Attenuation of endotoxin‐induced multiple organ dysfunction by 1‐amino‐2‐hydroxy‐guanidine, a potent inhibitor of inducible nitric oxide synthase
Attenuation of endotoxin‐induced multiple organ dysfunction by 1‐amino‐2‐hydroxy‐guanidine, a potent inhibitor of inducible nitric oxide synthase
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1-氨基-2-羟基胍（诱导型一氧化氮合酶的有效抑制剂）可减轻内毒素引起的多器官功能障碍
DOI：
--
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发表时间：
1996
影响因子：
7.3
通讯作者：
C. Thiemermann
中科院分区：
文献类型：
--
作者：
H. Ruetten;G. Southan;A. Abate;C. Thiemermann
1研究了几种胍类化合物对体外培养的小鼠巨噬细胞和大鼠主动脉平滑肌细胞（RASM）诱导型一氧化氮（NO）合酶（iNOS）活性的影响;和（ii）1-氨基-2-羟基-胍，发现的最有效的iNOS活性抑制剂，对血液动力学，多器官内毒素休克大鼠肝、肾、胰功能障碍与iNOS活性的关系。2合成的胍类似物对J774.2巨噬细胞和RASM细胞中脂多糖（LPS，1 μm ml−1）引起的亚硝酸盐形成的增加产生浓度依赖性抑制作用，效力顺序如下：1-氨基-2-羟基胍> 1-氨基-2-甲基胍> 1-氨基-1-甲基胍> 1-氨基-1，2-二甲基胍。有趣的是，1-氨基-2-羟基胍（IC 50：J774.2，68 μm; RASM，114 μm）在抑制LPS引起的亚硝酸盐形成方面比NG-甲基-L-精氨酸更有效，但不如氨乙基-异硫脲有效。3LPS使麻醉大鼠的平均动脉压（MAP）从115 ± 4 mmHg（时间0）下降到2 h的98 ± 5 mmHg（P<0.05，n=10）和6 h的69±5 mmHg（P<0.05，n= 10）。去甲肾上腺素（NA，1 mg kg−1，i. v.）在LPS后1至6 h也显著降低（血管低反应性）。用1-氨基-2-羟基-胍（10 mg kg−1，i. v.+10 mg kg−1 h−1，从LPS后2 h开始）处理LPS大鼠可预防LPS大鼠中观察到的迟发性低血压和血管低反应性。然而，1-氨基-2-羟基-胍对注射生理盐水而不是LPS的大鼠的MAP或NA引起的升压作用均无影响。4内毒素血症6小时导致血清天冬氨酸或丙氨酸氨基转移酶（即GOT或GPT）和胆红素水平显著升高，因此导致肝功能障碍。用1-氨基-2-羟基-胍处理LPS-大鼠显著减轻LPS引起的肝功能损害（P<0.05，n= 10）。注射LPS还引起血清尿素和肌酐水平的快速（几乎在2小时时达到最大）增加，因此，肾功能不全。1-氨基-2-羟基胍对肾功能不全无影响（P>0.05; n= 10）。内毒素血症还引起胰腺功能障碍（血清脂肪酶水平升高）以及代谢性酸中毒（PCO 2、HCO 3和碱过量福尔斯下降）。用1-氨基-2-羟基-胍处理LPS-大鼠，胰腺功能障碍和代谢性酸中毒均大大减轻。在输注生理盐水而非LPS的大鼠中，1-氨基-2-羟基-胍对肝脏、肾脏或胰腺功能无影响（n=4）。5内毒素血症6 h后，血清亚硝酸盐浓度升高（11.0±0.8 μm，P<0.01，n=10），1-氨基-2-羟基胍可显著降低血清亚硝酸盐浓度（6.5±0.7 μm，P<0.05，n=10）。内毒素血症6 h也与肺和肝中iNOS活性显著增加相关，在1-氨基-2-羟基-胍处理的LPS-大鼠的肺或肝匀浆中，iNOS活性显著降低。此外，内毒素血症6小时导致髓过氧化物酶活性（MPO），中性粒细胞浸润的指标，在肝脏中的显着增加。用1-氨基-2-羟基-胍处理LPS大鼠不会影响内毒素引起的肝脏MPO活性升高。6因此，1-氨基-2-羟基-胍是培养的巨噬细胞或RASM以及内毒素休克大鼠中iNOS活性的有效抑制剂。用l-氨基-2-羟基-胍抑制iNOS活性可预防迟发性循环衰竭，减轻肝脏和胰腺功能障碍以及内毒素血症引起的代谢性酸中毒。
1 We have investigated the effects of (i) several guanidines on the activity of the inducible isoform of nitric oxide (NO) synthase (iNOS) in murine cultured macrophages and rat aortic vascular smooth muscle cells (RASM); and (ii) 1‐amino‐2‐hydroxy‐guanidine, the most potent inhibitor of iNOS activity discovered, on haemodynamics, multiple organ (liver, renal, and pancreas) dysfunction and iNOS activity in rats with endotoxic shock. 2 The synthesized guanidine analogues caused concentration‐dependent inhibitions of the increase in nitrite formation caused by lipopolysaccaride (LPS, 1 μm ml−1) in J774.2 macrophages and RASM cells with the following rank order of potency: 1‐amino‐2‐hydroxy‐guanidine> 1‐amino‐2‐methyl‐guanidine> 1‐amino‐1‐methy 1‐guanidine> 1‐amino‐1,2‐dimethyl‐guanidine. Interestingly, 1‐amino‐2‐hydroxyguanidine (IC50: J774.2, 68 μm; RASM, 114 μm) was more potent in inhibiting nitrite formation caused by LPS than NG‐methyl‐L‐arginine, but less potent than aminoethyl‐isothiourea. 