Dose-dependent effects of a pyridoquinazoline thromboxane synthetase inhibitor on arachidonic acid metabolites and hemodynamics during E. Coli endotoxemia in anesthetized sheep

Morel, Denis R.; Hüttemeier, Peter C.; Skośkiewicz, M; Nguyenduy, Tuan; Melvin, C.; Robinson, Dwight R.; Zapol, Warren M.

doi:10.1016/0090-6980(87)90116-x

Cited by 7 publications

(1 citation statement)

References 31 publications

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“…We investigated the eicosanoid pathway as thromboxane release in known to cause pulmonary hypertension in an in vivo model (Morel et al 1987). The endotoxin effect is clearly dependent on the synthesis of eicosanoids, as it is prevented by pre-treatment with 4-BPAB or NDGA, inhibitors of phospholipase A2 and phospholipase C, and lipoxygenase, respectively.…”

Section: Discussionmentioning

confidence: 99%

Effects of Endotoxin Exposure on Cationic Amino Acid Transporter Function in Ovine Peripheral Blood Mononuclear Cells

Clark

Reade

Boyd

et al. 2003

Experimental Physiology

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Rodent models of sepsis differ from clinical human disease in that humans make substantially less whole‐body nitric oxide and have different cellular responses to endotoxin. Sheep, when exposed to endotoxin, behave in a manner more similar to humans. Many studies of rodent peripheral blood mononuclear cells (PBMCs) exposed to endotoxin demonstrate increased cationic amino acid transporter function (particularly through the y+ transporter) to supply arginine substrate to upregulated nitric oxide synthase. Whether this is true in sheep is not known. We have studied cationic amino acid transport in sheep PBMCs stimulated with endotoxin, using labelled lysine. PBMCs stimulated both in vitro and in vivo show an initial reduction in total and y+ lysine transport (after 1‐2 h exposure to endotoxin): a previously undescribed effect of endotoxin. In in vitro activated cells, the reduction in y+ transport was prevented by the lipoxygenase inhibitor, nordihydroguaretic acid (NDGA), and the phospholipase inhibitor 4‐bromophenacyl bromide (4‐BPAB), but not cyclohexamide or a number of other inhibitors of intracellular second‐messenger pathways. In contrast after 14 h incubation, the expected increase in total and y+ lysine transport was seen. The increase in y+ transport could be prevented by cyclohexamide, dexamethasone, ibuprofen, the protein kinase C inhibitor sphingosine, NDGA and 4‐BPAB. These results suggest that in response to endotoxin exposure there is an initial decrease in y+ activity mediated by a lipoxygenase product, followed by a substantial increase in y+ activity mediated by the products of either cyclo‐oxygenase or lipoxygenase. Cyclo‐oxygenase and/or lipoxygenase inhibition might be useful in reducing arginine transport, and hence nitric oxide production, in these cells.

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Section: Discussionmentioning

confidence: 99%

Effects of Endotoxin Exposure on Cationic Amino Acid Transporter Function in Ovine Peripheral Blood Mononuclear Cells

Clark

Reade

Boyd

et al. 2003

Experimental Physiology

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Ibuprofen Improves Survival but Does Not Ameliorate Increased Gut Mucosal Permeability in Endotoxic Pigs

Fink

Kaups²,

Wang³

et al. 1992

Arch Surg

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Intravenous lipopolysaccharide (LPS) decreases superior mesenteric arterial blood flow and increases ileal mucosal permeability in pigs. We tested the hypothesis that these phenomena can be ameliorated by pretreatment and posttreatment with ibuprofen. Pentobarbital-anesthetized immature swine were mechanically ventilated (fraction of inspired oxygen, 0.5) and infused with Ringer's lactate (RL) solution (0.8 mL/kg per minute). Animals in group RL (n = 10) received no other interventions. Animals in group RL + LPS (n = 15) were infused with LPS (50 micrograms/kg) from a time range equal to 0 through 60 minutes. Animals in group RL + LPS + ibuprofen (n = 10) were similarly infused with LPS, but in addition, they received ibuprofen (10 mg/kg at -30 minutes and 10 mg/kg per hour from -30 through 210 minutes). Intestinal permeability was assessed by measuring plasma-to-lumen clearances of two hydrophilic probes (chromium 51-labeled edetic acid monohydrate [EDTA] and urea) and by expressing the results as a clearance ratio (CEDTA/CUREA). Survival was 100%, 67%, and 100% in groups RL, RL + LPS, and RL + LPS + ibuprofen, respectively. Among survivors only, CEDTA/CUREA increased significantly over time in both endotoxic groups, but not in nonendotoxic controls. Treatment with ibuprofen transiently blocked LPS-induced mesenteric hypoperfusion. These data indicate that mediators other than cyclooxygenase-derived metabolites of arachidonic acid are responsible for the adverse effect of LPS on mesenteric permeability to hydrophilic solutes in this porcine model.

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Permeability Changes during Experimental Endotoxemia and Sepsis

Traber

Herndon

Fujioka

et al. 1991

Shock, Sepsis, and Organ Failure

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Dose-dependent effects of a pyridoquinazoline thromboxane synthetase inhibitor on arachidonic acid metabolites and hemodynamics during E. Coli endotoxemia in anesthetized sheep

Cited by 7 publications

References 31 publications

Effects of Endotoxin Exposure on Cationic Amino Acid Transporter Function in Ovine Peripheral Blood Mononuclear Cells

Effects of Endotoxin Exposure on Cationic Amino Acid Transporter Function in Ovine Peripheral Blood Mononuclear Cells

Ibuprofen Improves Survival but Does Not Ameliorate Increased Gut Mucosal Permeability in Endotoxic Pigs

Permeability Changes during Experimental Endotoxemia and Sepsis

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