Thromboxane synthesis and the platelet release reaction in Bernard-Soulier syndrome, thrombasthenia Glanzmann and Hermansky-Pudlak syndrome.
Explore the source record for details and available documents.
Adenosine Diphosphate↗
Biomedical subjects
B Samuelsson
Publications and source records attributed to B Samuelsson.
Transformation of arachidonic acid and homo-gamma-linolenic acid by rabbit polymorphonuclear leukocytes. Monohydroxy acids from novel lipoxygenases.
Addition of arachidonic acid and homo-gamma-linolenic acid to a suspension of rabbit peritoneal neutrophils led to the synthesis of 5-L-hydroxy-6,8,11,14-eicosatetraenoic acid and 8-L-hydroxy-9,11,14-eicosatrienoic acid, respectively. Both hydroxy acids were found to be the main metabolites of their respective unsaturated C-20 fatty acid precursor, constituting more than 50% of the total substrate conversion. The formation of the two metabolites was not inhibted bb indomethacin, indicating that the enzymes involved were unrelated to the prostaglandin synthetase system. The presence in the two compounds of a hydroxyl group alpha to a pair of conjugated cis/trans double bonds suggested that they were formed by action of lipoxygenease(s).
8,11,14-Eicosatrienoic Acid↗
Antagonism of the prostaglandin endoperoxide imhibition of hormone-stimulated adenylate cyclase by guanosine triphosphate and 5'-guanylyl-imidodiphosphate.
The prostaglandin endoperoxide prostaglandin H2 (15-hydroxy-9alpha, 11alpha-peroxidoprosta-5,13-dienoic acid) inhibits basal and hormone-stimulated adenylate cyclase in fat cell ghosts. This inhibition by prostaglandin H2 has been found to be antagonized by GTP and Gpp(NH)p. Dose response studies have shown GTP and Gpp(nh)p to be maximally effective at 3.3 muM, the lowest concentration tested. Although the system is exceedingly sensitive to modulation by GTP or Gpp(NH)p UTP, CTP, GMP, and cyclic GMP did not antagonize the antihormone activity of prostaglandin H2. Kinetic studies indicate that the GTP or Gpp(NH)p antagonism of prostaglandin H2 is observable on initial rates of cyclic AMP synthesis, and persists throughout the adenylate cyclase measurements. Preincubation of fat cell ghosts with GTP followed by washing and resuspension results in a prostaglandin H2-sensitive adenylate cyclase system. However, the same preincubation experiment with Gpp(NH)p produces an irreversible antagonism of the prostaglandin H2 inhibition of hormone-stimulated adenylate cyclase. It is suggested that prostaglandin H2 stabilizes the fat cell adenylate cyclase system in a state that is resistant to hormone stimulation, and GTP or Gpp(NH)p overcome this stabilization.
Adenylyl Cyclases↗
Metabolism of 8,11,14-eicosatrienoic acid in human platelets.
The following labeled compounds were isolated and identified after incubation of 8,11,14-eicosatrien [1-14C] oic acid with human platelets: 12-L-hydroxy-8,10,14-eicosatrienoic acid, 8,11,12-trihydroxy-9,14-eicosadienoic acid, 8,9,12-trihydroxy-10,14-eicosadienoic acid, 12-L-hydroxy-8,10-heptadecadienoic acid, prostaglandin E1, prostaglandin D1, and 8-(1-hydroxy-3-oxopropyl)-9,12-dihydroxy-10-heptadecenoic acid (thromboxane B1).
8,11,14-Eicosatrienoic Acid↗
Identification of an enzyme in platelet microsomes which generates thromboxane A2 from prostaglandin endoperoxides.
The microsomal fraction of horse and human platelets contains an enzyme which converts prostaglandin cyclic endoperoxides (PGG2 or PGH2) to a substance which is much more potent in contracting strips of rabbit aorta. This substance has the same characteristics as thromboxane A2, and can be distinguished from other products of arachidonic acid metabolism by differential bioassay.
Aorta↗
Uptake and localization of mercury in the brain of rats after prolonged oral feeding with mercuric chloride.
Uptake and localization of mercury was studied in rats orally intoxicated with inorganic mercury. By atomic absorption spectrophotometry large quantitative differences were found between test and control animals, particularly relating to blood, kidney and brain. By histochemical demonstration of heavy metals the uptake in the CNS was shown to occur particularly within the cytoplasm of large neurons in the cortex, pons and basal ganglia but also in other neurons, to some extent in the choroid plexus and the vessel walls, and least in the white matter. No lesions were detectable by light microscopy. The mercury was mostly in the methylated form, something that may be explained by gastrointestinal methylation by bacteria. A similar mechanism can be expected in human chronic inorganic mercury poisoning.
Administration, Oral↗
Decreased rate of metabolism induced by a shift of the double bond in prostaglandin F 2alpha from the delta5 to the delta4 position.
