We hypothesized that
platelet-activating factor (PAF) and
cyclooxygenase products might be important mediators of the cardiopulmonary effects induced by
tumor necrosis factor (
TNF-alpha) in anesthetized pigs. A 6-h infusion of human recombinant
TNF-alpha caused
hypoxemia,
leukopenia,
thrombocytopenia, decreased cardiac index (CI), increased pulmonary vascular resistance (PVR) and increased mean pulmonary arterial (Ppa) and intratracheal (Pt) pressures. Administration of the PAF receptor antagonist
SRI 63-441 or
indomethacin blocked the early (0.25-0.5 h) and attenuated the later increases in PVR and Ppa;
indomethacin also attenuated the increase in Pt and
hypoxemia associated with
TNF-alpha infusion.
WEB 2086 did not attenuate the
TNF-alpha-induced alterations in CI, PVR, Pt, or PaO2. The in vivo specificity of
SRI 63-441 and
WEB 2086 was tested by infusing exogenous PAF,
prostaglandin (PG) F2 alpha,
U-46619 [
thromboxane (Tx)A2 receptor mimetic], or
arachidonic acid (AA) before and during administration of
SRI 63-441 or
WEB 2086. Both antagonists blocked the cardiopulmonary effects induced by exogenous PAF.
SRI 63-441, but not
WEB 2086, significantly attenuated the increased PVR caused by
PGF2 alpha,
U-46619, and AA. We conclude that
SRI 63-441 is a less specific PAF receptor antagonist in vivo compared with
WEB 2086 and that
cyclooxygenase products, but not PAF, contribute significantly to the cardiopulmonary responses induced by exogenously infused
TNF-alpha in pigs.