Prostaglandins in neural crest-tumours

Prostaglandin and catecholamine concentrations were estimated in tumour tissues taken from four phaeochromocytomas and five other neural-crest tumours. Prostaglandins were found to be present in tumours both associated and non-associated with chronic diarrhoea. Prostaglandin F, as well as catecholamine, concentrations were higher in phaeochromocytomas than in the other tumours. The hypothesis has been made that while prostaglandins do not reach arterial circulation to give rise to pharmacological effects, such as chronic diarrhoea, prostaglandins F present in phaeochromocytomas may contribute to a higher catecholamine synthesis and/or release, resulting in a higher incidence of hypertension associated with these tumours.     

Prostaglandins in neural crest-tumors.

Prostaglandin and catecholamine concentrations were estimated in tumour tissues taken from four phaeochromcytomas and five other neural-crest tumours. Prostaglandins were found to be present in tumours both associated and non-associated with chronic diarrhoea. Prostaglandin F, as well as catecholamine, concentrations were higher in phaeochromocytomas than in other tumours. The hypothesis has been made that while prostaglandins do not reach arterial circulation to give rise to pharmacological effects, such as chronic diarrhoea, prostaglandins F present in phaeochromocytomas may contribute to a higher catecholamine synthesis and/or release, resulting in a higher incidence of hypertension associated with these tumours.     

Chromogranin a expression in phaeochromocytomas associated with von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2.

Chromogranin A (CGA) is a major secretory protein present in the soluble matrix of chromaffin granules of neuroendocrine cells and tumours, such as phaeochromocytomas. CGA has several functions, some of which may be involved in the distinct phenotypic differences of phaeochromocytomas in patients with von Hippel-Lindau (VHL) syndrome compared to multiple endocrine neoplasia type 2 (MEN 2). In this study, we therefore compared tumour and plasma levels of CGA in patients with phaeochromocytoma associated with the two syndromes. We show that phaeochromocytomas from MEN 2 patients express substantially more CGA than tumours from VHL patients at both the mRNA (3-fold greater) and protein (20-fold) level. We further show that relative to increases in plasma catecholamines, patients with phaeochromocytomas associated with MEN 2 have higher plasma concentrations of CGA than those with tumours in VHL syndrome. These data supplement other observations that phaeochromocytomas in VHL compared to MEN 2 patients express lower amounts of catecholamines and other chromaffin granule cargo, such as chromogranin B and neuropeptide Y. Possibly the differences in tumour CGA expression may contribute to differences in secretory vesicle formation and secretion in the two types of tumours. Alternatively the differences in expression in CGA and other secretory constituents may reflect downregulation of the entire regulated secretory pathway in VHL compared to MEN 2 tumours.     

In vitro production of prostaglandins E and F by the guinea pig ovarian tissue

The ability of guinea pig ovarian tissue to biosynthesize prostaglandins E and F from endogenous precursors has been investigated in vitro. Estimations of prostaglandins were carried out using a sensitive radioimmuno assay during seven days preceding, and up to one day, following oestrous. Prostaglandins E and F were present in the ovarian tissue throughout the period investigated. Prostaglandin concentrations in samples incubated without enzymic inhibition were significantly higher than in samples incubated after enzymic inhibition with ethanol. This indicates that guinea pig ovarian tissue is able to synthesize prostaglandins from endogenous precursors.     

Clinicopathological study of pancreatic and ganglioneuroblastoma tumours secreting vasoactive intestinal polypeptide (vipomas).

During a six-year period (1973-9) 52 patients with pancreatic tumours and 10 with ganglioneuroblastomas were found to have raised plasma vasoactive intestinal polypeptide (VIP) concentrations. All the patients had severe secretory diarrhoea, weight loss, dehydration, hypokalaemic acidosis, and a raised plasma urea concentration. Reduced gastric acid secretion was seen in 72% of patients. Plasma VIP concentrations were not raised in patients with diarrhoea due to other types of tumour or disease or in hormone-secreting tumours not associated with diarrhoea. Plasma VIP measurement may therefore give clinical guidance in a patient with persistent watery diarrhoea and hypokalaemic acidosis. Surgical excision was clearly the treatment of choice, but metastatic pancreatic tumours usually responded to streptozotocin.     

