the normal skin of COX-1-deficient mice, skin PGD2 level was lower than that of wild-type mice, although PGE2, PGI2 and PGF(2 alpha) levels were almost equal to those of wild type. In the scratched skin of COX-1-deficient mice, PGD2, PGE2, PGI2 and PGF(2 alpha) levels were lower than those of wild-type mice. These results suggested that cutaneous PGD2 could be mainly produced by COX-1, and PGE2 and PGI2 could be produced by COX-1 and COX-2, respectively, in mice.     

Central cardiovascular and thermal effects of prostaglandin F2 alpha in rats.

Administration of PGF2 ALPHA (0.2--6.4 micrograms) into the lateral cerebral ventricle (i.c.v.) induced dose-dependent increases in blood pressure, heart rate and body temperature in urethane-anaesthetised rats, but had no effect on these parameters when the same dose range was administered intravenously. Peripheral pretreatment with sodium meclofenamate (50 mg/kg s.c.) shifted all the dose-response curves for PGF2 alpha (i.c.v.) to the left, but indomethacin (50 mg/kg s.c.) did not significantly affect those changes. Central pretreatment with sodium meclofenamate or indomethacin (1.25 mg per rat i.c.v.) failed to modify significantly the effects of centrally administered PGF2 alpha. The results support previous suggestions that PGF2 alpha may participate in the central control of the cardiovascular and thermoregulatory systems, and also suggest that there may be differences in the sites and/or modes of action between sodium meclofenamate and indomethacin.     

Dose-dependent effects of a pyridoquinazoline thromboxane synthetase inhibitor on arachidonic acid metabolites and hemodynamics during E. coli endotoxemia in anesthetized sheep

We investigated the effects of a new pyridoquinazoline thromboxane synthetase inhibitor infused before administering Escherichia Coli endotoxin into 18 anesthetized sheep with lung lymph fistulas. In normal sheep increasing plasma Ro 23-3423 concentrations were associated with increased plasma levels of 6-keto-PGF1 alpha, a reduced systemic vascular resistance (SVR, r = -0.80) and systemic arterial pressure (SAP, r = -0.92), the mean SAP falling from 80 to 50 mm Hg at the 20 and 30 mg/kg doses. Endotoxin infused into normal sheep caused transient pulmonary vasoconstriction associated with increased TxB2 and 6-keto-PGF1 alpha levels while vasoconstriction and TxB2 increase were significantly inhibited by pretreatment with Ro 23-3423 in a dose-dependent manner. When compared to controls, plasma and lymph levels of 6-keto-PGF1 alpha, PGF2 alpha and PGE2 after endotoxin infusion were increased several-fold by administering Ro 23-3423 up to plasma levels of 10 micrograms/ml. Doses over 30 mg/kg with blood levels above 10 micrograms/ml reduced plasma and lymph levels of 6-keto-PGF1 alpha, PGF2 alpha and PGE2, suggesting cyclooxygenase blockade at this dose. The peak 6-keto-PGF1 alpha levels at 60 min after endotoxin infusion in sheep with Ro-23-3423 levels below 10 micrograms/ml were associated with the greatest systemic hypotension due to a reduced SVR (r = -0.86). After endotoxin infusion the leukotrienes B4, C4, D4 and E4 in lung lymph were assayed by radioimmunoassay and high pressure liquid chromatography and remained at baseline values.     

A thromboxane mimetic, U-46619, produces plasma exudation in airways of the guinea pig.

Thromboxane A2 (TxA2) has been implicated in airway responses to allergen and in the bronchial hyperresponsiveness observed in asthma. Furthermore a TxA2 receptor antagonist and a TxA2 synthase inhibitor inhibit plasma exudation in airways induced by inhaled platelet-activating factor. To evaluate whether TxA2 has any direct effect on plasma exudation in the airways, we studied the effect of a stable TxA2 mimetic (U-46619; 2, 20, and 200 nmol/kg iv) on lung resistance (RL) and Evans blue dye extravasation (marker of plasma albumin; 20 mg/kg iv) at the airway levels of trachea, main bronchi, and proximal and distal intrapulmonary airways in anesthetized, tracheostomized, and mechanically ventilated guinea pigs. Injection of U-46619 produced an immediate and marked dose-dependent increase in RL, which peaked at approximately 30 s. At the highest dose of U-46619, we also observed a later increase in RL, starting at approximately 3 min and reaching a second peak at approximately 8 min. Mean systemic blood pressure increased in a dose-dependent manner [maximum 82 +/- 8 (SE) mmHg]. U-46619 also produces dose-dependent plasma exudation, measured as Evans blue dye extravasation, at all airway levels as well as into the tracheal lumen. Airway responses to U-46619 (200 nmol/kg iv) were abolished in animals pretreated with the TxA2 receptor antagonist ICI-192605 (0.5 mg/kg iv). We conclude that U-46619, despite being a vasoconstrictor, is potent in inducing plasma exudation in airways and that this effect is mediated via a TxA2 receptor.     

