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Biomedical subjects

R R Gorman

Publications and source records attributed to R R Gorman.

At least 91 records · Page 5Linked to original sources
PubMed1978

An antiserum against 9-deoxy-6,9-epoxy-PGF1alpha recognizes and binds PGI2 (prostacyclin).

Antibodies were prepared against 9-deoxy-6,9-epoxy-PGF1alpha, the 5,6-dihydro analog of prostacyclin (PGI2). By using as the hapten, this structurally similar, stable analog, an antibody population was developed which recognized PGI2 and reversed its influence on platelet aggregation. The antibodies also opposed the normal effect of PGI2 on the cAMP and thromboxane B2 levels during aggregation. By anticipating the cross reaction between the analog and PGI2 and by considering it beneficial, the problem of raising antibodies against an unstable compound has been circumvented.

Animals↗
PubMed1978

Preparation and spectral properties of 12-hydroxyl eicosatetraenoic acid (HETE).

A convenient method for the biosynthesis of 12L-hydroxy-5,8,10,14-eicosatetraenoic acid (HETE) from archidonic acid with human platelets was developed, and milligram quantities were made for biological and spectroscopic characterization. This compound has only weak activity in two of five biological prostaglandin assays and no activity in the other three. The 13C and 1H NMR spectra of HETE were obtained and the signal due to each carbon atom was assigned.

Arachidonic Acids↗
PubMed1977

Electron capture gas chromatographic detection of thromboxane B2.

An electron capture gas chromatographic method is described for the detection of thromboxane B2. Thromboxane B2 is esterified with diazomethane, followed by treatment with pentafluorobenzylhydroxylamine hydrochloride and silylation with BSA. In pyridine, the free aldehyde form of the acetal ring is favored allowing rapid formation of a novel thromboxane B2 pentafluorobenzyloxime. The method has been applied to detect thromboxane B2 formation during aggregation of washed platelets. It must be emphasized that by ordinary analytical standards, the derivatization reproducibility from 50-375 nanograms is poor (+/- 11% - +/- 42%); however, the improved selectivity of the method and its ability to detect nanogram levels of thromboxane B2 make it a useful complement to commonly employed bioassay techniques.

Arachidonic Acids↗
PubMed1977

Modulation of human platelet adenylate cyclase by prostacyclin (PGX).

Prostacyclin (PGX) (57)-9-deoxy-6,9alpha-epoxy-delta5-PGF1alpha has been found to be a potent stimulator of cAMP accumulation in platelets than PGE1. The prostacyclin stimulation of platelet cAMP accumulation can be antagonized by the prostaglandin endoperoxide PGH2, and a PGH2-induced platelet aggregation is antagonized by prostacyclin. A model of platelet homeostasis is proposed that suggests platelet aggregation is controlled by a balance between the adenylate cyclase stimulating activity of prostacyclin, and the cAMP lowering activity of PGH2.

Adenylyl Cyclases↗
PubMed1977

Prostaglandins H1 and H2. Convenient biochemical synthesis and isolation. Further biological and spectroscopic characterization.

An easy biochemical preparation of the prostaglandin endoperoxides, PGH1 and PGH2, is described. Both of the endoperoxides are potent contractors of isolated gerbil colon smooth muscle. Contracture with PGH2 is about equal to that caused by the standard, PGE1, while contracture with PGH1 is about half of that caused by PGE1. PGH1 was found to inhibit platelet aggregation induced by PGH2 and is about 1/10 as potent a stimulator of cAMP accumulation as is PGE1. The mass spectra of the methyl esters of both PGH1 and PGH2 were obtained, as were the infrared spectra of the two compounds. The nuclear magnetic resonance spectrum of PGH2 is characterized by signals at 4.58 delta and 4.47 delta for the C-9 and C-11 protons, respectively.

Animals↗
PubMed1977

On the structure of slow reacting substance of anaphylaxis: evidence of biosynthesis from arachidonic acid.

The mononuclear cells in peritoneal washings from normal rats can be induced to produce large amounts of slow reacting substance of anaphylaxis by incubation with 10 mM cysteine in the presence of the calcium ionophore A-23187. This production of slow reacting substance could be inhibited by the addition of non-steroidal anti-inflammatory drugs, e.g., indomethacin, ibuprofen and flurbiprofen, Furthermore, mediator production was inhibited by eicosatetraynoic acid, the substrate analog of arachidonic acid, and by 9,11-azoprosta-5, 13-dienoic acid (AZO analog 1), a structural analog of the prostaglandin endoperoxide, PGH2, which known to inhibit thromboxane synthesis. Relatively high concentrations of hydrocortisone acetate inhibited mediator production; this inhibition could be partly reversed by the addition of arachidonic acid or to a lesser extent by eicosatrienoic acid. Preliminary results suggest that a small fraction of the 3H-labled arachidonic acid which was taken up by these cells in vitro was associated with slow reacting substance. We postulate that slow reacting substance of anaphylaxis may be derived from a prostaglandin endoperoxide which is formed during the oxidation of arachidonic acid by the prostaglandin fatty acid cyclooxygenase.