PGE1 not PGF2 alpha reverses the anti-actin antibody stimulation of protein phosphorylation and DNA synthesis in L cells

The effects of prostaglandins E1 and F2 alpha upon the anti-actin antibody-induced stimulation of DNA synthesis and protein phosphorylation were studied in L cells. This system was previously shown by us to exhibit a rapid turnover of arachidonic acid in phospholipids which was inhibited by non-toxic concentrations of indomethacin, suggesting participation of cyclooxygenase-derived prostaglandins (Lipids 19:239, 1984). Prostaglandin E1 in a dose dependent manner selectively inhibited both protein phosphorylation and DNA synthesis in anti-actin antibody-stimulated cells. Prostaglandin F2 alpha was without effect. Indomethacin also produced a dose related inhibition of the antibody stimulation of protein phosphorylation and DNA synthesis. We conclude that prostaglandins, possibly derived from liberated arachidonic acid, play an important regulatory role in the stimulatory signal conveyed to L cells by perturbing antibody ligands.     

Prostaglandins in the human fetal circulation in mid-trimester and term pregnancy

Concentrations of prostaglandins in fetal and maternal plasma during mid-pregnancy and fetal plasma at term have been measured. Fetal levels at both gestations were higher than found in maternal blood. The stable chemical breakdown product of prostacyclin, 6-keto-prostaglandin F_1∝, was consistently considerably higher in the fetus during mid-pregnancy compared with at term. Prostaglandin F levels were also significantly higher in mid-pregnancy, though there was no difference in the concentrations of the major circulating prostaglandin F metabolite, PGFM. Concentrations of prostaglandin E were similar at the two stages of pregnancy. The physiological significance of these findings is discussed.     

Prostaglandin biosynthesis and catabolism in the developing fetal sheep lung.

The prostaglandin biosynthetic and catabolic capacity of homogenates of lungs from fetal sheep of various gestational ages was measured. Prostaglandin biosynthesis was assayed by the deuterium-isotope dilution technique making use of mass fragmentography whereas prostaglandin catabolism was measured by the radioisotope-dilution method described previous (Pace-Asciak, C.R. and Rangaraj, G. (1976) J. Biol. Chem. 251, 3381-3385). Homogenates of lungs from fetuses of all ages tested (40 days to term) formed both prostaglandins E2 and F2alpha; although prostaglandin F2alpha was formed to a greater extent than prostaglandin E2 by the 40 days lung, prostaglandin E2 increased with increasing age until at term the ratio of both prostaglandins approached unity. Total prostaglandin biosynthesis (E2 + F2alpha) rose gradually with age (approx. 3 fold increase between 40 days and term). Prostaglandin F2alpha catabolism occurred mainly by the prostaglandin 15-hydroxy dehydrogenase pathway; this activity was detectable even at 40 days and remained unchanged up to 80 days. Prostaglandin catabolic activity rose sharply at 90 days (approx. 3 fold) with a maximum around 110 days (approx. 4 fold) decreasing back to 40 day levels by term (143 days). The increasing prostaglandin catabolic activity around 90-100 days in this species is discussed in relation to the hemodynamic changes in the lungs starting around this age and the appearance of surfactant. Prostaglandin catabolism might play an important role in the developing organ controlling steady state concentrations of prostaglandins during certain periods of organogenesis.     

