Bopp Ch, Gust R, Taut F, Gries A, Martin E, Klein A
University of Heidelberg, Department of Anaesthesiology, Heidelberg, Germany.
Eur J Anaesthesiol. 2007 Apr;24(4):362-9. doi: 10.1017/S0265021506001463. Epub 2006 Nov 10.
In isolated-perfused lungs of lipopolysaccharide (LPS)-challenged rats, vasodilatation to inhaled nitric oxide (NO) is impaired. Inhibition of nitric oxide synthase 2 (NOS2) by aminoguanidine (AG) prevented hyporesponsiveness to inhaled NO. Here, we investigated whether NOS2-mediated nitrite/nitrate synthesis modulates responsiveness to inhaled NO.
Sprague-Dawley rats received intraperitoneally 0.5 mg kg(-1) LPS. Four hours later, LPS-treated rats received 3, 10 or 30 mg kg(-1) AG or 0.01, 0.1 or 1 mg kg(-1) S-methylisothiourea (SMT) by intraperitoneal injection. Sixteen to eighteen hours later, lungs were isolated and perfused, and pulmonary artery pressure (PAP) was elevated by 6-8 mmHg using the thromboxane analogue U46619. The decrease of PAP in response to inhaled NO and nitrate/nitrite levels in serum and perfusate was measured.
In rats treated with LPS alone or 0.01 or 0.1 mg kg(-1) SMT, 40 ppm NO decreased PAP less than in rats treated with AG and 1 mg kg(-1) SMT (-1.8 mmHg (95% confidence interval: -1.5 to -2.1) vs. -6.0 mmHg (-5.7 to -6.3), P < 0.01). Improved NO responsiveness was associated with lower serum and perfusate nitrite/nitrate levels than in rats with hyporesponsiveness to inhaled NO (102 micromol (82-122) vs. 282 micromol (261-303) and 8.1 micromol (6.9-9.3) vs. 19.8 micromol (17.2-22.4), respectively, P < 0.01).
These observations demonstrate that in isolated-perfused lungs of LPS-treated rats, NOS2 inhibition improved responsiveness to inhaled NO. Here, responsiveness to inhaled NO is dependent on the ability of NOS2 inhibitors to reduce nitrite and nitrate levels in serum and released in the lung.
在脂多糖（LPS）攻击的大鼠离体灌注肺中，对吸入一氧化氮（NO）的血管舒张作用受损。氨基胍（AG）抑制一氧化氮合酶2（NOS2）可预防对吸入NO的反应性降低。在此，我们研究了NOS2介导的亚硝酸盐/硝酸盐合成是否调节对吸入NO的反应性。
将0.5mg/kg LPS腹腔注射给Sprague-Dawley大鼠。4小时后，LPS处理的大鼠通过腹腔注射接受3、10或30mg/kg AG或0.01、0.1或1mg/kg S-甲基异硫脲（SMT）。16至18小时后，分离并灌注肺，使用血栓素类似物U46619使肺动脉压（PAP）升高6-8mmHg。测量吸入NO后PAP的降低以及血清和灌注液中的硝酸盐/亚硝酸盐水平。
单独用LPS或0.01或0.1mg/kg SMT处理的大鼠，40ppm NO使PAP降低的幅度小于用AG和1mg/kg SMT处理的大鼠（-1.8mmHg（95%置信区间：-1.5至-2.1）对-6.0mmHg（-5.7至-6.3），P<0.01）。与对吸入NO反应性降低的大鼠相比，NO反应性改善与血清和灌注液中亚硝酸盐/硝酸盐水平较低有关（分别为102μmol（82-122）对282μmol（261-303）以及8.1μmol（6.9-9.3）对19.8μmol（17.2-22.4），P<0.01）。
这些观察结果表明，在LPS处理的大鼠离体灌注肺中，抑制NOS2可改善对吸入NO的反应性。在此，对吸入NO的反应性取决于NOS2抑制剂降低血清和肺中释放的亚硝酸盐和硝酸盐水平的能力。
