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.).     

Involvement of cyclooxygenase-dependent pathway in contraction of isolated ileum by urotensin II

We previously reported that urotensin II induced biphasic (brief- and long-lasting) contractions and the brief contraction was mediated by acetylcholine release from ganglionic cholinergic neurons in a segment of guinea-pig ileum. In the present work, we studied the mechanism contributing to long-lasting contractions induced by urotensin II. Treatment with 0.1 microM tetrodotoxin, 300 nM omega-conotoxin GVIA (an inhibitor of N-type Ca2+ channels) and 10 microM indomethacin (an inhibitor of cyclooxygenases) markedly inhibited 100 nM urotensin II-induced long-lasting contractions. The addition of 1 microM prostaglandin F2alpha (PGF2alpha) caused a limited brief contraction following long-lasting contraction, while 1 microM PGE2 induced marked biphasic contractions. Treatment with neurotoxins inhibited the long-lasting contractions induced by PGF2alpha and PGE2 without changing the PGE2-induced brief contractions. Treatment with 1 microM atropine markedly inhibited the urotensin II- and PGF2alpha-induced long-lasting contractions, but was less effective on the PGE2 responses. Treatment with a phospholipase A2 inhibitor decreased the urotensin II-induced contractions. These findings suggest that urotensin II induces, at least partially, long-lasting contractions via PG-sensitive cholinergic neurons and muscarinic acetylcholine receptors in the ileum.     

Pharmacological responses by different portions of guinea pig vas deferens circular muscle preparation

The different segments of the guinea pig vas deferens circular muscle exhibit differential response patterns upon pharmacological stimulation. Namely, apart from barium chloride, the affinity and intrinsic activity of certain agonists and the strength of maximum contractions they induce appear to decrease along the path from the epididymis toward the prostate. If one subdivides the vas deferens into 3 parts of equal length such as epididymal, medial and prostatic portions, then adrenaline, acetylcholine, acetyl-beta-methylcholine, dopamine, histamine and bradykinin induce contractions on each of the 3 parts; whereas tyramine, ephedrine elicit responses in the epididymal and medial portions; amphetamine, DMPP, serotonin and PGF2 alpha in turn provoking contractions exclusively on the epididymal portion. The effects of adrenaline and noradrenaline are blocked by phentolamine and tolazoline; the responses to acetylcholine, acetyl-beta-methylcholine and carbamyl-beta-methylcholine are antagonized by atropine over a specific concentration range. The effects of tyramine, ephedrine and amphetamine are inhibited by phentolamine in an remarkably low dose range (pA2 = 13.51 +/- 0.09; 14.54 +/- 0.31; 14.35 +/- 0.12). The situation was the same when tyramine-dibenamine and tyramine-phenoxybenzamine combinations were tested (pD'2 = 14.03 +/- 0.37; 13.26 +/- 0.03). Based on these findings the presence of a peculiar alpha adrenergic receptor is suggested on the sympathetic postganglionic fibres. In addition to the already identified alpha adrenergic, muscarinic cholinergic and histamine H1 receptors, we could show the presence of dopaminergic receptors too in the vas deferens circular muscle.     

The combined use of isolated strips of guinea-pig lung parenchyma and ileum as a sensitive and selective bioassay for leukotriene B4

