一氧化氮合酶抑制剂N（G）-硝基-L-精氨酸甲酯和氨基乙基异硫脲对大鼠内毒素血症肝脏微循环的影响。

Effects of the nitric oxide synthase inhibitors N(G)-nitro-L-arginine methyl ester and aminoethyl-isothiourea on the liver microcirculation in rat endotoxemia.

作者信息

Corso C O, Gundersen Y, Dörger M, Lilleaasen P, Aasen A O, Messmer K

机构信息

Institute for Surgical Research, Munich University, Germany.

出版信息

J Hepatol. 1998 Jan;28(1):61-9. doi: 10.1016/s0168-8278(98)80203-1.

DOI:10.1016/s0168-8278(98)80203-1

PMID:9537865

Abstract

BACKGROUND/METHODS: The question whether nitric oxide protects or impairs organ perfusion during early endotoxemia has not been completely answered. To evaluate the regulative function of nitric oxide on organ microvascular perfusion and leukocyte accumulation during endotoxemia, we studied the influence of a non-selective nitric oxide inhibitor and a preferential inducible nitric oxide synthase inhibitor (respectively, N(G)-nitro-L-arginine methyl ester and aminoethyl-isothiourea) on liver microcirculation (intravital fluorescence microscopy) in a rat model.

RESULTS

Two hours after intraportal injection of lipopolysaccharide (5 mg/kg in 10 min) the rats were randomly treated and received a bolus dose of N(G)-nitro-L-arginine methyl ester (10 mg/kg, n = 7), aminoethyl-isothiourea (10 mg/kg, n = 6) or normal saline, (n = 7). After 1 h, N(G)-nitro-L-arginine methyl ester blockade yielded a higher rate of non-perfused sinusoids than normal saline (27 +/- 2% vs 19 +/- 5%, p < 0.05). LPS-induced leukocyte stagnation in sinusoids was further increased (p < 0.05) in all groups after 1 h treatment, but N(G)-nitro-L-arginine methyl ester clearly accentuated leukocyte accumulation in sinusoids as compared to normal saline (69 +/- 19% vs 16 +/- 4%, p < 0.05). Both modalities of nitric oxide blockade elicited a significant enhancement in the number of leukocytes adherent to the postsinusoidal venules in contrast to normal saline (N(G)-nitro-L-arginine methyl ester 48 +/- 17%, aminoethyl-isothiourea 33 +/- 9% vs normal saline 1 +/- 5%, p < 0.05).

CONCLUSIONS

We conclude that complete nitric oxide blockade aggravates lipopolysaccharide-induced hepatic microvascular perfusion failure and enhances leukocyte accumulation, in both sinusoids and post-sinusoidal venules. The preferential inducible nitric oxide synthase inhibitor aminoethyl-isothiourea has a moderate negative effect, favoring leukocyte adhesion in postsinusoidal venules, and its usefulness demands further research, especially concerning its late effects.

摘要

背景/方法：关于一氧化氮在早期内毒素血症期间对器官灌注是起保护作用还是损害作用的问题尚未得到完全解答。为了评估一氧化氮在内毒素血症期间对器官微血管灌注和白细胞聚集的调节功能，我们在大鼠模型中研究了一种非选择性一氧化氮抑制剂和一种选择性诱导型一氧化氮合酶抑制剂（分别为N(G)-硝基-L-精氨酸甲酯和氨基乙基异硫脲）对肝脏微循环（活体荧光显微镜检查）的影响。

结果

在门静脉内注射脂多糖（5毫克/千克，10分钟内注射完毕）两小时后，将大鼠随机分组并分别给予一次大剂量的N(G)-硝基-L-精氨酸甲酯（10毫克/千克，n = 7）、氨基乙基异硫脲（10毫克/千克，n = 6）或生理盐水（n = 7）。1小时后，N(G)-硝基-L-精氨酸甲酯阻断组未灌注的肝血窦比例高于生理盐水组（27±2%对19±5%，p < 0.05）。治疗1小时后，脂多糖诱导的肝血窦内白细胞停滞在所有组中均进一步增加（p < 0.05），但与生理盐水组相比，N(G)-硝基-L-精氨酸甲酯明显加剧了肝血窦内白细胞的聚集（69±19%对16±4%，p < 0.05）。与生理盐水组相比，两种一氧化氮阻断方式均使肝血窦后小静脉上黏附的白细胞数量显著增加（N(G)-硝基-L-精氨酸甲酯组为48±17%，氨基乙基异硫脲组为33±9%，生理盐水组为1±5%，p < 0.05）。