Anaphylaxis↗
PubMed1977

Inhibition of PGE1-stimulated cAMP accumulation in human platelets by thromboxane a2.

The prostaglandin endoperoxide PGH2, HHT, HETE, thromboxane A2, and thromboxane B2, which are all products of arachidonic acid metabolism of human platelets, were tested for their ability to modulate platelet cyclic nucleotide levels. None of the compounds tested altered the basal level of cAMP or cGMP, and only PGH2 and thromboxane A2 inhibited PGE1-stimulated cAMP accumulation. Thromboxane A2 was found to be a more potent inhibitor of PGE1-stimulated cAMP accumulation and inducer of platelet aggregation than PGH2.

Blood Platelets↗
PubMed1977

Platelet rich plasma transforms exogenous prostaglandin endoperoxide H2 into thromboxane A2.

Platelet rich plasma transforms exogenous prostaglandin endoperoxide H2 into thromboxane A2 immediately prior to the initiation of irreversible aggregation. Selective thromboxane synthetase inhibitors block thromboxane A2 formation and aggregation. Thromboxane A2 formation appears to be essential during arachidonate mediated aggregation. The results presented reconcile the previously accepted paradoxical behavior of thromboxane synthetase in platelet rich plasma toward the prostaglandin endoperoxide H2 substrate.

Arachidonic Acids↗
PubMed1977

Inhibition of human platelet thromboxane synthetase by 9,11-azoprosta-5,13-dienoic acid.

The synthetic prostaglandin analog 9,11-azoprosta-5,13-dienoic acid (azo analog I) has been found to be a potent inhibitor of human platelet thromboxane synthetase by three independent analytical methods: electron-capture gas chromatography, radioisotopic thin-layer chromatography, and radioimmunoassay. In the presence of azo analog I, human platelet aggregation induced by either the prostaglandin endoperoxide PGH2 or arachidonic acid was antagonized. The addition of azo analog I shifted the transformation of endoperoxides away from thromboxane synthesis and toward prostaglandin E2 synthesis. The specificity of azo analog I is demonstrated by its selective inhibition of the second wave of either ADP- or epinephrine-induced platelet aggregation. These data indicate that PGH2 must be converted to thromboxane A2 in order to induce human platelet aggregation.

Arachidonic Acids↗
PubMed1977

Comparative effects of endoperoxide PGH2 and an analog on the pulmonary vascular bed.

The effects of the prostaglandin endoperoxide, PGH2, and a stable endoperoxide analog were compared on the canine pulmonary vascular bed under conditions of controlled blood flow. The analog produced dose-related increases in lobar arterial and small vein pressure when injected into the perfused lobar artery. The increase in resistance in response to the analog was greater during retrograde perfusion than during forward perfusion. These data suggest that the analog increases resistance to flow by constricting pulmonary veins and upstream vessels. The increase in resistance was similar when the lung was perfused with dextran or blood and the response was not different when the lung was ventilated or collapsed. The response was notattenuated by indomethacin, an inhibitor of prostaglandin synthesis. These data suggest that the response to the analog is not related to changes in bronchomotor tone, platelet aggregation, or enhanced prostaglandin synthesis. Although the analog was a potent pressor substance, PGH2 itself produced only small increases in pulmonary vascular resistance. However, PGH2 had greater contractile activity than the analog on isolated helical segments of canine intrapulmonary vein. The present study suggests that endoperoxides may represent an active form of the prostaglandins in the lung but that their effects would be localized in the tissue in which they are formed because of their extremely short biologic half-life.

Animals↗
PubMed1977

Stimulation of human eosinophil and neutrophil polymorphonuclear leukocyte chemotaxis and random migration by 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid.

A human platelet lipoxygenase-generated product of arachidonic acid, identified by thin-layer chromatographic and mass spectrometric properties as 12-L-hydroxy-5,8,10,14-eicosatertraenoic acid (HETE), was selectively chemotactic in vitro for human polymorphonuclear leukocytes (PMN), as compared to mononuclear leukocytes, with a preference for eosinophils. Preincubation of PMN with partially-purified HETE at peak chemotactic concentrations of 8-24 mug/ml reduced their random and chemotactic migration and stimulated the activity of their hexose monophosphate shunt; minimally chemotactic concentrations of 0.03-1 mug/ml enhanced PMN random migration without influencing other functions. HETE may thus be capable of preferentially attracting eosinophils to foci of tissue reaction associated with platelet activation.

Arachidonic Acids↗
PubMed1976

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↗