The biological effects of leukotriene (LT)B4 were compared, on a molar basis, with those of LTC4, LTD4, LTE4, 5-hydroxyeicosatetraenoic acid (5-HETE), PGD2, PGE1, PGE2, PGF2 alpha, PGI2, 6-oxo-PGF1 alpha, bradykinin (BK) and angiotensin II (Ang II) on isolated strips of guinea-pig lung parenchyma (GPP) and ileum smooth muscle (GPISM) superfused in series. LTB4 was similar to LTC4 and LTD4 on GPP, in relation to potency and contractions induced, but differed from LTE4 in being ten times more active and causing contractions of a much shorter duration of action on this tissue. However, unlike the other LTs, LTB4 produced contractions which were resistant to FPL 55712 (1.9 microM) and, when given repeatedly, caused tachyphylaxis in GPP. LTB4 was considerably more active on GPP than the other substances investigated. Further, PGD2, PGF2 alpha and PGI2 contracted GPP, the order of potency being PGD2 greater than PGF2 alpha approximately equal to PGI2, whereas PGE1 and PGE2 relaxed this tissue. In contrast to all other agonists tested which contracted GPISM, LTD4 displaying the highest activity, LTB4 was inactive on this tissue. 5-HETE and 6-oxo-PGF1 alpha were inactive on both GPP and GPISM. On the basis of differential effects of LTB4 on GPP and GPISM, this assay represents a simple and selective means to distinguish LTB4-like materials from other naturally-occurring substances likely to be generated in inflammatory fluids.     

Histamine H1 receptors and prostaglandin-histamine interactions modulating contractility of rabbit and rat testicular capsules in vitro

The stimulatory effect of histamine on rabbit and rat testicular capsule was blocked by the H1 blocker, diphenhydramine, but not by the H2 blocker, cimetidine, suggesting the presence of H1 histamine receptors in both rabbit and rat testicular capsules. In the rabbit, both anti-prostaglandin F (PGF) and anti-prostaglandin E (PGE) effaced spontaneous autorhythmic contractions. They markedly inhibited PGF 2 alpha, PGE1 and histamine-stimulated contractions of the rabbit testicular capsule. In the rat, anti-PGF or anti-PGE had no inhibitory effects on the capsular tone, but they both inhibited the stimulatory effects of histamine. These data suggest that the action of histamine on the rabbit and rat testicular capsules could be due partly to a secondary release of the PG's, PGE2 and PGF2 alpha.     

L-641,953 (R-8-fluoro-dibenzo[b, f]thiepin-3-carboxylic acid-5-oxide): a novel thromboxane-prostaglandin endoperoxide antagonist

The effects of L-641,953 (R-8-fluoro-dibenzo[b, f]thiepin-3-carboxylic acid-5-oxide) have been studied on pulmonary and other smooth muscle preparations in vitro and in vivo. When studied in vitro on guinea-pig tracheal chains, L-641,933 produced significant shifts in the dose-response curves to the prostaglandin endoperoxide analogues, U-44069 (pA2 7.06) and U-46619 (pA2 7.14), and prostaglandin (PG) F2 alpha (pA2 6.33) had minimal activity against contractions induced by histamine (pA2 4.38), 5-hydroxytryptamine (pA2 4.63), and acetylcholine (pA2 4.56) and slightly enhanced relaxation induced by PGE2. When tested on the guinea-pig gall bladder strip in vitro, L-641,953 antagonized contractions induced by U-44069 (pA2 7.03) but was less active against those induced by PGF2 alpha (pA2 6.03), PGE1 (pA2 5.62), and histamine (pA2 4.84). When tested in vitro on the guinea-pig pulmonary artery, L-651-953 significantly antagonized contractions induced by U-44069 (pA2 7.04), U-46619 (pA2 7.14), and PGF2 alpha (pA2 7.16) but was less effective against contractions induced by histamine (pA2 4.19). Schild analysis indicated that L-641,953 was fully competitive against contractions of either the guinea-pig tracheal chain induced by U-46619 or the guinea-pig pulmonary artery induced by U-44069 and U-46619. When tested on human platelets in vitro L-641,953 inhibited aggregation induced by U-44069 (IC50 1.3 X 10(-6) M) but not ADP.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of some natural prostaglandins on isolated human circular bronchial muscle.

PGE1 relaxed isolated human circular bronchial muscle over a wide concentration range as did isoprenaline. Surprisingly isoprenaline was more potent than PGE1. PGF2alpha weakly contracted this muscle preparation whereas histamine was more potent. PGE2, however, produced paradoxical results, relaxing some tissues and contracting others, always in a concentration-related manner irrespective of tissue tone. In preparations that contracted to PGE2, tachyphylaxis induced to PGF2alpha also applied to PGE2, but did not affect PGE1 relaxations of histamine contractions. These findings suggest that pge2 can stimulate either PGF2alpha or PGE1 receptors of isolated human bronchial muscle.     

