Effect of platelet-activating factor receptor antagonism on endotoxin-induced lung dysfunction in awake sheep.
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)
Christman
B W
BW
Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232.
Lefferts
P L
PL
Blair
I A
IA
Snapper
J R
JR
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D003243:Consciousness; D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins / Q000009:adverse effects*; D004926:Escherichia coli; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D010980:Platelet Membrane Glycoproteins; D011292:Premedication; D011806:Quinolinium Compounds / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000503:physiopathology*; D012756:Sheep; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011806:Quinolinium Compounds; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; C050531:SRI 63-441; C052518:WEB 2086; D013930:Thromboxane-A Synthase