Identification of metabolites from peroxisomal beta-oxidation of prostaglandins

We have recently shown that isolated rat liver peroxisomes can chain-shorten prostaglandin F2 alpha and prostaglandin E2 to tetranor-metabolites. In the present report dinor-metabolites of these two prostaglandins were also identified, suggesting that the peroxisomal chain-shortening reaction of prostaglandins is a beta-oxidation reaction. Furthermore, an intermediate containing an extra double bond was isolated from incubates of prostaglandin F2 alpha with peroxisomes. This intermediate was tentatively assigned the structure 2,3-dehydroprostaglandin F2 alpha. Prostaglandin E1 and a major circulating prostaglandin F2 alpha metabolite were also metabolized to chain-shortened products by peroxisomes. The accumulation of the 2,3-dehydro-metabolite and the dinor-metabolites suggest that the peroxisomal beta-oxidation sequence is not tightly coupled, in contrast to mitochondrial fatty acid oxidation.     

F prostaglandins function as potent olfactory stimulants that comprise the postovulatory female sex pheromone in goldfish

This study establishes that ovulated female goldfish release F type prostaglandins (PGFs) to the water where they stimulate male spawning behavior and comprise the goldfish postovulatory pheromone. We first demonstrated that ovulated and prostaglandin-injected female goldfish release immunoreactive PGFs to the water. Next, using electro-olfactogram recording (EOG), we determined that waterborne prostaglandins function as potent olfactory stimulants for mature male goldfish. Prostaglandin F2 alpha (PGF2 alpha) and its metabolite 15-keto-prostaglandin F2 alpha (15K-PGF2 alpha) were the most potent prostaglandins; the former had a detection threshold of 10(-10) M and the latter a detection threshold of 10(-12) M. Studies of prostaglandin-injected fish indicated that PGF metabolites are an important component of the pheromone. Cross-adaptation experiments using the EOG demonstrated that goldfish have separate olfactory receptor sites for PGF2 alpha and 15K-PGF2 alpha that are independent from those that detect other olfactory stimulants. Finally, we established that male goldfish exposed to low concentrations of waterborne PGFs exhibit reproductive behaviors similar to those elicited by exposure to the odor of ovulated fish. Together with our recent discovery that a steroidal maturational hormone functions as a preovulatory "priming" pheromone for goldfish, these findings suggest that hormones and their metabolites may commonly serve as reproductive pheromones in fish.     

Influence of prostaglandins and thyrotropin releasing hormone (TRH) on hormone secretion and growth in wether lambs.

A series of experiments were conducted in ewes and whether (castrate male) lambs to evaluate the influence of prostaglandins on secretion of anabolic hormones and to determine if repeated injections of prostaglandin (PG) F2alpha would chronically influence the secretion of these hormones and perhaps growth rate as well. A single intravenous injection of PGA1 and PGB1 (100 microgram/kg) exerted no significant (P greater than .10) influence on plasma concentrations of prolactin (PRL), growth hormone (GH) or thyrotropin (TSH) in ewes. PGA1, but not PGB1, stimulated an increase in the plasma concentration of insulin. Infusion of PGF2alpha for 5.5 hr into ewes resulted in increased (P less than .05) plasma concentrations of both GH and ARL while TSH and insulin were not significantly influenced. Prostaglandin F2alpha, when injected subcutaneously into wether lambs (10 mg twice weekly) stimulated (P less than .05) plasma GH concentrations after the first injection, but not after 3 weeks of treatment. Changes in plasma PRL or TSH were not observed consistently in the lambs treated chronically with PGF2alpha or TRH. Prostaglandin F2alpha, in the present studies, and PGE1 in previously reported studies (1-3), has been demonstrated to be stimulatory to the secretion of PRL and GH. In contrast, PGA1 and PGB1, which lack an 11-hydroxyl group, failed to influence the secretion of either PRL or GH. It would, therefore, appear that the 11-hydroxyl group is a structural requirement for prostaglandins to influence the secretion of these two hormones in sheep. Treatment with thyrotropin releasing hormone (TRH), alone or in combination with PGF 2alpha, significantly (P less than .05) increased growth rate (average daily gains) while PGF2alpha did not, despite the fact that both compounds exerted similar effects on plasma GH.     