Uterine motility in the reptile Anolis carolinensis: interactive effects of tension, prostaglandins, calcium, and vasotocin

Uteri of Anolis carolinensis exhibited spontaneous rhythmic contractions in vitro. Addition of arginine vasotocin (AVT) caused an immediate, strong, tonic contraction followed by rhythmic contractions with the same frequency as spontaneous contractions but of a greater amplitude. At low tension (1.5 g) the AVT-induced tonic contraction was blocked by low dose of indomethacin, suggesting that it is influenced by calcium rather than prostaglandins (PGs). An increase in tension (from 1.5 to 15 g) reduced the duration of the AVT-induced tonic contraction; this stretch-induced decrease was also blocked by indomethacin. Stretch also decreased the duration of the rhythmic contractions, but this stretch effect was not inhibited by indomethacin. The rest interval between rhythmic contractions was decreased by PGF2alpha and PGE2, and indomethacin or stretch blocked these PG effects. Indomethacin, AVT, or stretch alone did not affect PGF2alpha secretion from AVT-treated uteri. Stretch also reduced PGF2alpha secretion from AVT-treated uteri, an effect inhibited by indomethacin.     

Effects of indomethacin, prostaglandin E2 and prostaglandin F2 alpha on mouse blastocyst attachment and trophoblastic outgrowth in vitro

A study was performed in order to investigate the participation of prostaglandins (PGs) during implantation. The effects of indomethacin on mouse blastocyst attachment and trophoblastic outgrowth were examined in vitro. Studies were also carried out on cultures supplemented with PGE2 and/or PGF2 alpha along with indomethacin. (1) Blastocyst attachment and trophoblastic outgrowth were inhibited by indomethacin dose-dependency. (2) In the cultures supplemented with indomethacin and PGE2 or PGF2 alpha, respectively, the inhibitory effects of indomethacin were reduced. (3) In the cultures supplemented with all three substances with treatment (1) and (2), inhibition of indomethacin was partially reversed, but still lower than control group without indomethacin. The above results indicate that both PGE2 and PGF2 alpha have a promoting effect on implantation, and PGF2 alpha was more effective than PGE2.     

Interrelationship between nitric oxide and prostaglandins in bovine granulosa cells

It is well recognized that prostaglandins of the E (PGE) and F (PGF) series play an important role in ovarian physiology; in addition, nitric oxide (NO) has been recently demonstrated to be an important mediator of granulosa cell function. There is now evidence for a biologic relationship between PGs and the NO biosynthetic pathway. The aim of this study was to investigate the relationship between NO and PGE2 and PGF2alpha in bovine granulosa cells. Granulosa cells collected from small (<5mm) and large (>8mm) follicles were treated with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) or with indomethacin, an inhibitor of PGs synthesis, and PGE2 and PGF2alpha were quantified; in addition, the effects of PGE2 PGF2alpha and indomethacin on steroidogenesis and NO production were determined. The highest concentration of SNAP inhibited (P < 0.001) PGE2 production in cells from both kinds of follicles, while the lowest dose was effective only in cells from small follicles. The highest concentration of SNAP inhibited and stimulated (P < 0.001) PGF2alpha production in cells from small and large follicles, respectively. Progesterone (P4) production was stimulated by PGE2 and inhibited by PGF2alpha (P < 0.001) in cells from both types of follicles. Estradiol 17beta (E2) secretion was inhibited in cells from small and stimulated in those from large follicles by PGE2 (P < 0.05), while PGF2alpha was stimulatory in cells from both kinds of follicles (P < 0.001). P4 production by cells from small follicles was inhibited and stimulated by those from large follicles by indomethacin (P < 0.001), which also increased E2 output in cells from small follicles (P < 0.001). NO production was inhibited by both PGE2 and PGF2alpha except at the lowest concentration, which was stimulatory (P < 0.001). Indomethacin stimulated (P < 0.001) NO production. Taken together, the present data suggest a cross-talk between NO and PGs biosynthetic pathways, which needs to be further clarified.     

