ASSOCIATION OF MICROVASCULAR LEAKAGE WITH INDUCTION OF NITRIC-OXIDE SYNTHASE - EFFECTS OF NITRIC-OXIDE SYNTHASE INHIBITORS IN VARIOUS ORGANS
ASSOCIATION OF MICROVASCULAR LEAKAGE WITH INDUCTION OF NITRIC-OXIDE SYNTHASE - EFFECTS OF NITRIC-OXIDE SYNTHASE INHIBITORS IN VARIOUS ORGANS
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DOI：
10.1016/0014-2999(95)00281-o
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发表时间：
1995-09-05
影响因子：
5
通讯作者：
MONCADA, S
中科院分区：
文献类型：
--
作者：
LASZLO, F;WHITTLE, BJR;MONCADA, S
内毒素（大肠埃希菌脂多糖0111：B4，3 mg/kg i. v.）诱导钙非依赖性一氧化氮（NO）合酶的表达，通过放射性标记的L-精氨酸转化为L-瓜氨酸进行评估，在心脏、肝脏、肺和肾脏组织中5小时后测定。通过放射性标记人血清白蛋白的血管渗漏评估，在这些清醒大鼠中广泛诱导NO合酶与微血管损伤相关。同时施用NO合酶抑制剂N-G-硝基-L-精氨酸甲酯（L-NAME，1-5 mg/kg s.c.）与内毒素一起，在2小时内在各种器官中引起急性血管渗漏。相比之下，延迟注射L-NAME（1-5 mg/kg s.c.）或N-G-单甲基-L-精氨酸（12.5-50 mg/kg s.c.）直到内毒素攻击后3小时，抑制了这些器官中随后的微血管渗漏。NO合酶抑制剂的这些作用被L-精氨酸（300 mg/kg s.c.）预处理这些结果支持了组成型NO合酶在内毒素休克早期的保护作用。这些作用与诱导型NO合酶的产物在内毒素血症状态下广泛微血管损伤的发展中的积极作用形成对比。
Endotoxin (Escherichia coli lipopolysaccharide 0111:B4, 3 mg/kg i.v.) induced the expression of a calcium-independent nitric oxide (NO) synthase, determined after 5 h in cardiac, hepatic, pulmonary and renal tissues, as assessed by the conversion of radiolabelled L-arginine to L-citrulline. This widespread induction of NO synthase in these conscious rats was associated with microvascular injury, as assessed by the vascular leakage of radiolabelled human serum albumin. Concurrent administration of the NO synthase inhibitor, N-G-nitro-L-arginine methyl ester (L-NAME, 1-5 mg/kg s.c.) with endotoxin, provoked acute vascular leakage within 2 h in the various organs. By contrast, the delayed injection of L-NAME (1-5 mg/kg s.c.) or N-G-monomethyl-L-arginine (12.5-50 mg/kg s.c.) until 3 h after endotoxin challenge inhibited the subsequent microvascular leakage in these organs. These effects of NO synthase inhibitors were reversed by L-arginine (300 mg/kg s.c.) pretreatment. These results support a protective role of constitutive NO synthase in the early phase of endotoxin shock. Such actions contrast with the aggressive actions of the products of inducible NO synthase in the development of widespread microvascular injury in endotoxemic states.