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Biomedical subjects

G J Blackwell

Publications and source records attributed to G J Blackwell.

At least 19 recordsLinked to original sources
PubMed1995

Development of a novel series of trialkoxyaryl derivatives as specific and competitive antagonists of platelet activating factor.

The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives, as specific and competitive inhibitors of platelet activating factor (PAF), are described. Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N-[2-[(3,4,5-trimethoxybenzoyl)oxy]ethyl]-N,N,N-trimethylammonium iodide (1) from the Wellcome registry of compounds and to the synthesis of the lead compound N-[2-[[4-(hexyloxy)-3,5-dimethoxybenzoyl]oxy]ethyl]-N,N,N- trimethylammonium iodide (3, pKb 5.43). Further SAR considerations directed the design to 2-(hexyloxy)-1,3-dimethoxy-5-[4-(4-methylthiazol-5-yl)butyl] benzene (38) (pKb 7.14), a novel, specific, and competitive inhibitor of the PAF receptor in rabbit-washed platelets.

Animals↗
PubMed1985

Carbon tetrachloride-induced eicosanoid synthesis and enzyme release from rat peritoneal leucocytes.

When rat peritoneal leucocytes were incubated with carbon tetrachloride, a PLA2 was activated, eicosanoids were generated and lysosomal and cytoplasmic enzymes were released. The predominant eicosanoid generated was TXB2 with lesser amounts of PGE2, 6-keto PGF1 alpha and LTB4. Preincubation of the cells with two structurally unrelated thromboxane synthetase inhibitors reduced PLA2 activity and enzyme release and also reduced the total amounts of eicosanoids liberated. An anti-PGI2 antibody partially reversed the effects of thromboxane synthetase inhibitors indicating a role for endogenous PGI2 generation in the cytoprotective effects of these agents in this system. Exogenous PGI2 was also cytoprotective but the timing of its administration was critical. The cytoprotective effect of PGI2 was potentiated by a phosphodiesterase inhibitor, indicating a possible pivotal role of cAMP in cell protection.

Animals↗
PubMed1985

Stimulation and inhibition of secretion by phorbol myristate acetate in different cell types.

In washed human platelets and in HL60 granulocytes phorbol myristate acetate (PMA, 1-2000nM) synergised with threshold concentrations of secretogogues to induce a sustained maximum secretory response. Likewise, superoxide production from HL60 cells maintained a maximal response at PMA concentrations between 30-300nM. At concentrations up to 10nM PMA also augmented calcium ionophore, A23187, stimulated histamine release from rat peritoneal mast cells. However, in the mast cell PMA concentrations above 10nM reduced maximum histamine release in a dose-dependent manner.

Animals↗
PubMed1985

Inhibition of human platelet aggregation by vitamin K.

The effect of several vitamin K (Vit K) analogues on the aggregation of human platelets was examined. The analogues were potent inhibitors of aggregation induced by ADP, thrombin, collagen and arachidonate but were less active against aggregation induced by the calcium ionophore A23187. Vit K3 also prevented platelet membrane phosphatide breakdown induced by collagen. These effects were not due to a direct inhibition of enzymes involved in the liberation of arachidonate or its subsequent transformation. The analogues exerted no effects on enzymes regulating intraplatelet cAMP. However, these effects could be overcome by increasing extracellular Ca++ levels, indicating a possible interaction with Ca++ regulation in platelets.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1983

Specificity and inhibition of glucocorticoid-induced macrocortin secretion from rat peritoneal macrophages.

The secretion of the phospholipase A2-inhibitor macrocortin and the binding of dexamethasone were studied in suspensions of rat peritoneal macrophages. Corticosteroid-induced macrocortin secretion was specific for glucocorticoids and did not occur in response to glucocorticoid antagonists or other steroids or in response to non-steroid macrophage activators (formyl-methionyl-leucyl-phenylalanine f-MLP), the calcium ionophore A23187, phorbol myristate acetate (PMA) and lipopolysaccharide-E.-coli(LPS) ). The apparent potency of competition by secretory glucocorticoids for dexamethasone binding to the macrophage parallelled their ability to induce secretion, implying that these binding sites represent the receptors by which macrocortin secretion is initiated. Agents which interfere with microtubule assembly (colchicine, vinblastine and trimethylcolchicinic acid) and prostacyclin and dibutyryl cyclic AMP inhibit macrocortin secretion. Inhibition studies of glucocorticoid-induced macrocortin secretion also suggest dependence upon metabolic energy, a source of Ca2+ and proteolysis and glycosylation prior to secretion.