Effect of indomethacin on prostaglandin content of several rabbit tissues

The prostaglandin (PG) content of several tissues and fluids from 6 day pregnant rabbits was evaluated following treatment with indomethacin or vehicle . PGE and PGF were measured by radioimmunoassay. More complete depletion of PGE and PGF was accomplished by 3 injections of indomethacin (s.c.) given during the 18 h before sacrifice at a dose of 10 mg indomethacin per kg body weight than was accomplished by 1 injection of the same amount of indomethacin (i.v.) 1.5 h before sacrifice. Levels of PGF were more easily depressed by indomethacin than were those of PGE. PG levels in the kidney and blastocysts were depressed to a greater extent by indomethacin than were those in the uterus, uterine fluid or peritoneal fluid. Evaluation of the effect of indomethacin on a particular physiological function should be interpreted with caution unless the extent of PG depletion in that tissue is also measured.     

Prostaglandin E1 and F2alpha specific binding in bovine corpora lutea: comparison with luteolytic effects.

Preliminary characterization indicated the presence of separate prostaglandin (PG)E1 and (PG)F2alpha binding sites in membrane fractions prepared from bovine corpora lutea. These differ in the rate and temperature dependence of the specific binding. Equilibrium binding data indicate the apparent dissociation constants as 1.32 x 10(-9)M and 1.1 x 10(-8)M for PGE1 and PGF2alpha, respectively. Competition of several natural prostaglandins for the PGE1 and PGF2alpha bovine luteal specific binding sites indicates specificity for the 9-keto or 9alpha-hydroxyl moiety, respectively. Differences in relative ability to inhibit 3H-PG binding were found due to sensitivity to the absence or presence of the 5, 6-cis-double bond as well. Bovine luteal function was affected following treatment of heifers with 25 mg PGF2alpha as measured by reduced estrous cycle length, decreased corpus luteum size and significantly decreased plasma progesterone levels. In contract, treatment with 25 mg PGE1 resulted in cycle lengths comparable to those of non-treated herdmates with no apparent modification in corpus luteum size. However, plasma progesterone levels were increased significantly following PGE1 treatment compared to pretreatment values. In so far as data obtained in vitro on PGF2alpha relative binding affinity to the bovine CL can be compared to data obtained independently in vitro on PGF2alpha induced luteolysis in the bovine, PGF2alpha relative binding to the CL and luteolysis appeared to be associated. By similar reasoning, there was no apparent relationship between PGE1 relative binding affinity in the luteal fractions and luteolysis in estrous cyclic cattle.     

Effect of indomethacin in vivo on prostaglandin content of several rabbit tissues

The prostaglandin (PG) content of several tissues and fluids from 6 day pregnant rabbits was evaluated following treatment with indomethacin or vehicle in vivo. PGE and PGF were measured by radioimmunoassay. More complete depletion of PGE and PGF was accomplished by 3 injections of indomethacin (s.c.) given during the 18 h before sacrifice at a dose of 10 mg indomethacin per kg body weight than was accomplished by 1 injection of the same amount of indomethacin (i.v.) 1.5 h before sacrifice. Levels of PGF were more easily depressed by indomethacin than were those of PGE. PG levels in the kidney and blastocysts were depressed to a greater extent by indomethacin than were those in the uterus, uterine fluid or peritoneal fluid. Evaluation of the effect of indomethacin on a particular physiological function should be interpreted with caution unless the extent of PG depletion in that tissue is also measured.     

