Kruse-Elliott K T, Dodam J R, Johnson L W, Olson N C
Department of Anatomy, Physiological Sciences, and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh 27606.
Am J Physiol. 1992 Sep;263(3 Pt 2):H761-70. doi: 10.1152/ajpheart.1992.263.3.H761.
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.
我们推测，血小板活化因子（PAF）和环氧化酶产物可能是肿瘤坏死因子（TNF-α）诱导麻醉猪心肺效应的重要介质。输注人重组TNF-α 6小时可导致低氧血症、白细胞减少、血小板减少、心脏指数（CI）降低、肺血管阻力（PVR）增加以及平均肺动脉压（Ppa）和气管内压（Pt）升高。给予PAF受体拮抗剂SRI 63-441或吲哚美辛可阻断早期（0.25 - 0.5小时）PVR和Ppa的升高，并减轻后期升高；吲哚美辛还可减轻与TNF-α输注相关的Pt升高和低氧血症。WEB 2086并未减轻TNF-α诱导的CI、PVR、Pt或PaO2变化。通过在给予SRI 63-441或WEB 2086之前及期间输注外源性PAF、前列腺素（PG）F2α、U-46619 [血栓素（Tx）A2受体模拟物]或花生四烯酸（AA），测试了SRI 63-441和WEB 2086在体内的特异性。两种拮抗剂均阻断了外源性PAF诱导的心肺效应。SRI 63-441可显著减轻PGF2α、U-46619和AA引起的PVR升高，但WEB 2086无此作用。我们得出结论，与WEB 2086相比，SRI 63-441在体内是一种特异性较低的PAF受体拮抗剂，并且环氧化酶产物而非PAF对猪外源性输注TNF-α诱导的心肺反应有显著贡献。