Profiles of eicosanoid production from 14C-arachidonic acid and prostaglandin metabolism by rabbit esophageal mucosa and muscularis

In an attempt to elucidate the possible involvements of eicosanoids in esophageal functions and disorders, we have investigated the formation of both cyclooxygenase and lipoxygenase metabolites from 14C-arachidonic acid by rabbit esophageal tissues. Homogenates of rabbit esophageal mucosa and muscularis were incubated with 14C-arachidonic acid and after ether extraction eicosanoids were separated and quantified by reverse phase high performance liquid chromatography. The predominant cyclooxygenase products were 6-keto-PGF1 alpha, PGF2 alpha, and PGE2 for mucosa and 6-keto-PGF1 alpha, and PGE2 for muscularis. The formation of these products was inhibited both by indomethacin and the dual pathway inhibitor, nordihydrogualaretic acid (NDGA). In mucosa the major eicosanoid was 12-HETE (12-hydroxyeicosatetraenoic acid) which was inhibited by NDGA but not by indomethacin which on the contrary enhanced its formation. Additionally four polar products were synthesized which appeared to be lipoxygenase-dependent as their formation was inhibited by NDGA but not by indomethacin. Muscularis produced as a minor lipoxygenase product only 12-HETE, which was inhibited by NDGA but unchanged in the presence of indomethacin. In addition, both tissues, but mucosa more than muscularis, possessed large prostaglandin catabolizing capacity. The present findings indicate that rabbit esophageal tissues can convert 14C-arachidonic acid into lipoxygenase as well cyclo-oxygenase products which may have a role in esophageal physiology and pathophysiology.     

Oxytocin enhances the basal release of uterine prostaglandin F2 alpha, but not that of PGE1, or of PGE2, and changes the metabolism of exogenous arachidonate, favouring the formation of prostaglandin F2 alpha and 5-HETE. Relationships with its uterotonic action and modulation by estradiol

We attempted to explore possible mechanism(s) subserving the influence of oxytocin on uterine motility by studying the action of the hormone on: 1) the contractile activity of isolated rat uteri in the presence or absence of indomethacin; 2) the synthesis and release of prostaglandins (PGs) into the solution incubating the uterine tissue as well as the metabolism of labelled arachidonic acid; 3) the uptake of 45Ca2+ by uterine strips. The experiments were bone with uterine preparations isolated from spayed rats treated or not with 17-beta-estradiol. The values of isometric developed tension (IDT) and of frequency of contractions (FC) induced by oxytocin in uterine strips isolated from spayed and spayed-estrogenized rats, were not modified by indomethacin at 10(-6) M. On the other hand, uterine strips from untreated spayed rats, release into the incubating medium approximately equal amounts of PGE1, PGE2 and PGF2 alpha. The in vitro presence of oxytocin (50 mU/ml) increased significantly (p 0.05) the output of PGF 2 alpha without changing the release of PGE1 or PGE2. Uteri from spayed rats injected prior to sacrifice with 17-beta-estradiol released significantly less PGE1 and PGE2 (p less than 0.005) than preparations from non-injected animals, whereas the output of PGF2 alpha in the suspending solution remained unchanged. Following estrogenization the addition of oxytocin to preparations obtained from spayed-estrogenized rats also increased the output of uterine PGF2 alpha (p less than 0.001) without changing that of PGs E1 or E2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasoactive intestinal polypeptide induces neurogenic contraction of guinea-pig ileum. Involvement of acetylcholine and substance P.