3 In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 115 ± 4 mmHg (time 0) to 98 ± 5 mmHg at 2 h (P<0.05, n=10) and 69±5 mmHg at 6 h (P<0.05, n= 10). The pressor effect of noradrenaline (NA, 1 mg kg−1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS‐rats with 1‐amino‐2‐hydroxy‐guanidine (10 mg kg−1, i.v. plus 10 mg kg−1 h−1 starting at 2 h after LPS) prevented the delayed hypotension and vascular hyporeactivity seen in LPS‐rats. However, 1‐amino‐2‐hydroxy‐guanidine had no effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 4 Endotoxaemia for 6 h caused a significant rise in the serum levels of aspartate or alanine aminotransferase (i.e. GOT or GPT) and bilirubin, and hence, liver dysfunction. Treatment of LPS‐rats with 1‐amino‐2‐hydroxy‐guanidine significantly attenuated the liver dysfunction caused by LPS (P<0.05, n= 10). Injection of LPS also caused a rapid (almost maximal at 2 h) increase in the serum levels of urea and creatinine, and hence, renal dysfunction. This renal dysfunction was not affected by 1‐amino‐2‐hydroxy‐guanidine (P>0.05; n= 10). Endotoxaemia also caused a dysfunction of pancreas (rise in serum levels of lipase) as well as a metabolic acidosis (falls in PCO2, HCO3 and base excess). Both pancreatic dysfunction and metabolic acidosis were largely attenuated by treatment of LPS‐rats with 1‐amino‐2‐hydroxy‐guanidine. In rats infused with saline rather than LPS, 1‐amino‐2‐hydroxy‐guanidine had no effect on liver, renal or pancreatic function (n=4). 5 Endotoxaemia for 6 h resulted in a rise in the serum levels of nitrite (11.0±0.8 μm, P<0.01, n=10), which was significantly reduced by 1‐amino‐2‐hydroxy‐guanidine (6.5±0.7 μm, P<0.05, n=10). Endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver, which was significantly reduced in lung or liver homogenates obtained from LPS‐rats treated with 1‐amino‐2‐hydroxy‐guanidine. In addition, endotoxaemia for 6 h resulted in a significant increase in myeloperoxidase activity (MPO), an indicator of neutrophil infiltration, in the liver. Treatment of LPS‐rats with 1‐amino‐2‐hydroxy‐guanidine did not affect the rise in MPO‐activity in the liver caused by endotoxin. 6 Thus, 1‐amino‐2‐hydroxy‐guanidine is a potent inhibitor of iNOS activity in macrophages or RASM in culture as well as in rats with endotoxic shock. Inhibition of iNOS activity with l‐amino‐2‐hydroxy‐guanidine prevents the delayed circulatory failure and attenuates the dysfunction of liver, and pancreas, as well as the metabolic acidosis caused by endotoxaemia.
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人肝细胞中诱导型一氧化氮合酶的分子克隆和表达
DOI：
10.1073/pnas.90.8.3491
发表时间：
1993-04-15
影响因子：
11.1
作者：
GELLER, DA;LOWENSTEIN, CJ;BILLIAR, TR
通讯作者：
BILLIAR, TR
影响因子：
5
作者：
T. P. Misko;W. M. Moore;T. Kasten;G. Nickols;J. Corbett;R. Tilton;M. Mcdaniel;J. Williamson;M. Currie
通讯作者：
T. P. Misko;W. M. Moore;T. Kasten;G. Nickols;J. Corbett;R. Tilton;M. Mcdaniel;J. Williamson;M. Currie
暴露于革兰氏阴性菌脂多糖的大鼠的肝损伤是由凝血系统而非循环纤维蛋白原引起的。
DOI：
--
发表时间：
1995
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Hewett,JA;Roth,RA
通讯作者：
Roth,RA
影响因子：
56.9
作者：
STAMLER, JS;SINGEL, DJ;LOSCALZO, J
通讯作者：
LOSCALZO, J
人类诱导型一氧化氮合酶基因的分子克隆、结构和染色体定位。
DOI：
--
发表时间：
1994
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Chartrain,NA;Geller,DA;Koty,PP;Sitrin,NF;Nussler,AK;Hoffman,EP;Billiar,TR;Hutchinson,NI;Mudgett,JS
通讯作者：
Mudgett,JS