Basal level of human platelet prostaglandins: PGE1 is more elevated than PGE2.

Radioimmunoassays of platelet prostaglandins E1 and F1 alpha in platelet rich plasma or platelet suspension, demonstrate that both PGE1 and PGF1 alpha are present at higher concentrations than prostaglandins E2 and F2 alpha. Gas chromatography--mass spectrometry determinations of prostaglandins E1 and E2 in resting washed platelets confirm this difference. Lastly, there is a greater incorporation of [1--14C] acetate into prostaglandins E1 and F1 alpha compared to that into prostaglandins E2 and F2 alpha.     

Prostaglandin 9-hydroxydehydrogenase activity in the adult rat kidney. Identification, assay, pathway, and some enzyme properties.

Prostaglandin F2alpha is converted to 15-keto-13,14-dihydroprostaglandin E2 by adult rat kidney homogenates. A variety of substrates labeled as either the 9beta position alone or at several other positions in the prostaglandin molecule were used to define the step at which the crossover from the F type to the E type prostaglandins takes place. Time course studies further confirmed that 15-keto-13,14-dihydroprostaglandin F2alpha is the immediate substrate for this enzyme which we have termed prostaglandin 9-hydroxydehydrogenase. An assay system based on specific loss of tritium from 9beta-tritiated prostaglandin F2alpha is described. Enzyme activity with prostaglandin F2alpha as substrate is linear with time up to 10 min, stimulated by NAD+, saturable at low concentrations of substrate, stable to storage at minus 25 degrees in phosphate buffer (up to 3 weeks), and has a broad pH optimum around 7.5. The product, 15-keto,13,14-dihydroprostaglandin E2 was identified by mass spectrometry through a sodium borohydride-sodium borodeuteride reduction method.     

Prostaglandins and inflammation: enhancement of monocyte chemotactic responsiveness by prostaglandin E2.

The effects of prostaglandins on human monocyte chemotaxis were studied in vitro. None of the prostaglandins tested, including members of the A, B, E or F series, were chemotactic for monocytes. Prostaglandin E2 however, enhanced the chemotactic responsiveness of monocytes to complement - activated human serum by almost 200%. The enhancement of chemotaxis was not directly related to the ability of PGE2 to raise intracellular cyclic AMP levels. These studies support a role for prostaglandins as modulators of the inflammatory response.     

Uterine vein prostaglandin levels in late pregnant dogs.

We studied the uterine venous plasma concentrations of prostaglandins E2, F2 alpha, 15 keto 13,14 dihydro E2 and 15 keto 13,14 dihydro F2 alpha in late pregnant dogs in order to evaluate the rates of production and metabolism of prostaglandin E2 and F2 alpha in pregnancy in vivo. We used a very specific and sensitive gas chromatography-mass spectrometry assay to measure these prostaglandins. The uterine venous concentrations of prostaglandin E2 and 15 keto 13,14 dihydro E2 were 1.35 +/- .27 ng/ml and 1.89 +/- .37 ng/ml, respectively; however, we could not find any prostaglandin F2 alpha and very little of its plasma metabolite in uterine venous plasma. Since uterine microsomes can generate prostaglandin F2 alpha and E2 from endoperoxides, prostaglandin F2 alpha production in vivo must be regulated through an enzymatic step after endoperoxide formation. Prostaglandin E2 is produced by pregnant canine uterus in quantities high enough to have a biological effect in late pregnancy; however, prostaglandin F2 alpha does not appear to play a role at this stage of pregnancy.     

