To test the hypothesis that PAF partially mediates
endotoxin-induced lung dysfunction, we studied the effects of two structurally dissimilar PAF receptor antagonists (
SRI 63-441 and
WEB 2086) on
endotoxin-induced lung dysfunction in chronically instrumented awake sheep. Each animal was studied three times in varied order: infusion of
endotoxin alone (
Escherichia coli endotoxin 0.5 micrograms/kg over 20 min [E]), infusion of the competitive
platelet-activating factor (PAF) receptor antagonist alone, or with
endotoxin given 1 h after beginning the 6-h
drug infusion (E + SRI, E + WEB). Neither
drug alone had significant effects on any of the measured variables, but both were able to abolish the pulmonary pressor effect of a 0.25-micrograms/kg bolus of PAF.
SRI 63-441 (10 to 20 mg/kg/h) attenuated the
endotoxin-induced
pulmonary hypertension (peak pulmonary arterial pressure, 53 +/- 12 versus 65 +/- 7 cm H2O; p greater than 0.05) and fall in dynamic compliance of the lungs (to 65.1 +/- 9.8% baseline versus 32.6 +/- 5.1% baseline). Lung lymph flow increased 6.1- and 5.8-fold at 2 and 5 h for (E) versus 1.9- and 2.5-fold at identical time points for (E + SRI).
SRI 63-441 attenuated the acute
leukopenia noted after
endotoxemia.
WEB 2086 (20 mg/kg/h) similarly attenuated the late alterations in lung mechanics and lymph flow caused by
endotoxin, but it had little effect on the early
pulmonary hypertension and lung mechanic changes. Both agents significantly attenuated the rise in lymph
thromboxane B2 levels after
endotoxemia.(ABSTRACT TRUNCATED AT 250 WORDS)