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PubMed1985

Prostaglandins and human platelet aggregation. Implications for the anti-aggregating activity of thromboxane-synthase inhibitors.

Selective pharmacological blockade of thromboxane-synthase in human platelets by dazoxiben resulted in the reorientation of cyclic-endoperoxides towards PGE2, PGD2 and PGF2 alpha. At concentrations which can be reached when thromboxane-synthase is inhibited, PGE2 (100-500 nM) exerted a marked, concentration-dependent pro-aggregatory effect. This required the formation of endogenous or the addition of exogenous endoperoxides and was prevented by PGD2 or 13-aza-prostanoic acid, a selective antagonist of PGH2/TxA2 receptors. The anti-aggregating effect of PGD2 was evident at concentrations lower than those obtained in dazoxiben-treated platelets. It is proposed that in the absence of TxA2 generation, a combination of endoperoxides and PGE2 may result in normal aggregation. The latter may be inhibited by PGD2. No interference of PGF2 alpha on platelet function could be shown.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1980

Metabolism of prostacyclin and 6-keto-prostaglandin F1 alpha in man.

Labeled and unlabeled prostacyclin and 6-keto-PGF1 alpha were infused into healthy volunteers; urine was chromatographed on different systems including high pressure liquid chromatography. The peaks obtained by the latter method were derivatized to the methoxime methyl ester trimethyl silyl ether and analyzed by gas-liquid chromatography-mass spectrometry. After infusion of prostacyclin the following metabolites could be identified: dinor-4-keto-7,9,13-trihydroxy-prosta-11,12-enoic acid (20.5%), dinor-4,13-diketo-7,9-dihydroxy-prostanoic acid (6.8%), dinor-4,13-diketo-7,9-dihydroxy-prostan-1,18-dioic acid (19.7%), and 6-keto-PGF1 alpha (14.2%), the in vitro hydrolysis product of prostacylin. 6-Keto-PGF1 alpha infusion resulted in the same metabolites with the relative amounts of 22.4, 5.4, 7.0, and 6.8%, respectively. Additionally, 6,15-diketo,13,14-dihydro-PGF1 alpha (5.7%) could be identified. These data show that the metabolic pathway of prostacyclin involves hydrolysis to 6-keto-prostaglandin F1 alpha, subsequent beta-oxidation, dehydrogenation at C-15, reduction of the double bond between C-13 and C14, and omega-oxidation to the dicarboxyl metabolite. We conclude that dinor-4-keto-7,9,13-trihydroxy-prosta-11,12-enoic acid and dinor-4,13-diketo-7,9-dihydroxy-prostan-1,18-dioic acid represent the major urinary metabolites of prostacyclin in man. 6-keto-PGF1 alpha is a minor urinary excretory product following the administration of prostacyclin or 6-keto-PGF1 alpha.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Metabolic disposition of prostaglandin E1 in man.

Metabolism of [17, 18-3H]prostaglandin E1 was investigated in three healthy male volunteers during intravenous infusion. The infusion rate was 5.0 ng/kg per min. Blood samples were obtained before the end of the infusion as well as 5, 10, 20, 40, 90 and 180 min afterwards; urine and feces were collected until 96 and 72 h, respectively, after the experiment. All samples were analyzed for radioactivity. Urine was further chromatographed, including by high-pressure liquid chromatography, and subsequently analyzed by gas chromatography-mass spectrometry. Radioactivity in plasma rapidly declined during the first 10 min after termination of the infusion, and then was eliminated exponentially with a mean half-life of 181 min, probably reflecting slow excretion of one or more metabolite. 12% of the administered radioactivity could be recovered from feces and 88% from urine. From the radioactive material obtained from urine the following metabolites could be identified (each number represents data of one volunteer): 7 alpha-hydroxy-5,11-diketotetranor-prostane-1,16-dioic acid (10.4, 20.4 and 30.1%), 7 alpha-hydroxy-5,11-diketotetranor-prostanoic acid (8.2, 6.9 and 9.3%), 5 alpha, 7 alpha-dihydroxy-11-ketotetranor-prostane-1,16-dioic acid and its delta-lactone (together accounting for 4.1, 2.1 and 3.8%).

Adult↗
PubMed1985

12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) is an excellent substrate for NAD+-dependent 15-hydroxyprostaglandin dehydrogenase.

12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) was found to be an excellent substrate for NAD+ dependent 15-hydroxyprostaglandin dehydrogenase from porcine kidney. Kcat/Km value of HHT was comparable to that of prostaglandin E although HHT is not a prostanoic acid derivative. Product of enzyme catalyzed oxidation of HHT was identified as 12-keto-5,8,10-heptadecatrienoic acid by gas chromatography-mass spectrometry. The fact that HHT is an excellent substrate for 15-hydroxyprostaglandin dehydrogenase suggest that HHT may have profound unrecognized biological actions and its inactivation may be via oxidation of the hydroxyl group.

Animals↗
PubMed1999

Protein adducts of iso[4]levuglandin E2, a product of the isoprostane pathway, in oxidized low density lipoprotein.