Effect of atropine, PGF2 alpha and cimetidine on the beta-carotene induced cytoprotection in ethanol-treated rats

The aim of the study was to evaluate the influence of atropine, PGF2 alpha and cimetidine on the gastric cytoprotective effect of beta-carotene. Mucosal damage was produced by intragastric (i.g.) addition of 96% ethanol in CFY-strain rats of both sexes weighing 180-220 g. Gastric cytoprotection caused by i. g. pretreatment with 1.0 mg/kg beta-carotene 30 minutes before ethanol administration, was observed after 1 hour. Atropine (0.5 mg/kg), cimetidine (50 mg/kg) and PGF2 alpha (200 micrograms/kg) were given intraperitoneally (i.p.) 30 minutes before ethanol administration with and without beta-carotene and the changes in the number and severity of the gastric ulcers were detected. PGF2 alpha did not influence the gastric cytoprotective effect of beta-carotene meanwhile it was inhibited by atropine and markedly by cimetidine. Deleterious effect of cimetidine on the beta-carotene-induced cytoprotection may be explained perhaps by the adverse effect of the two compounds on ATP-cAMP transformation hereby counteracting one another, but more data are needed to the better understanding of drug interactions relating to mucosal cytoprotection.     

Prostaglandin F2alpha (PGF2alpha) and prolactin secretion in rats.

Plasma prolactin and F-prostaglandins (PGF) were measured anesthetized male Sprague-Dawley rats before and at 15, 30, 45 and 60 minutes following i.v. injection of either PGF2alpha (4 mg/kg), chlorpromazine, 1 mg/kg or chlorpormazine (1 mg/kg) after pretreatment with i.p. indomethacin (2 mg/kg). Following PGF2alpha administration, plasma prolactin levels increased significantly only at 15 and 30 minutes in spite of extremely high PGF levels throughout 60 minutes. Besides the expected rise in plasma prolactin, chlorpromazine caused a transient but statistically significant increase in PGF. Indomethacin blocked the chlorpormazine-induced PGF rise but not prolactin increase. Animals stressed with ether anesthesia showed elevation of plasma prolactin, which was not blocked by indomethacin although PGF concentration fell. Theese results indicate that PGF2alpha can stimulate prolactin release. This effect does not appear to be physiologic since very high PGF levels are required. Furthermore, blockade of prostaglandin synthesis by indomethacin does not prevent the release of prolactin in response to chlorpormazine or stress. Our findings do not support a possible role of PGFs as intermediaries in prolactin release. However, it is possible that PGFs may work through other mechanisms not investigated in our study.     

Effect of mifepristone on pregnancy,pregnancy-specific protein B (PSPB), progesterone,estradiol-17beta,prostaglandin F2alpha (PGF2alpha) and prostaglandin E (PGE) in ovariectomized 90-day pregnant ewes

The objective of this experiment was to determine the effect of mifepristone, a progesterone receptor antagonist, on pregnancy and secretion of steroids, pregnancy-specific protein B (PSPB) and prostaglandins at mid-pregnancy in ewes. Ninety-day pregnant ewes were ovariectomized (OVX) and treatments were initiated 72 h post-OVX. Ewes received (1) vehicle, (2) prostaglandin F2alpha (PGF2alpha, 8 mg/58 kg/bw, i.m.) 84 h post-OVX, (3) mifepristone (50 mg intrajugular at 72, 84, 96, and 108 h post-OVX), (4) mifepristone (50mg) + PGF2alpha, (5) mifepristone (100 mg intrajugular at 72, 84, 96, and 108 h), and (6) mifepristone (100 mg) + PGF2alpha. Ewes treated with vehicle or PGF2alpha alone did not abort (P > or = 0.05). But, 60, 80, 60, and 100% of ewes treated with mifepristone (50 mg), mifepristone (50 mg) + PGF2alpha, mifepristone (100 mg), and mifepristone (100 mg) + PGF2alpha, respectively, aborted (P < or = 0.05). Profiles of progesterone, estradiol-17beta, prostaglandin E (PGE), or PSPB did not differ (P > or = 0.05) among treatment groups. Profiles of PGF2alpha of treatment groups receiving mifepristone with or without PGF2alpha differed (P < 0.05) from vehicle or PGF2alpha alone-treated ewes. It is concluded that progesterone actions are necessary to suppress uterine/placental secretion of PGF2alpha and that maintenance of critical progesterone: estradiol-17beta and PGE:PGF2alpha ratios are necessary for maintenance of pregnancy.     

