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Biomedical subjects

J Vane

Publications and source records attributed to J Vane.

35 records · Page 2Linked to original sources
PubMed1990

Cultured astrocytoma cells inhibit platelet aggregation by releasing a nitric oxide-like factor.

Cultured astrocytoma cells were tested for their ability to generate a nitric-oxide like factor using platelet aggregation as a bioassay. Incubation of astrocytoma cells with human washed platelets resulted in an inhibition of thrombin-induced platelet aggregation which was proportional to the number of astrocytoma cells added. The inhibition was potentiated by superoxide dismutase (SOD) and prevented by oxyhaemoglobin (oxyHb). The inhibitory activity of astrocytoma cells was also prevented by the NO biosynthesis inhibitor NG-monomethyl-L-arginine (MeArg), an effect reversed by co-incubation with L-arginine (L-Arg) but not D-arginine (D-Arg). These results demonstrate that astrocytoma cells release, independent of added agonist, a factor with the same pharmacological profile as NO, which is likely to be derived from L-arginine.

Astrocytoma↗
PubMed1990

Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo.

E. coli lipopolysaccharide (LPS; 15 mg kg-1 i.v.) produced a long-lasting reduction in mean arterial blood pressure (MAP) in the anaesthetized rat. Inhibition of nitric oxide endothelium-derived relaxing factor (EDRF) synthesis with NG-monomethyl-L-arginine (MeArg, 1 mg kg-1 min-1 i.v. for 30 min) produced an increase in MAP and largely attenuated the LPS-induced hypotension; both effects were significantly reversed with L-arginine (6 mg kg-1 min-1 i.v.). When compared to MeArg, phenylephrine (300 mg kg-1 h-1 i.v.) produced a similar pressor response, but much less attenuation of the hypotensive response to LPS. Thus, a stimulation of EDRF release contributes to the LPS-induced hypotension in the anaesthetized rat.

Anesthesia↗
PubMed1990

Synthesis of a nitric oxide-like factor from L-arginine by rat serosal mast cells: stimulation of guanylate cyclase and inhibition of platelet aggregation.

Rat serosal mast cells were tested for their ability to generate a nitric oxide-like factor by two bioassay systems: inhibition of platelet aggregation and stimulation of mast cell guanylate cyclase. Incubation of rat serosal mast cells with human washed platelets resulted in an inhibition of thrombin-induced platelet aggregation proportional to the number of cells. The inhibition was potentiated by superoxide dismutase (SOD) and reversed by oxyhaemoglobin (oxyHb). The inhibitory activity of mast cells was also prevented by NG-monomethyl-L-arginine (MeArg), an effect reversed by co-incubation with L-Arg but not D-Arg. When mast cells alone were stirred at 1,000 rpm, a time-dependent increase in the levels of their cGMP but not cAMP was observed. This increase was reduced by pretreatment with MeArg. The inhibitory effect of MeArg was reversed by L-Arg but not D-Arg. These results demonstrate that rat mast cells release a factor with the same pharmacological profile as NO, and that this NO-like factor is derived from L-arginine.

Animals↗
PubMed1990

Immediate release of a nitric oxide-like factor from bovine aortic endothelial cells by Escherichia coli lipopolysaccharide.

Incubation of human washed platelets with bovine aortic endothelial cells (ECs) treated with indomethacin resulted in an inhibition of thrombin-induced platelet aggregation that was dependent on the number of ECs added. Preincubation of ECs with Escherichia coli lipopolysaccharide (LPS; 0.5-2.0 micrograms/ml) for 1 min significantly enhanced their inhibitory activity. This effect was potentiated by superoxide dismutase (60 units/ml) and reversed by oxyhemoglobin (5-10 microM), indicating that the inhibition was due to the release of endothelium-derived relaxing factor (nitric oxide). When the ECs were pretreated with NG-monomethyl-L-arginine (30-300 microM) before LPS, the antiaggregatory activity was strongly reduced. The reduction of activity by NG-monomethyl-L-arginine was reversed by L-arginine (100 microM) but not by D-arginine (100 microM). Under similar conditions, LPS also enhanced the antiaggregatory activity of ECs grown on beads. The immediate enhancement by LPS of the release of endothelium-derived relaxing factor from endothelial cells may contribute to the rapid fall in blood pressure associated with endotoxin shock in vivo.

Animals↗
PubMed1990

The use of oxyhaemoglobin to explore the events underlying inhibition of platelet aggregation induced by NO or NO-donors.

1. Full inhibition of thrombin-induced platelet aggregation was elicited by the least maximal platelet inhibitory concentrations of nitric oxide (NO; 7 +/- 1 microM) or NO-donors which included sodium nitroprusside (NaNp; 80 +/- 13 microM) 3-morpholinosydnonimine (SIN-1; 3 +/- 0.1 microM) or endothelial cells (EC; 2.36 +/- 0.12 x 10(5) added 1 min before thrombin. Oxyhaemoglobin (oxyHb; 10 microM) administered 30s to 10 min after stimulation with thrombin caused a time-dependent reversal of the inhibition induced by these agents. OxyHb was ineffective when these agents were co-incubated with the non-selective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 0.05 mM). 2. OxyHb did not reverse the platelet inhibition with IBMX (0.2 mM) or that caused by a selective guanosine 3'; 5'-cyclic monophosphate (cyclic GMP) phosphodiesterase inhibitor 2-O-propoxyphenyl-8-azapurin-6-one, (M & B 22948; 20 microM). In addition, oxyHb did not reverse the inhibition with iloprost (1 nM) which inhibits platelet aggregation through stimulation of adenylate cyclase. 3. The inhibition of platelet aggregation by NO (7 +/- 1 microM) or NaNp (80 +/- 13 microM) was accompanied by a 13 fold increase in cyclic GMP levels occurring within 15 s of addition of these agents. In the continued presence of NO or NaNp, the reversing effect of oxyHb given 1 min after thrombin was associated with a pronounced decrease in cyclic GMP levels. 4. We conclude that the inhibition of platelet aggregation by activators of guanylate cyclase depends in the first few minutes on continuous stimulation of the enzyme in order to maintain intracellular concentrations of cyclic GMP, except when its breakdown is inhibited. 5. The addition of agents such as oxyHb after the inhibition of platelet aggregation offers another way of investigating the biochemical changes involved in maintaining platelets in an inactive state.