The synthesis of an isomer of prostaglandin F 2alpha,9alpha,11alpha,15(S)-trihydroxyprosta-4-cis,13-transdienoic acid is described. The metabolism of this compound in the rat has been investigated. The rate of degradation by beta-oxidation was slowed down considerably. Thus 10-20% of the injected isomer was excreted in the urine unchanged indicating a longer half-life in the circulation than for prostaglandin F 2alpha. More over 2% was excreted as C20 metabolites, 11-18% as C18 metabolites and 8-15% as C16 metabolites. This relative resistance to degradation by beta-oxidation is of considerable biochemical and pharmacological interest.
Animals↗
Cyclic AMP inhibits synthesis of prostaglandin endoperoxide (PGG2) in human platelets.
Explore the source record for details and available documents.
Arachidonic Acids↗
Localization of a prostaglandin F2alpha receptor in bovine Corpus luteum plasma membranes.
The distribution of a prostaglandin F2alpha receptor in various subcellular fractions from bovine corpora lutea obtained by differential and gradient centrifugation paralleled very closely the distribution in these fractions of 5'-nucleotidase, a marker enzyme for plasma membranes. The fractions most enriched in the receptor and 5'-nucleotidase were relatively free of mitochondria and lysosomes but were contaminated to some extent by elements of the endoplasmic reticulum. From these results it can be concluded that the prostaglandin F2alpha receptor is localized on the plasma membranes of the corpus luteum cells. A simple method is described for the purification of plasma membranes from bovine corpora lutea by differential centrifugation.
Animals↗
Identification and assay of tetranor-prostaglandin E1 in human urine.
Explore the source record for details and available documents.
Animals↗
A comparison of the vasodepressor effects of the cyclic effects of the cyclic endoperoxides PGG, and PGH2 with those of PGD2 and PGE2 in hypertensive and normotensive rats.
The vasodepressor actions of the cyclic endoperoxides PGG2 and PGH2 were compared with those of their products PGD2 and PGE2 using anaesthetised normotensive and genetically hypertensive rats. Given into the aortic arch of normotensives PGE2 was approximately 6 times more potent than PGH2 and 11 times more potent than PGG2 and PGD2. Hypertensive animals were 1.5-10 times more sensitive than normotensives to the depressor effects of PGG2 and PGH2, but their sensitivity to either PGD2 or PGE2 was similar. Thus in hypertensives the endoperoxides may be converted more readily to PGE2 and other products. In both types of rat PGG2 and PGH2 given intravenously were as active or more active than after intra-arterial. Therefore PGG2 and PGH2 may be converted more readily to more active products during passage through the lungs but whereas small doses of PGE2 are almost completely eliminated large doses may saturate uplmonary removal mechanisms.
Animals↗
A method for measuring the unstable thromboxane A2: radioimmunoassay of the derived mono-O-methyl-thromboxane B2.
A radioimmunoassay was developed for a mono-O-methyl derivative of thromboxane B2. The antibodies showed high specificity for this compound and cross reacted only 1.2% with thromboxane B2 and less than 0.1% with prostaglandins and prostaglandin metabolites. The method had a sensitivity of 7 picog. The radioimmunoassay was employed in studies where thromboxane A2 was generated in human platelets and immediately converted into mono-O-methyl thromboxane B2 by treatment of the sample with a large volume of methanol. In some of the experiments, thromboxane B2 was simultaneously measured by a separate radioimmunoassay. Using these two assays it was demonstrated that thromboxane A2 could be detected only during the earlier stages of the platelet aggregation, whereas thromboxane B2 rapidly reached a constant level. In a separate experiment, the half-life of thromboxane A2 in buffer was found to be 32.5 + 2.5 (S.D.) sec at 37 degrees C; the compound was more stable at lower temperatures. The t1/2 for thromboxane A2 was also considerably longer in plasma.
Antibody Specificity↗
Effects of stimulation and inhibition of the renal prostaglandin synthetase system on renin release in vivo and in vitro.
1. The prostaglandin precursor arachidonic acid (C20:4) increases plasma renin activity in the rabbit and rat when it is infused into the renal arteries. 2. The increase in plasma renin activity after C20:4 in rats is not changed by volume expansion. 3. The inhibitor of prostaglandin synthesis indomethacin decreases plasma renin activity in the rabbit. 4. The increase plasma in renin activity after total renal ischaemia is abolished by pretreatment with indomethacin. 5. C20:4 increases dose- and time-dependent renin release from slices of rabbit kidney cortex. 6. Indomethacin or 5,8,11,14-eicosatetraynoic acid pretreatment in vivo, and addition to the incubation medium, reduces basal as well as C20:4-stimulated renin release in vitro. 7. The stimulating effect of C20:4 on renin release is assumed to be caused directly by formation of prostaglandin endoperoxides in the kidney cortex and not by prostaglandins since in vitro a natural prostaglandin endoperoxide (PGG2) and two stable synthetic prostaglandin endoperoxide analogues (EPA I and EPA II) do increase the release of renin, but PGE2 has no effect and PGF2alpha inhibits renin release.
