Abstract |
The role of platelet-activating factor (PAF) as a mediator of endotoxin-induced pathophysiology has been studied in several animal models with conflicting results. We evaluated the effect of a new, potent, and specific PAF receptor antagonist, ABT-299 (Abbott Laboratories) against endotoxin ( lipopolysaccharide; LPS)-induced cardiopulmonary dysfunction in a porcine model. In initial experiments, the potency of ABT-299 was confirmed in vitro by its ability to inhibit PAF-induced porcine platelet aggregation at an IC50 of .047 +/- .01 microM, and in vivo by the ability of low doses (.12 mg/kg + .03 mg/kg/h) to block the cardiopulmonary pathologic response to exogenous PAF infusion. To evaluate the effect of ABT-299 administration during endotoxemia, pigs were randomly assigned to one of three groups: controls (n = 7), LPS (n = 9), or ABT-299 + LPS (n =7). ABT-299 was given at 1.0 mg/kg from -0.5 to 0 h plus .3 mg/kg/h from 0 to 6 h. LPS was given at .5 micrograms/kg/hr from 0 to 6 h. ABT-299 reduced the early LPS-induced fall in cardiac index and stroke volume, pulmonary hypertension and vasoconstriction, bronchoconstriction, and hypoxemia. Administration of LPS resulted in 44% mortality (before 6 h), which was blocked by ABT-299. Results with this antagonist indicate that PAF contributes to endotoxin-induced cardiopulmonary dysfunction in the pig, and is associated with mortality in this model.
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Authors | K T Kruse-Elliott, D H Albert, J B Summers, G W Carter, J J Zimmerman, J E Grossman |
Journal | Shock (Augusta, Ga.)
(Shock)
Vol. 5
Issue 4
Pg. 265-73
(Apr 1996)
ISSN: 1073-2322 [Print] United States |
PMID | 8721386
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Lipopolysaccharides
- Platelet Activating Factor
- Platelet Aggregation Inhibitors
- Platelet Membrane Glycoproteins
- Prodrugs
- Pyridinium Compounds
- Receptors, Cell Surface
- Receptors, G-Protein-Coupled
- Thiazoles
- platelet activating factor receptor
- Thromboxane B2
- ABT 299
- Peroxidase
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Topics |
- Animals
- Blood Pressure
(drug effects)
- Cardiac Output
(drug effects)
- Dose-Response Relationship, Drug
- Lipopolysaccharides
(toxicity)
- Lung
(drug effects, enzymology, pathology)
- Peroxidase
(drug effects, metabolism)
- Platelet Activating Factor
(metabolism, pharmacology)
- Platelet Aggregation Inhibitors
(administration & dosage, pharmacology)
- Platelet Membrane Glycoproteins
(agonists, antagonists & inhibitors)
- Prodrugs
(administration & dosage, pharmacology)
- Pyridinium Compounds
(administration & dosage, pharmacology)
- Receptors, Cell Surface
- Receptors, G-Protein-Coupled
- Shock, Septic
(drug therapy, mortality, physiopathology)
- Stroke Volume
(drug effects)
- Swine
- Thiazoles
(administration & dosage, pharmacology)
- Thromboxane B2
(blood)
- Vascular Resistance
(drug effects)
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