The effect and mode of action of vasoactive intestinal polypeptide (VIP), a peptidergic neuromodulator in the gastrointestinal nervous system, were investigated in isolated muscle strips of the guinea-pig ileum. VIP induced concentration-dependent (20 nM-1 microM) contractions of longitudinal ileal strips. TTX (1 microM), a mixture of atropine (3 microM) and spantide (30 microM), a mixture of atropine (3 microM) and omega-conotoxin GVIA (100 nM), somatostatin (60 nM) and dynorphin (100 nM) abolished the effect of VIP. In most cases a small relaxation became evident. Desensitization to substance P in the presence of atropine prevented VIP-induced contraction. A partial inhibition was observed in the presence of atropine (3 microM), spantide (30 microM), omega-conotoxin GVIA (100 nM), beta-endorphin (265 nM), met-enkephalin (1100 nM) and a mixture of spantide (30 microM) and omega-conotoxin GVIA (100 nM). The action of VIP was not significantly modified by guanethidine (3 microM) or hexamethonium (150 microM). In circular ileal strips VIP (10-300 nM) caused concentration-dependent relaxations through a direct myogenic effect. These results indicate that the VIP produced contractions of the guinea-pig ileum are exclusively neurally mediated and involve a cholinergic as well as a noncholinergic-nonadrenergic (NANC) pathway. It is concluded that besides acetylcholine (Ach) VIP releases the peptidergic transmitter substance P from postganglionic nerve fibers of myenteric plexus. Opioid peptides and somatostatin modulate the activity of cholinergic and peptidegic nerves in the guinea-pig ileum. The release of substance P appears to depend completely on N-type voltage sensitive calcium channels.     

Effect of prostaglandin F2 alpha on propulsive activity of the isolated segmental colon of the guinea-pig.

The effects of prostaglandin F2alpha (PGF 2alpha) on propulsive activity in segments of isolated colon and on isolated strips of guinea-pig colon were investigated. Using experimental conditions under which spontaneous propulsive activity was negligible, PGF2alpha (5X10(-8)X1X10(-6)M), added to the bathing medium increased propulsive activity in a concentration dependent manner. This increase of propulsive activity was abolished in the presence of atropine or tetrodotoxin (1X10(-7)g/ml). The contractions produced by PGF2alpha (5X10(-7) -1X10(-5)M) in isolated longitudinal and circular smooth muscle strips of guinea-pig colon were unaffected in the presence of atropine or tetrodotoxin (1X10(-7) g/ml). From these results it is concluded that under the conditions employed in this study propulsive activity stimulated by PGF2alpha may depend on the contractions of both muscle layers and stimulation of the peristalic reflex.     

Regulation of pyruvate kinase expression and growth in P-815 mastocytoma cells. II. Potential role of prostaglandins

P-815 mastocytoma cells increase the level of pyruvate kinase (PK) expression in response to chloroform-methanol extracts of conditioned media, butyrate, and dibutyryl cyclic AMP (but2cAMP) plus theophylline. The butyrate effect is indomethacin sensitive, suggesting a prostaglandin (PG) is the active signaling factor. Moreover, the chloroform-methanol extracts contain PGE2 and PGF2 alpha and additions of the latter enhance PK activity. PGE2 alone has little or no effect but acts synergistically with PGF2 alpha. These data show that PGF2 alpha can regulate PK levels. On the other hand, other factors may also be active, since the endogeneous and the but2cAMP plus theophylline effects are indomethacin insensitive. Most of the factors that increase PK activity also inhibit cellular growth; however, regulation of PK expression can be uncoupled from growth inhibition.     

Modulating effects of prostaglandins on parasympathetic-mediated secretory activities of rat salivary glands

