Effects of platelet-activating factor antagonist SRI 63-441 on endotoxemia in sheep.
We investigated whether platelet-activating factor (PAF) mediates endotoxin-induced systemic and pulmonary vascular derangements by studying the effects of a selective PAF receptor antagonist, SRI 63-441, during endotoxemia in sheep. Endotoxin infusion (1.3 micrograms/kg over 0.5 h) caused a rapid, transient rise in pulmonary arterial pressure (Ppa) from 16 +/- 3 to 36 +/- 10 mmHg (P less than 0.001) and pulmonary vascular resistance (PVR) from 187 +/- 84 to 682 +/- 340 dyn.s.cm-5 (P less than 0.05) at 0.5 h, followed by a persistent elevation in Ppa to 22 +/- 3 mmHg and in PVR to 522 +/- 285 dyn.s.cm-5 at 5 h in anesthetized sheep. Arterial PO2 (PaO2) decreased from 341 +/- 79 to 198 +/- 97 (P less than 0.01) and 202 +/- 161 Torr at 0.5 and 5 h, respectively (inspired O2 fraction = 1.0). SRI 63-441, 20 mg.kg-1.h-1 infused for 5 h, blocked the early rise in Ppa and PVR and fall in PaO2, but had no effect on the late phase pulmonary hypertension or hypoxemia. Endotoxin caused a gradual decrease in mean aortic pressure, which was unaffected by SRI 63-441. Infusion of SRI 63-441 alone caused no hemodynamic alterations. In follow-up studies, endotoxin caused an increase in lung lymph flow (QL) from 3.8 +/- 1.1 to 14.1 +/- 8.0 (P less than 0.05) and 12.7 +/- 8.6 ml/h at 1 and 4 h, respectively. SRI 63-441 abolished the early and attenuated the late increase in QL.(ABSTRACT TRUNCATED AT 250 WORDS)
Sessler
C N
CN
Department of Medicine, Medical College of Virginia, Richmond.
Glauser
F L
FL
Davis
D
D
Fowler
A A
AA
D000818:Animals; D004731:Endotoxins / Q000633:toxicity; D006439:Hemodynamics / Q000187:drug effects; D007970:Leukopenia / Q000209:etiology; D008196:Lymph / Q000187:drug effects / Q000502:physiology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011806:Quinolinium Compounds / Q000494:pharmacology*; D012756:Sheep; D014115:Toxemia / Q000097:blood / Q000209:etiology / Q000503:physiopathology*
D004731:Endotoxins; D010972:Platelet Activating Factor; D011806:Quinolinium Compounds; C050531:SRI 63-441; D011451:Prostaglandin-Endoperoxide Synthases