Fatty acid and prostaglandin metabolism in children with diabetes mellitus. II. The effect of evening primrose oil supplementation on serum fatty acid and plasma prostaglandin levels

Our previous study demonstrated that levels of dihomo-gamma-linolenic acid (DGLA) and arachidonic acid in serum total lipids decreased in association with increased plasma levels of prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha) in patients with insulin-dependent diabetes mellitus. In this study, 11 children with insulin-dependent diabetes mellitus completed a double-blind, placebo-controlled study to assess the effect of dietary supplementation with gamma-linolenic acid (GLA) on serum essential fatty acid and plasma PGE2 and PGF2 alpha levels. GLA was given as the seed oil from the evening primrose (EPO) and all patients received either EPO capsules (containing 45 mg of GLA and 360 mg of linoleic acid) or indistinguishable placebo capsules for 8 months. Initially patients took 2 capsules daily for 4 months then 4 capsules daily for a further 4 months. All patients were assessed at the start of the study, after 4 months and at the end of the study, by measuring serum essential fatty acid and plasma PGE2 and PGF2 alpha levels. After administration of 4 capsules daily the DGLA levels increased and PGE2 levels decreased significantly (p less than 0.01) in the EPO compared with the placebo group. Neither fatty acid nor PGE2 and PGF2 alpha levels were altered by administration of 2 EPO capsules daily. This suggests that the altered essential fatty acid and PG metabolism in diabetes may be reversed by direct GLA supplementation.     

Pathophysiology of Experimental Bovine Endotoxicosis: Endotoxin Induced Synthesis of Prostaglandins and Thromboxane and the Modulatory Effect of Some Non-Steroidal Anti-Inflammatory Drugs

Endotoxin-induced synthesis of thromboxane A2 (TXA2), prostacyclin (PGI2) and prostaglandin E2 (PGE2) was studied in 3 cows after intravenous E. coli endotoxin (055:B5–0.025 mg/kg b.w.) administration. Blood sampling and monitoring of clinical signs were performed from 2 h prior to until 6 h after endotoxin challenge. Blood samples were analyzed for stable hydrolysis products of TXA2 (TXB2), PGI2 (6-keto PGF) and PGE2 (bicyclic PGE2), biochemical and haematological parameters. In a similar experimental design the efficacy of the non-steroidal anti-inflammatory drugs (NSAID) flunixin meglumine (FM) and phenylbutazone (PB) in suppressing eicosanoid synthesis and clinical signs in response to endotoxin challenge was investigated. Two groups of cows, each comprising 2 animals, were treated with FM and PB prior to endotoxin challenge. It was observed that plasma concentrations of TXB2, 6-keto PGF and bicyclic PGE2 increased rapidly after endotoxin challenge. Concentrations were significantly elevated for hours and were correlated to the severity of clinical signs of endotoxicosis. Pretreatment with NSAID suppressed mediator production and alleviated clinical signs. The experiments suggest a certain pathophysiological role of TXA2, PGI2 and PGE2 for the early systemic ill-effects of bovine endotoxicosis.     

Effects of infusion of some prostaglandins in essential fatty acid-deficient and normal rats

Infusion of 1 mg/kg per day of prostaglandin E(1) (PGE(1)) for 2 and 7 wk failed to correct the dermal signs of essential fatty acid (EFA) deficiency in rats despite the known conversion of EFA to certain prostaglandins. PGE(1) caused no significant changes in serum cholesterol, triglycerides, or phospholipids or in liver neutral lipids in EFA-deficient or normal rats. In normal rats epinephrine-induced lipolysis was greater in fat pads from infused than from untreated rats. The effect on epinephrine-induced lipolysis was greater after the 7 wk infusion than after the 2 wk infusion. The 7 wk infusion also lowered plasma free fatty acid (FFA) concentrations. Infusion of PGE(2) and PGF(2alpha) in combination for 4 wk had no significant effect on either dermal signs of EFA deficiency, lipolysis, or plasma FFA concentrations.     

