Differential effects of WEB 2086 and SRI 63-441 on TNF-alpha-induced alterations in cardiopulmonary function

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.