Exogenously administered PGE1 or PGE2, like atropine, markedly decreased both the flow and calcium concentration of parasympathetically evoked rat parotid saliva; PGF2 alpha was less effective. Despite the fact that prostaglandins greatly reduced the Ca concentration of nerve-evoked saliva, they did not change the glandular Ca concentration of either control or parasympathetically stimulated parotid glands. Prostaglandins (20 micrograms/kg, i.a.) decreased the Na or K concentration of nerve-evoked parotid saliva, but at lower doses had no significant effect. PGE1, PGE2, PGF2 alpha or atropine markedly decreased flow rates of similarly evoked rat submandibular saliva. Prostaglandins and atropine, however, decreased the Na concentration and increased the K concentration of parasympathetically evoked submandibular saliva. PGF2 alpha, like atropine, increased the Ca concentration of such saliva. Drug vehicle, ethanol, slightly decreased the flow of both parotid and submandibular saliva but not the ion secretion, Endogenous prostaglandins themselves may not play a role in secretory activities during parasympathetic nerve stimulation of rat salivary glands, since administration of indomethacin, and inhibitor of prostaglandin biosynthesis, prior to or during nerve stimulation did not significantly alter nerve-evoked salivary secretion, The mechanisms by which prostaglandins modulate secretory responses of salivary glands during parasympathetic stimulation are not understood.     

Effects of indomethacin, prostaglandin E2, prostaglandin F2 alpha and 6-keto-prostaglandin F1 alpha on hatching of mouse blastocysts

The present study has been performed to investigate how PGs would participate the hatching process. Effects of indomethacin, an antagonist to PGs biosynthesis, on the hatching of mouse blastocysts were examined in vitro. Furthermore, it was studied that prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha) or 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were added to the culture media with indomethacin. The hatching was inhibited by indomethacin yet the inhibition was reversible. In the groups with indomethacin and PGE2, no improvement was seen in the inhibition of hatching and the inhibition was irreversible. In the groups with indomethacin and PGF2 alpha, inhibition of hatching was improved in comparison with the group with indomethacin. In the groups with indomethacin and 6-keto-PGF1 alpha, no improvement was seen. The above results indicated that PGF2 alpha possibly had an accelerating effect on hatching and a high concentration of PGE2 would exert cytotoxic effect on blastocysts.     

Is the epithelium-derived inhibitory factor in guinea-pig trachea a prostanoid?

To examine further the possible prostanoid involvement in the influence of the epithelium on guinea-pig tracheal smooth muscle responsiveness, we have analyzed the effects of LTD4, methacholine and histamine on the level of airway smooth muscle tone and on the amounts of PGE2, PGF2 alpha and PGI2 (determined by radioimmunoassay) in the presence and absence of the epithelium. Removal of the epithelium increased the sensitivity of guinea-pig trachea to the contractile effects of LTD4, methacholine and histamine. LTD4 (3-100 nM), methacholine (0.1-10 microM) or histamine (0.3-30 microM) did not increase prostanoid release above control values in either the presence or absence of the epithelium. The unstimulated release of PGE2 and PGF2 alpha, but not PGI2, was decreased in tissues lacking epithelium. Indomethacin (1 microM) reduced the baseline tone to a smaller extent in the absence of epithelium. In the presence but not the absence of the epithelium, indomethacin increased the sensitivity of preparations to the contractile effect of methacholine. The results support the postulate of an epithelium-derived inhibitory factor modulating guinea-pig tracheal smooth muscle responsiveness. The identity of this factor is not known but is not PGI2 and is unlikely to be PGF2 alpha or PGE2. However, the possibility remains that the basal release of PGE2 and/or PGF2 alpha derived from the epithelium may markedly affect the responsiveness of guinea-pig tracheal smooth muscle. Furthermore, the epithelium is a significant source of PGE2 and PGF2 alpha which may be involved in the maintenance of baseline tone.     

Effect of prostaglandin F2alpha (PGF2alpha), indomethacin, tamoxifen or estradiol-17beta on prostaglandin E (PGE), PGF2alpha and estradiol-17beta secretion in 88 to 90-day pregnant sheep