Animals↗
PubMed1982

Prostacyclin prolongs viability of washed human platelets.

The functional viability of stored human platelets, washed in the presence and absence of prostacyclin, was examined over a 96 h period. Platelet counts, aggregation responses and cyclic AMP levels were monitored as well as the spontaneous generation of thromboxane B2 and the liberation of labelled oleate from cellular phosphatides. In suspensions prepared without prostacyclin in the medium, platelet counts declined rapidly as did the sensitivity to aggregating agents. In addition, substantial amounts of thromboxane B2 were generated during preparation and storage and oleate liberation occurred at a rapid rate. In contrast, in prostacyclin-washed platelets, aggregation was maintained throughout the study period and there was little generation of thromboxane B2. Moreover, only a gradual decrease in platelet count and a slow increase in the rate of oleate liberation was observed when compared with controls. However, cyclic AMP levels rapidly declined when platelets were resuspended in prostacyclin-free medium.

Adult↗
PubMed1982

Glucocorticoids induce the formation and release of anti-inflammatory and anti-phospholipase proteins into the peritoneal cavity of the rat.

1 Dexamethasone and hydrocortisone induced the release of anti-phospholipase proteins into the peritoneal cavities of rats. 2 Adrenocorticotrophic hormone (ACTH) also releases these proteins in normal but not in adrenalectomized rats. 3 Peritoneal lavage proteins were separated by ion-exchange and size exclusion chromatography. The anti-phospholipase activity occurred in four separate fractions with the major component having an apparent mol. wt. of 40 k. 4 Column fractions containing these anti-phospholipase proteins had anti-inflammatory effects in the rat carrageenin pleurisy model whereas other fractions were inactive. 5 The proteins appear to be identical to macrocortin and lipomodulin, the 'second messengers' of glucocorticoid hormone action on the arachidonate system.

Adrenocorticotropic Hormone↗
PubMed1980

Macrocortin: a polypeptide causing the anti-phospholipase effect of glucocorticoids.

Anti-inflammatory glucocorticoids inhibit prostaglandin (PG) biosynthesis by preventing arachidonic acid release from phospholipids rather than inhibiting the cyclooxygenase. As in other cells, this steroid action depends on receptor occupation and de novo protein/RNA biosynthesis. We have previously shown in guinea pig perfused lungs and rat peritoneal leukocytes that the effect of steroids in PG generation is mediated by an uncharacterized 'second messenger'. Now, we report that this factor (which we have named 'macrocortin') is an intracellular polypeptide whose release and synthesis are stimulated by steroids. Macrocortin derived from rat peritoneal leukocytes is very similar to that released from guinea pig lungs.

Animals↗
PubMed1980

On the preparation of highly purified slow reacting substance of anaphylaxis (SRS-A) from biological extracts.

1 Very highly purified (greater than 100,000 u/mg) slow reacting substance of anaphylaxis (SRS-A) has been prepared by reversed phase high pressure liquid chromatographic (HPLC) techniques. 2 High resolution liquid chromatography suggests that SRS-A may exist in at least three distinct forms which are possible tautomeric. 3 SRS-A collected by antigen challenge in vivo and by calcium ionophore-induced release in vitro are chromatographically indistinguishable. 4 Treatment of SRS-A with diazomethane but not sodium borohydride results in a loss of biological activity but treatment of the methyl ester with base results in a partial recovery of activity. 5 Highly purified SRS-A was examined by infrared and ultra-violet spectroscopy, and found to have a benzene-aromatic and probably an amino acid.

Animals↗
PubMed1978

Phospholipase A2 activity of guinea-pig isolated perfused lungs: stimulation, and inhibition by anti-inflammatory steroids.

1 A simple double-isotope assay for phospholipase A2 activity of perfused organs is described; Guinea-pig lungs perfused through the pulmonary circulation exhibit a low background enzyme activity. This activity is blocked by dexamethasone, betamethasone and hydrocortisone, mepacrine, procaine or chlorpromazine. Aspirin and indomethacin are without effect. 3 Mechanical trauma, antigen challenge or injections of bradykinin, rabbit aorta contracting substance-releasing factor (RCS-RF) or histamine increase "basal" phospholipase activity. The effect of these agents, except that of bradykinin, is blocked by dexamethasone or mepacrine. 4 The blocking effect of steroids is cumulative and dose-dependent. They do not work in cell-free systems. Inhibition by mepacrine is rapid and is effective in cell-free lung homogenates. 5 It is suggested that agents which liberate prostaglandin endoperoxides and thromboxane A2 from perfused lungs do so by activating phospholipase A2.

Animals↗