Animals↗
Evaluation of the clinical performance and skill in paediatrics of medical students.
Explore the source record for details and available documents.
Child↗
Formation and action of prostaglandin endoperoxides in the isolated human umbilical artery.
The effects on the isolated human umbilical artery (HUA) of the recently isolated endoperoxide intermediates in prostaglandin (PG) biosynthesis, PGG2 and PGH2, were studied. Both endoperoxides were potent contractors of the artery strips, the threshold concentrations being 3 (1-4) ng/ml for PGG2 and 1 (1-12) ng/ml for PGH2, as compared with 200 (40-400) ng/ml for PGE2. The hemiacetal derivative of 8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid (thromboxane B2), a metabolite of PGG2, appeared in the bath medium indicating PG and thromboxane generation in the isolated HUA. The formation of thromboxane B2 was inhibited by indomethacin (8-40 mug/ml) and by eicosa-5,8,11,14-tetraynoic acid (ETA) (25 mug/ml), ETA also inhibited the contractile responses to both endoperoxides. The results support the view that local generation of PGs might be involved in the closure of the HUA at birth.
5,8,11,14-Eicosatetraynoic Acid↗
On the formation and effects of thromboxane A2 in human platelets.
Incubation of arachidonic acid and prostaglandin G2 with a suspension of human platelets led to formation of an unstable (t1/2, 41+/-7 s) compound, thromboxane A2. Thromboxane A2 induced irreversible aggregation of washed platelets and of platelets in platelet-rich plasma and caused release of serotonin and ADP from platelets in platelet-rich plasma.
Adenosine Diphosphate↗
Stimulation of renin release from rabbit renal cortex by arachidonic acid and prostaglandin endoperoxides.
The mechanism by which renal prostaglandins stimulate renin secretion in vivo is unknown. In this in vitro study we measured the effects of activation of the prostaglandin (PG) system on renin release from slices of rabbit renal cortex. The PG precursor arachidonic acid (C20:4), a natural PG endoperoxide (PGG2), two stable synthetic PG endoperoxide analogues (EPA I and II), PGE2, PGF2alpha, and two different PG synthesis inhibitors [indomethacin and 5,8,11,14-eicosatetraynoic acid (ETA)] were used to evaluate the possibility of a direct action of the cortical PG system on renin secretion. Renin release increased significantly with time after addition of C20:4, PGG2, EPA I, and EPA II to the incubation medium. Stimulation of renin release was se-related for C20:4 in concentrations of 0.6 to 4.5 X 10(-6) M, for EPA I in concentrations of 0.7 to 2.8 X 10(-6) M, and for EPA II in concentrations of 1.4 to 14.0 X 10(-6) M. Indomethacin (10(-4) M) and ETA (10(-4) M) significantly decreased basal renin release as well as the renin release stimulated by C20:4 and EPA I. PGE2(10(-12) to 10(-6) M) had no effect on renin release, whereas PGF2alpha (10(-12) to 10(-6) M) decreased renin release in a dose-dependent manner. These data raise the possibility of a direct action of the renal cortical PG system on renin secretion. The results further indicate that stimulation of renin release by C20:4 may depend more specifically on the action of PG endoperoxides than on the primary prostaglandins.
5,8,11,14-Eicosatetraynoic Acid↗
Prostaglandin endoperoxides and thromboxanes: role in platelets and in vascular and respiratory smooth muscle.
1. Two groups of unstable (t 1/2 = 5 min) endoperoxides, PGG and PGH compounds, have been isolated and shown to be precursors of the prostaglandins. 2. A new group of compounds (thromboxanes) derived from the endoperoxides has been discovered. Thromboxanes have so far been found in platelets, leucocytes, lung tissue, spleen, kidney and umbilical artery. In platelets the thromboxane constitute the major products derived from the endoperoxides. 3. A highly unstable (t 1/2 = 30-40 s) intermediate, thromboxane A2, between the endoperoxides and thromboxane B2 has been detected. Structural work indicates that it has a bicyclic oxaneoxetane structure. 4. Thromboxane A2 induces platelet aggregation and causes contraction of the isolated rabbit aorta. Rabbit aorta contracting substance (RCS) discovered by PIPER and VANE consists mainly of thromboxane A2 and to some extent of the endoperoxides PGG2 and PGH2. 5. Endoperoxides and thromboxanes are essential for platelet aggregation. Platelet cyclo-oxygenase deficiency gives rise to a hemostatic defect due to an abnormal release mechanism. 6. The endoperoxides have unique actions on vascular and air-way smooth muscle. The effects are not due to conversion to the stable prostaglandins (PGE, PGF etc). 7. The biologically active compounds formed from polyunsaturated fatty acids via the cyclo-oxygenase catalyzed pathway can be divided into three groups depending on the stability, viz. the stable prostaglandins (PGE etc.), the endoperoxides (PGG and PGH) and the thromboxanes.
Animals↗