Treatment with PGF2alpha plus estradiol-17beta aborts 90-day pregnant ewes, whereas PGF2alpha or estradiol-17beta alone does not abort ewes. The objective of this experiment was to evaluate whether tamoxifen, an estrogen receptor antagonist, estradiol-17beta, prostaglandin F2alpha (PGF2alpha), indomethacin, or some of their interactions affected ovine uterine/placental secretion of PGF2alpha, estradiol-17beta or prostaglandins E (PGE), because a single treatment with PGF2alpha and estradiol-17beta given every 6 h aborts 90-day pregnant ewes. Concentrations of PGF2alpha in uterine venous blood were increased (P < or = 0.05) by estradiol-17beta, PGF2alpha + estradiol-17beta, and PGF2alpha + tamoxifen, and decreased (P < or = 0.05) by indomethacin or PGF2alpha + indomethacin at 72 h when compared to the 0 h samples. Concentrations of PGE in uterine venous blood were decreased (P < or = 0.05) by indomethacin and PGF2alpha + indomethacin and increased (P < or = 0.05) by PGF2alpha + estradiol-17beta at 72 h when compared to the 0 h samples. Concentrations of PGF2alpha in inferior vena cava blood at 6 h were increased (P < or = 0.05) by PGF2alpha either alone or in combination with indomethacin, tamoxifen, or estradiol-17beta, which is due to the PGF2alpha injected. Concentrations of PGF2alpha in inferior vena cava blood in PGF2alpha + estradiol-17beta-treated 88- to 90-day pregnant ewes increased (P < or = 0.05) linearly over the 72-h sampling period and averaged 4.0 + 0.4 ng/ml. Concentrations of PGF2alpha in inferior vena cava blood of control, PGF2alpha, tamoxifen, PGF2alpha + indomethacin, PGF2alpha + tamoxifen, and estradiol-17beta-treated ewes did not differ (P > or = 0.05) and averaged 0.4 + 0.04 ng/ml. Profiles of PGE in inferior vena cava blood of 88- to 90-day pregnant ewes treated with vehicle, PGF2alpha, estradiol-17beta, tamoxifen, tamoxifen + PGF2alpha, or estradiol-17beta + PGF2alpha did not differ (P > or = 0.05). Concentrations of PGE in inferior vena cava blood of 88- to 90-day pregnant ewes treated with indomethacin or PGF2alpha + indomethacin were lower (P < or = 0.05) than in control ewes. Concentrations of estradiol-17beta in jugular venous plasma of PGF2alpha + estradiol-17beta-treated 88- to 90-day pregnant ewes increased linearly and differed (P < or = 0.05) from controls. Profiles of estradiol-17beta in jugular venous plasma of PGF2alpha, indomethacin, tamoxifen, and PGF2alpha + tamoxifen and PGF2alpha + indomethacin, estradiol-17beta, and controls did not differ (P > or = 0.05). It is concluded that treatment with a single injection of PGF2alpha and estradiol-17beta given every 6 h causes a linear increase in PGF2alpha and estradiol-17beta.     

The actions of prostaglandins and cyclo-oxygenase inhibition on the resistance vessels supplying the human fetal placenta

The resistance arteries supplying individual exchange villi of the full-term human fetal placenta were examined for their reactivity to various prostaglandins (PG's) as well as for their ability to synthesize biologically active PG's. PGA1, PGF2 alpha, PGE2 and PGE1 produced dose-dependent contractions between 10(-7) and 10(-5)M. The order of potency observed was PGA1 approximately PGF2 alpha greater than PGE2 greater than PGE1. TXB2 was without activity in this preparation. Prostacyclin (PGI2) produced a dose-dependent relaxation of pre-contracted strips between 10(-8)M and 10(-5)M. Arachidonic acid (A.A.) produced stable dose-dependent contractions (10(-5) M to 10(-3)M) which were totally abolished by pretreatment with 10(-7)M meclofenamate (MF). At no concentration of A.A. was any evidence of vascular relaxation observed. Larger concentrations of MF (greater than 10(-6)M) resulted in a non-specific depression of the placental vascular smooth muscle. Meclofenamate (10(-7)M) pretreatment of strips subjected to dose-response studies using PGF2 alpha, PGE2, bradykinin (B K) and angiotensin II (AII) revealed a significant reduction in tension developed to both BK and AII. This finding suggests that the vasoactive peptides BK and AII stimulate the synthesis of vasoconstricting PG's in the fetal placental resistance arteries which relax in response to PGI2 and contract in response to the other PG's tested.