Levuglandin (LG) E2, a cytotoxic seco prostanoic acid co-generated with prostaglandins by nonenzymatic rearrangements of the cyclooxygenase-derived endoperoxide, prostaglandin H2, avidly binds to proteins. That LGE2-protein adducts can also be generated nonenzymatically is demonstrated by their production during free radical-induced oxidation of low density lipoprotein (LDL). Like oxidized LDL, LGE2-LDL, but not native LDL, undergoes receptor-mediated uptake and impaired processing by macrophage cells. Since radical-induced lipid oxidation produces isomers of prostaglandins, isoprostanes (isoPs), via endoperoxide intermediates, we postulated previously that a similar family of LG isomers, isoLGs, is cogenerated with isoPs. Now iso[4]LGE2-protein epitopes produced by radical-induced oxidation of arachidonic acid in the presence of protein were detected with an enzyme-linked immunosorbent assay. Iso[4]LGE2-protein epitopes are also generated during free radical-induced oxidation of LDL. All of the LGE2 isomers generated upon oxidation of LDL are efficiently sequestered by covalent adduction with LDL-based amino groups. The potent electrophilic reactivity of iso-LGs can be anticipated to have biological consequences beyond their obvious potential as markers for specific arachidonate-derived protein modifications that may be of value for the quantitative assessment of oxidative injury.

Antibody Specificity↗
PubMed1979

Metabolism of prostacyclin in the rabbit kidney.

In the isolated rabbit kidney perfused with Tyrode's solution, we examined the metabolism of radiolabeled prostacyclin. [9-3H]Prostacyclin was infused into the kidney and the radiolabeled products from the renal venous effluent were separated by thin layer chromatography and identified by gas chromatography-mass spectrometry. The major products were 7,9-dihydroxy-4,13-diketo-dinor-prostanoic acid and dinor-6-keto-prostaglandin F1alpha. They represented 25% and 10% of the total radioactivity, respectively. Metabolism of prostacyclin by the kidney may be an important determinant of the effects of prostacyclin on renal function.

Animals↗
PubMed1985

Epoxidation of prostacyclin in the rabbit kidney.

In the isolated Tyrode's perfused rabbit kidney, metabolism of [9-3H]prostacyclin was examined. In addition to 7,9-dihydroxy-4,13-diketo-dinor-prostanoic acid, dinor-6-keto-prostaglandin F1 alpha, and pentanorprostaglandin (PG)F1 alpha gamma-lactone, a new, previously unreported, metabolite was isolated and identified by radio-gas chromatography and gas chromatography-mass spectrometry as 5-hydroxy-6-keto-PGF1 alpha. The structure of this metabolite was further confirmed by comparison of the mass spectra to that of the synthetic standard. The formation of 5-hydroxy-6-keto-PGF1 alpha in the kidney suggested epoxidation of prostacyclin via the renal epoxygenase pathway.

Animals↗
PubMed1987

The multimolecular cascade of spinal cord injury. Studies on prostanoids, calcium, and proteinases.

Experimental spinal cord injury in animals induced by weight drop produces neurological deficit and paralysis. Correlation of the progressive morphological changes in the lesion by both light and electron microscopy with the biochemical alterations revealed ischemia, edema, hemorrhage, tissue necrosis, granular changes in axons, vesicular degeneration of myelin and axonal calcification. The biochemical pathology was that of degradation of axonal (neurofilaments) and myelin proteins (MBP and PLP) with increased activities of proteolytic enzymes and particularly the neutral proteinase. The level of total calcium increased progressively in the lesion to a peak at 8 hrs. and subsequently remained constant thereafter. The capacity of calcium for activating proteinases and lipases and fostering the degradation of axon and myelin proteins as well as the liberation of arachidonic acid required for the synthesis of prostanoids must be relevant. An increased production of prostanoids is indicated by elevation of thromboxane (TxB2), a stable metabolite of TXA2 at 1 hour after injury. The 6-keto-PG1(1)a was also increased but to a lesser extent. We suspect that the activation of arachidonic acid metabolism contributes to post-traumatic vascular injury and the progressive ischemia. These putative roles for calcium in proteolysis and lipolysis, inducing degradation of macromolecules and production of prostanoids which initiate edema, lysolecithin a myelinolytic factor and mitochondrial dysfunction in spinal cord injury are discussed.

Calcium↗
PubMed1982

Prostaglandin formation in man during intake of different amounts of linoleic acid in formula diets.

