Dobrowsky R T, Voyksner R D, Olson N C
Department of Anatomy, Physiological Sciences, and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh 27606.
Am J Physiol. 1991 May;260(5 Pt 2):H1455-65. doi: 10.1152/ajpheart.1991.260.5.H1455.
We evaluated the effect of SRI 63-675, a specific platelet-activating factor (PAF) receptor antagonist, on hemodynamics and PAF biosynthesis during 4 h of porcine endotoxemia. Hexadecyl PAF was extracted from blood, purified by normal-phase and reverse-phase high-performance liquid chromatography (RP-HPLC), and quantitated by stable isotope dilution and thermospray mass spectrometry. Infusion of either saline or SRI 63-675 alone caused no change in hexadecyl PAF concentrations. In contrast, endotoxin increased blood hexadecyl PAF concentrations from 1.5 +/- 0.1 ng/ml at 0 h (baseline) to a peak value of 8.3 +/- 1.9 ng/ml at 0.5 h of endotoxemia (P less than 0.05). Blood PAF levels gradually declined toward the baseline value after 0.5 h of endotoxemia. Because endotoxin did not modify plasma acetylhydrolase activity ex vivo, the increased hexadecyl PAF levels were probably secondary to increased PAF biosynthesis and not decreased biodegradation. Bioassay of RP-HPLC fractions that were derived from endotoxemic blood and that eluted at a retention time consistent with [3H]alkyl PAF caused aggregation of washed rabbit platelets that was inhibited by SRI 63-675. The PAF receptor antagonist blocked the 0.5 h endotoxin-induced increase in blood hexadecyl PAF concentration concomitant with blockade of thrombocytopenia. The endotoxin-induced pulmonary hypertension, decreased cardiac index, and increases in pulmonary vascular resistance and alveolar-arterial O2 gradient were attenuated by SRI 63-675. The data suggest that PAF-stimulated PAF biosynthesis may substantially contribute to blood hexadecyl PAF levels and cardiopulmonary dysfunction during the initial phase of endotoxemia.
我们评估了特异性血小板活化因子（PAF）受体拮抗剂SRI 63-675对猪内毒素血症4小时期间血流动力学和PAF生物合成的影响。从血液中提取十六烷基PAF，通过正相和反相高效液相色谱（RP-HPLC）进行纯化，并通过稳定同位素稀释和热喷雾质谱法定量。单独输注生理盐水或SRI 63-675均未引起十六烷基PAF浓度的变化。相比之下，内毒素使血液十六烷基PAF浓度从0小时（基线）时的1.5±0.1 ng/ml增加到内毒素血症0.5小时时的峰值8.3±1.9 ng/ml（P<0.05）。内毒素血症0.5小时后，血液PAF水平逐渐降至基线值。由于内毒素在体外未改变血浆乙酰水解酶活性，因此十六烷基PAF水平升高可能继发于PAF生物合成增加而非生物降解减少。对源自内毒素血症血液且在与[3H]烷基PAF一致的保留时间洗脱的RP-HPLC馏分进行生物测定，导致洗涤过的兔血小板聚集，该聚集被SRI 63-675抑制。PAF受体拮抗剂在阻断血小板减少症的同时，阻断了0.5小时内毒素诱导的血液十六烷基PAF浓度升高。SRI 63-675减轻了内毒素诱导的肺动脉高压、心脏指数降低以及肺血管阻力和肺泡-动脉氧梯度增加。数据表明，PAF刺激的PAF生物合成可能在内毒素血症初始阶段对血液十六烷基PAF水平和心肺功能障碍有很大贡献。