1-Methyl-3-isobutylxanthine↗
PubMed1987

The evolution of non-steroidal anti-inflammatory drugs and their mechanisms of action.

The pro-inflammatory effects of prostaglandins have been clearly demonstrated with the use of various animal models of inflammation. Furthermore, the anti-inflammatory effects and some of the side effects of aspirin and other non-steroidal anti-inflammatory agents have been shown to depend on their ability to inhibit cyclo-oxygenase. These drugs, therefore, reduce the synthesis of prostaglandins, prostacyclin and thromboxane. They do not affect leukotriene production and there is no firm evidence to suggest that they alleviate inflammation through any other mechanism. In contrast, the corticosteroids facilitate the release of lipocortin which, through inhibition of phospholipase A2 reduces arachidonic acid release. These drugs possess potent anti-inflammatory properties and attempts have been made to develop non-steroidal drugs, such as BW755C, that display similar anti-inflammatory activity through inhibition of the 2 main pathways of the arachidonic acid cascade. Administration of low dose aspirin 40 mg/day selectively inhibits production of thromboxane A2 without affecting prostacyclin. This may be because, firstly, about 60% of an administered dose of aspirin is deacylated to salicylate during first-pass metabolism and, secondly, platelets cannot regenerate cyclo-oxygenase. Thus, absorbed aspirin irreversibly affects platelet thromboxane production in the pre-systemic circulation, but the systemic plasma aspirin concentration is likely to be too low to affect prostacyclin synthesis. Studies in experimental inflammation have shown that after the administration of aspirin, the concentration of salicylate in inflammatory exudate is considerably higher than that of aspirin. In addition, a comparison of prostaglandin synthesis inhibitory potencies shows that the concentration of salicylate, but not of aspirin, at the inflammatory site is high enough to substantially inhibit prostaglandin synthesis.

Adrenal Cortex Hormones↗
PubMed1987

Inflammation and the mechanism of action of anti-inflammatory drugs.

Inflammation is caused by release of chemicals from tissues and migrating cells. Most strongly implicated are the prostaglandins (PGs), leukotrienes (LTs), histamine, bradykinin, and, more recently, platelet-activating factor (PAF) and interleukin-1. Evidence for their involvement comes from studies with competitive antagonists for their receptors and inhibitors of their synthesis. H1 histamine antagonists are effective for hay fever and some skin allergies such as urticaria, which indicates the importance of histamine in these conditions. Symptoms of rheumatoid arthritis are alleviated by the aspirinlike anti-inflammatory drugs, which inhibit the cyclo-oxygenase enzyme and reduce synthesis of prostanoids. Corticosteroids prevent the formation of both PGs and LTs by causing the release of lipocortin, which by inhibition of phospholipase A2 reduces arachidonic acid release. They suppress the inflammation of rheumatoid arthritis and asthma. Currently, high doses of nonsedating H1 antihistamines and PAF antagonists are being tested for the treatment of allergic asthma.

Animals↗
PubMed1982

[Clinical study of prostacyclin in extracorporeal circulation. Effects on hemodynamics and coagulation].

The effects of prostacycline (PGI2), the most powerful known platelet antiaggregant on platelet count and function during cardiopulmonary bypass, were assessed in a double blind study. One group of 13 patients received 2,5 mg/Kg of Heparin with an infusion of 25 ng/Kg/min of prostacycline instituted 15 minutes before the Heparin, continued at the beginning of cardiopulmonary bypass at a dose of 50 ng/Kg/min and terminated at the end of bypass. A second group of 15 patients were studied by the same protocol with a placebo infusion. The platelet count was significantly higher at the end of cardiopulmonary bypass in the Prostacycline group. Platelet aggregation was reduced by comparison with the control group from the beginning of Prostacycline infusion. The active thrombin time was significantly longer in the Prostacycline group. However, blood loss did not differ significantly between the two groups although it was less in the study group. The platelet count and function during cardiopulmonary bypass with Prostacycline was therefore increased and resulted in a reduction in Heparin consumption.

Anticoagulants↗
PubMed1980

Prostacyclin eliminates the thrombocytopenia associated with charcoal hemoperfusion and minimizes heparin and fibrinogen consumption.

To evaluate the effects of prostacyclin (PGI2) on the bioincompatibility of charcoal hemoperfusion (CHP), platelet counts, platelet aggregate formation as measured by screen filtration pressure (SFP), plasma fibrinogen levels, and heparin activity monitored by calcium-thrombin clotting times (Ca-TCT) were compared during CHP in healthy dogs with heparin alone or heparin plus PGI2. Platelet losses (25 +/- 6 vs 83 +/- 2%: mean +/- SEM), rise in SFP (65 +/- 6 vs 249 +/- 25 mmHg), and fibrinogen consumption (20 +/- 5 vs 46 +/- 6%) were significantly less during CHP with PGI2 than with heparin only. In addition, rapid neutralization of heparin, as monitored by Ca-TCT, during CHP was prevented by PGI2. The use of PGI2 may allow a proper evaluation of the efficacy of CHP in conditions such as fulminant hepatic failure where, hitherto, incompatibility between blood and charcoal may have had deleterious effects.

Animals↗