Comparison of the effect of nonsteroidal and steroidal antiinflammatory agents on prostaglandin production during ovulation in the rabbit

The antiinflammatory agents diclofenac, fenoprofen and aspirin were tested to determine how well they inhibit the pre-ovulatory elevation in prostaglandin (PG) production in rabbit follicles in comparison to indomethacin. In addition, the antiinflammatory agent dexamethasone and the antipyretic agent acetaminophen were tested. The agents were administered 8 h after the ovulatory process was stimulated by hCG (50 I.U./kg). At 10 h after hCG (i.e., at the expected time of ovulation) control follicles had PGF and PGE levels of 370.0 and 582.6 pg/mg of follicle, respectively. Diclofenac inhibited PG production the most-reducing PGF and PGE to 22.8 and 53.6 pg/mg, respectively. Indomethacin reduced the PGF and PGE levels to 27.4 and 76.6 pg/mg, respectively. Fenoprofen was less effective, reducing the PGF and PGE to 77.8 and 222.4 pg/mg, respectively. Aspirin reduced the PGF and PGE to 123.4 and 174.6 pg/mg, respectively. Dexamethasone and acetaminophen did not inhibit PG production. Ovulation was completely inhibited by diclofenac and indomethacin, partially inhibited by fenoprofen, and unaffected by aspirin, acetaminophen, or dexamethasone. The results suggest that any potent antiinflammatory agent can inhibit ovulation provided it adequately reduces PG production; whereas antiinflammatory agents are ineffective. The anti-inflammatory agent must completely abolish the preovulatory elevation in PGs in mature follicles in order to totally inhibit ovultion.     

Effect of indomethacin invivo on prostaglandin content of several rabbit tissues

The prostaglandin (PG) content of several tissues and fluids from 6 day pregnant rabbits was evaluated following treatment with indomethacin or vehicle $\text{in}$$\text{vivo}$. PGE and PGF were measured by radioimmunoassay. More complete depletion of PGE and PGF was accomplished by 3 injections of indomethacin (s.c.) given during the 18 h before sacrifice at a dose of 10 mg indomethacin per kg body weight than was accomplished by 1 injection of the same amount of indomethacin (i.v.) 1.5 h before sacrifice. Levels of PGF were more easily depressed by indomethacin than were those of PGE. PG levels in the kidney and blastocysts were depressed to a greater extent by indomethacin than were those in the uterus, uterine fluid or peritoneal fluid. Evaluation of the effect of indomethacin on a particular physiological function should be interpreted with caution unless the extent of PG depletion in that tissue is also measured.     

Evidence for the development of tolerance to PGF2 alpha on the ethanol-induced gastric mucosal damage

PGF2 alpha, 100 micrograms/kg intraperitoneally, applied 30 min before 1.0 ml intragastric ethanol (96%) exerts cytoprotective effect on the gastric mucosal membrane. After a week long pretreatment of the animals with 0.25; 0.5 and 1.0 mg/day PGF2 alpha resulted in a diminishing cytoprotective effect. The gastric tissue cAMP level raised simultaneously and after the PGF2 alpha pretreatment with the taming cytoprotection the cAMP level diminished parallel in a dose dependent manner. It is assumed that after PGF2 alpha pretreatment the density of the cellular PGF2 alpha receptors decreases, according to the observed phenomenon.     

Prostaglandin F2α (PGF2α) and prolactin secretion in rats

Plasma prolactin and F-prostaglandins (PGF) were measured in anesthetized male Sprague-Dawley rats before and at 15, 30, 45 and 60 minutes following i.v. injection of either PGF_2α (4 mg/kg), chlorpromazine, 1 mg/kg or chlorpromazine (1 mg/kg) after pretreatment with i.p. indomethacin (2 mg/kg). Following PGF_2α administration, plasma prolactin levels increased significantly only at 15 and 30 minutes in spite of extremely high PGF levels throughout 60 minutes. Besides the expected rise in plasma prolactin, chlorpromazine caused a transient but statistically significant increase in PGF. Indomethacin blocked the chlorpromazine-induced PGF rise but not prolactin increase. Animals stressed with ether anesthesia showed elevation of plasma prolactin, which was not blocked by indomethacin although PGF concentration fell. These results indicate that PGF_2α can stimulate prolactin release. This effect does not appear to be physiologic since very high PGF levels are required. Furthermore, blockade of prostaglandin synthesis by indomethacin does not prevent the release of prolactin in response to chlorpromazine or stress. Our findings do not support a possible role of PGFs as intermediaries in prolactin release. However, it is possible that PGFs may work through other mechanisms not investigated in our study.