Attenuation of endotoxin-induced pathophysiology by a new potent PAF receptor antagonist.
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.
Kruse-Elliott
K T
KT
Department of Surgical Sciences, University of Wisconsin, Madison, USA 53706.
Albert
D H
DH
Summers
J B
JB
Carter
G W
GW
Zimmerman
J J
JJ
Grossman
J E
JE
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000819:agonists / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012772:Shock, Septic / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology*; D013318:Stroke Volume / Q000187:drug effects; D013552:Swine; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000097:blood; D014655:Vascular Resistance / Q000187:drug effects
D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011355:Prodrugs; D011726:Pyridinium Compounds; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles; C039351:platelet activating factor receptor; D013929:Thromboxane B2; C093306:ABT 299; D009195:Peroxidase