ATTENUATION OF ENDOTOXIN-INDUCED PATHOPHYSIOLOGY BY A NEW POTENT PAF RECEPTOR ANTAGONIST

The role of platelet-activating factor (PAF) as a mediator of endotoxi n-induced pathophysiology has been studied in several animal models wi th conflicting results. We evaluated the effect of a new, potent, and specific PAF receptor antagonist, ABT-299 (Abbott Laboratories) agains t endotoxin (lipopolysaccharide; LPS)-induced cardiopulmonary dysfunct ion 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 mu M, and in vivo by t he ability of low doses (.12 mg/kg + .03 mg/kg/h) to block the cardiop ulmonary pathologic response to exogenous PAF infusion. To evaluate th e effect of ABT-299 administration during endotoxemia, pigs were rando mly 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 mu g/kg/hr from 0 to 6 h. ABT-299 reduced the early LPS-induced fall in cardiac index a nd stroke volume, pulmonary hypertension and vasoconstriction, broncho constrition, and hypoxemia. Administration of LPS resulted in 44% mort ality (before 6 h), which was blocked by ABT-299. Results with this an tagonist indicate that PAF contributes to endotoxin-induced cardiopulm onary dysfunction in the pig, and is associated with mortality in this model.