Prostaglandin formation in healthy female volunteers was investigated during intake of different amounts of linoleic acid in liquid formula diets (LFD). The average amounts of the metabolites convertible to tetranorprostanedioic acid (TNPDA) were 123 +/- 5.2 (x +/- SEM), 175 +/- 7.0 and 352 +/- 10.8 microgram/day, during 2-week periods with a linoleic acid supply of 0, 4 or 20% of energy, respectively. The day-by-day variations in prostaglandin formation were less than the changes observed due to different amounts of linoleic acid. High linoleic acid intake was followed by an increase of TNPDA in the urine after 3-4 days, which was more pronounced when the linoleic acid intake during the period before had been low. In all persons, the highest amount of TNPDA, 411 +/- 13.2 microgram/day, was found between days 5 and 10 of high linoleic acid intake. From day 11 through day 14 an average of 372 +/- 14.3 microgram/day was found and the values were lower in 5 of 6 persons as compared to the values found between days 5 and 10. At the end of the experiment with LFD providing a linoleic acid supply of 0, 4 or 20% of energy, the percentage of cholesteryl linoleate in plasma increased (35 +/- 1.8, 48 +/- 1.0, 63 +/- 0.6) while those of cholesterylarachidonate decreased (14 +/- 1.0, 10 +/- 0.6, 8 +/- 0.6). During the periods without linoleic acid intake the TNPDA excretion was lowest in all persons. A reduction in linoleic acid supply resulted in a decrease of urinary TNPDA within 1 day.

Adult↗
PubMed1985

Enhancement of collagen-induced phosphoinositide turnover by thromboxane A2 analogue through Ca2+ mobilization in human platelets.

In human washed platelets, collagen-induced phosphoinositide turnover was inhibited by indomethacin, an inhibitor of thromboxane A2 (TXA2) formation, particularly at lower doses of collagen. This inhibition was counteracted by the addition of 9,11-epithio-11,12-methano-TXA2 (STA2), a stable analogue of TXA2 as well as by the Ca2+ ionophore A23187. STA2 and A23187 did not stimulate phosphoinositide turnover markedly, but significantly increased cytoplasmic free Ca2+ concentrations. The actions of STA2 were blocked by 13-azaprostanoic acid, a TXA2 receptor antagonist. The results suggest that TXA2 is generated during the action of collagen and increases cytoplasmic free Ca2+ which then stimulates phosphoinositide turnover in cooperation with collagen.

Blood Platelets↗
PubMed1980

Elevated thromboxane levels in the rat during endotoxic shock: protective effects of imidazole, 13-azaprostanoic acid, or essential fatty acid deficiency.

The potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A(2), in endotoxic shock was investigated in rats. Plasma thromboxane A(2) was determined by radioimmunoassay of its stable metabolite thromboxane B(2). After intravenous administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma thromboxane B(2) levels increased from nondetectable levels (<375 pg/ml) in normal control rats to 2,054+/-524 pg/ml (n = 8), within 30 min to 2,071+/-429 at 60 min, and decreased to 1,119+/-319 pg/ml, at 120 min. Plasma levels of prostaglandin E also increased from 146+/-33 pg/ml in normal controls (n = 5) to 2,161+/-606 pg/ml 30 min after endotoxin (n = 5). In contrast to shocked controls, rats pretreated with imidazole, a thromboxane synthetase inhibitor, or essential fatty acid-deficient rats, which are deficient in arachidonate and its metabolites, did not exhibit significant elevations in plasma levels of thromboxane B(2). Imidazole did not however inhibit endotoxin-induced elevations in plasma prostaglandin E. Essential fatty acid deficiency significantly reduced mortality to lethal endotoxic shock. This refractoriness could be duplicated in normal rats pretreated with the fatty acid cyclo-oxygenase inhibitor, indomethacin (10 mg/kg), intravenously 30 min before endotoxin injection. Imidazole (30 mg/kg) administered intraperitoneally 1 h before or intravenously 30 min before endotoxin, also significantly (P < 0.01) reduced mortality from lethal endotoxin shock to 40% compared to a control mortality of 95% at 24 h. Likewise pretreatment with 13-azaprostanoic acid (30 mg/kg), a thromboxane antagonist, reduced mortality from endotoxic shock at 24 h from 100% in control rats to only 50% (P < 0.01). The results suggest that endotoxin induces increased synthesis of thromboxane A(2) that may contribute to the pathogenesis of endotoxic shock.

Animals↗
PubMed1987

What about the effects of dietary lipids on endogenous prostanoid synthesis? A state-of-the-art review.

The endogenous prostanoid synthesis can principally be influenced by a variation of the polyunsaturated fatty acid supply in food. Withholding an essential fatty acid supply in food for a length of time results in a low rate of formation of prostanoids. However, there is no simple correlation between the amount of prostaglandin precursor fatty acid supplied with food and the biosynthesis of prostanoids in the different organs. A progressive increase of the intake of polyunsaturated fatty acids results in irregular changes in the prostanoid synthesis of the organism. The impact of various parameters should be taken into account, e.g., the period of feeding, the preexperimental state of the organism, the kind of polyunsaturated fatty acid related to a particular family of fatty acids, interactions with other components of food, differences of the species, organ specificities, aspects of chronoperiodicity, interactions of the prostanoids (and polyunsaturated fatty acids, respectively) with other metabolic circuits on a different level of integration, and details in the methods applied in the determination of prostanoids. Above all, care must be taken to prevent too general conclusions being drawn about the influence on the endogenous synthesis of prostanoids by dietary polyunsaturated fatty acids.

Animals↗