Effects of prostaglandins F alpha on dog thyroid cyclic AMP level and function

Prostaglandins F1 alpha and F2 alpha, at high concentrations (greater than or equal to 28 microM) enhanced cyclic AMP accumulation in dog thyroid slices. At lower concentrations, they inhibited the cyclic AMP accumulation induced by thyrotropin (TSH), prostaglandin E1, and cholera toxin. This effect was rapid in onset and of short duration, calcium-dependent and suppressed by methylxanthines. Prostaglandin F alpha also inhibited TSH-induced secretion and activated iodide binding to proteins. These characteristics are similar to those of carbamylcholine action, except that prostaglandins F did not enhance cyclic GMP accumulation. The effect of prostaglandin F alpha was not inhibited by atropine, phentolamine and adenosine deaminase and can therefore not be ascribed to an induced secretion of acetylcholine, norepinephrine or adenosine. It is suggested that prostaglandins F act by increasing influx of extracellular Ca2+. Arachidonic acid also inhibited the TSH-induced cyclic AMP accumulation. However this effect was specific for TSH, it was enhanced in the absence of calcium and was not inhibited by methylxanthines or by indomethacin at concentrations which completely block its conversion to prostaglandin F alpha. Arachidonic acid action is sustained. This suggests that arachidonic acid inhibits thyroid adenylate cyclase at the level of its TSH receptor and that this effect is not mediated by prostaglandin F alpha or any other cyclooxygenase product.     

The role of prostaglandin F in the symptoms of endometriosis.

Prostaglandin F (PGF) levels in endometriotic tissue in vitro have been shown to be higher than the levels in healthy ovarian tissue and uterine endometrium. The results of a study of nine women with endometriosis support this finding and suggest that prostaglandins have an important role in the pathogenesis of the symptoms and infertility in such women.     

Pre-parturition profile of steroids and prostaglandin in cows with or without foetal membrane retention

Retained foetal membranes in cattle is one of the most common complications associated to the reduction in milk yield and impaired fertility in dairy cattle. In order to determine some endocrine mechanisms controlling parturition and delivery of foetal membranes, plasma concentrations of steroids and prostanoids were determined in 20 healthy Holstein cows. Samples were taken within the interval of 5 days pre-parturition to 12h after calving. Progesterone (P4) levels were similar in cows with (PR) and without (NPR) placental retention. While the estradiol-17beta (E2) peak at parturition was lower in PR than in NPR cows, cortisol levels were greater in PR cows 12 and 24h pre-parturition. The Prostaglandin F2alpha metabolite (PGFM) levels were higher at parturition in NPR compared with the PR group, but 12h later, these levels in the PR group increased so that concentrations were greater as compared with NPR cows. The Prostaglandin E2 metabolite (PGEM), 24, 48 and 72 h pre-parturition, were higher in PR cows. However, the PGFM:PGEM ratio was greater in cows up NPR at all time when included, indicating the importance of higher levels of Prostaglandin F2alpha (PGF2alpha) than Prostaglandin E2 (PGE2) for normal placental delivery. In conclusion, placental retention was related to both estrogen and PGF2alpha deficiency, which may be a consequence of metabolic stress leading to PGE2 and maternal cortisol synthesis before parturition.     

Prostaglandin Production by Experimental Tumours and Effects of Anti-inflammatory Compounds

THE presence of small quantities of prostaglandin-like material has been demonstrated in medullary carcinoma of the thyroid¹ and in Kaposi's sarcoma²; the diarrhoea often associated with these tumours has been attributed to prostaglandins. Diarrhoea is also often present in mice bearing the BP8/P₁ tumour. Preliminary investigations of the ascitic fluid from mice inoculated with this tumour showed the presence of pharmacologically active substances and prostaglandin E₂-like activity was found in small amounts³. Subsequent examination of the BP8/P₁ cells has revealed concentrations of prostaglandin E₂ in excess of 100 times that of the fluid. Significant amounts have also been found in another tumour, sarcoma 180 (S180).     

Itch: Role of Prostaglandins

Prostaglandin E₁ lowers the threshold of human skin to histamine-evoked itching. Though histamine and other mediators may produce itching by a direct action, itching in inflamed skin can also be explained by a pharmacological synergism in which low concentrations of prostaglandins, which do not themselves cause itching, potentiate itching due to histamine and possibly other agents. Alteration of threshold responses of components of inflammation to other mediators may be an important general role of prostaglandins.