Handley D A, Van Valen R G, Tomesch J C, Melden M K, Jaffe J M, Ballard F H, Saunders R N
Immunopharmacology. 1987 Apr;13(2):125-32. doi: 10.1016/0162-3109(87)90049-x.
Intravenous administration of platelet-activating factor (PAF) produces dose-dependent hypotension in several species. We have evaluated a recently developed PAF antagonist, SRI 63-441, for its ability to inhibit the hypotensive effect of PAF in the rat and dog. In the rat, 100 ng/kg PAF produced a 38.6 +/- 5.1% decrease in carotid mean arterial pressure (MAP), followed by a 3.2 +/- 0.7 min recovery period for MAP to return to baseline values. SRI 63-441 reduced the hypotension response in the rat, where the ED50 values for inhibition of MAP were 0.16 mg/kg i.v. and 0.19 mg/kg i.v. for the recovery period. Dogs challenged with 1.5 micrograms/kg PAF i.v. demonstrated a 52 +/- 8% decrease in MAP that persisted for at least 15 min. The ED50 for inhibition of MAP by SRI 63-441 was 0.20 mg/kg i.v. Following injection of tritium-labeled SRI 63-441, 56.8 +/- 2.4% of the dose was recovered in the urine and 43.2 +/- 8.9% in the feces in the rats while in dogs 38.7 +/- 5.6% and 60.9 +/- 23.5% of the dose was excreted in the urine and feces, respectively. In the rat model of endotoxin-induced hypotension, SRI 63-441 given 1 min after a 5 mg/kg endotoxin challenge (which produced a 52 +/- 7% decrease in MAP), reversed the systemic effects, with an ED50 of 0.18 mg/kg i.v. The ED50 for reversal 6 min after endotoxin injection was 0.01 mg/kg. These results of inhibition and reversal by SRI 63-441 strongly implicate PAF as a pivotal mediator of hypotension and shock.
静脉注射血小板活化因子（PAF）在多种动物中会产生剂量依赖性低血压。我们评估了一种新开发的PAF拮抗剂SRI 63 - 441抑制PAF对大鼠和犬类低血压作用的能力。在大鼠中，100 ng/kg的PAF使颈动脉平均动脉压（MAP）降低38.6±5.1%，随后MAP恢复至基线值需要3.2±0.7分钟的恢复期。SRI 63 - 441减轻了大鼠的低血压反应，抑制MAP的ED50值在静脉注射时为0.16 mg/kg，恢复期为0.19 mg/kg。静脉注射1.5μg/kg PAF的犬类，MAP降低了52±8%，且持续至少15分钟。SRI 63 - 441抑制MAP的ED50为静脉注射0.20 mg/kg。注射氚标记的SRI 63 - 441后，大鼠尿液中回收了56.8±2.4%的剂量，粪便中回收了43.2±8.9%；而在犬类中，分别有38.7±5.6%和60.9±23.5%的剂量经尿液和粪便排出。在内毒素诱导的大鼠低血压模型中，在5 mg/kg内毒素攻击（使MAP降低52±7%）1分钟后给予SRI 63 - 441，可逆转全身效应，静脉注射的ED50为0.18 mg/kg。内毒素注射6分钟后逆转的ED50为0.01 mg/kg。SRI 63 - 441的这些抑制和逆转结果有力地表明PAF是低血压和休克的关键介质。
