Pullamsetti Soni Savai, Maring Daniel, Ghofrani Hossein Ardeschir, Mayer Konstantin, Weissmann Norbert, Rosengarten Bernhard, Lehner Martin, Schudt Christian, Boer Rainer, Grimminger Friedrich, Seeger Werner, Schermuly Ralph Theo
Departmennt of Internal Medicine, Justus-Liebig-University Giessen, Klinikstrasse 36, 35392 Giessen, Germany.
Thromb Haemost. 2006 Apr;95(4):720-7.
Treatment of hemodynamic instability in septic shock often demands the administration of vasopressor agents, although these may have deleterious effects on microcirculatory homeostasis. Inhibition of nitric oxide synthase (NOS) has been suggested as an alternative therapeutic approach, as NO formation may be excessively increased in sepsis. To compare the effects of epinephrine titration, non-selective NOS inhibition by L-NMMA and selective inhibition of inducible NOS (iNOS) by 1400W on hemodynamics and on the regulation of microcirculation in a rat model of endotoxic shock, we intravenously injected endotoxin (LPS) or saline to male Wistar rats and after 2 hours randomized LPS treated rats into four different groups that received either saline, norepinephrine, L-NMMA or 1400W (n = 6 per group). Three hours after LPS administration, rats presented with severe systemic arterial hypotension (64 +/- 3 vs. 115 +/- 4 mmHg, p < 0.001), unresponsiveness to volume treatment, lactate acidosis and a marked increase in plasmatic nitrite and nitrate levels (15 +/- 8 vs. 263 +/- 47 microM, p < 0.001). Measurement of the tissue oxygenation in the ileum mucosal layer by the Erlangen micro-lightguide spectrophotometer (EMPHO) technique demonstrated marked heterogeneity of hemoglobin saturation, with appearance of low oxygenated areas. Norepinephrine, usually stabilizing blood pressure (99 +/- 7 vs. 67 +/- 4 mmHg 60 min after infusion, p < 0.01), increased lactate formation (7.9 +/- 0.2 vs. 3.7 +/- 0.5 mM, p < 0.001) and drastically increased low oxygenated regions in the ileum mucosal layer. L-NMMA similarly increased blood pressure (92 +/- 6 vs. 67 +/- 4 mmHg 60 min after infusion, p < 0.05), but did not enhance lactate acidosis. However, some further deterioration of mucosa oxygenation was again noted. 1400W forwarded stabilization of blood pressure (88 +/- 5 vs. 67 +/- 4 mmHg 60 min after injection, p < 0.05), reduced plasmatic nitrite and nitrate levels similar to L-NMMA, without an aggravation of lactate acidosis. In addition, mucosal oxygenation did not deteriorate in response to this agent. Thereby, we conclude that in a rat model of endotoxic shock selective iNOS inhibitors are superior to non-specific NOS inhibitors and in particular to norepinephrine for the treatment of macro- and microcirculatory abnormalities in experimental septic shock.
感染性休克血流动力学不稳定的治疗通常需要使用血管升压药，尽管这些药物可能对微循环稳态产生有害影响。由于脓毒症时一氧化氮（NO）生成可能过度增加，因此抑制一氧化氮合酶（NOS）被认为是一种替代治疗方法。为了比较肾上腺素滴定、L-NMMA非选择性抑制NOS以及1400W选择性抑制诱导型NOS（iNOS）对内毒素休克大鼠模型血流动力学和微循环调节的影响，我们给雄性Wistar大鼠静脉注射内毒素（LPS）或生理盐水，2小时后将接受LPS治疗的大鼠随机分为四组，分别接受生理盐水、去甲肾上腺素、L-NMMA或1400W（每组n = 6）。给予LPS 3小时后，大鼠出现严重的全身性动脉低血压（64±3 vs. 115±4 mmHg，p < 0.001），对容量治疗无反应，乳酸酸中毒，血浆亚硝酸盐和硝酸盐水平显著升高（15±8 vs. 263±47 μM，p < 0.001）。用埃尔朗根微光导分光光度计（EMPHO）技术测量回肠黏膜层组织氧合，结果显示血红蛋白饱和度存在明显异质性，出现低氧区域。去甲肾上腺素通常可稳定血压（输注60分钟后为99±7 vs. 67±4 mmHg，p < 0.01），但会增加乳酸生成（7.9±0.2 vs. 3.7±0.5 mM，p < 0.001），并使回肠黏膜层低氧区域急剧增加。L-NMMA同样可升高血压（输注60分钟后为92±6 vs. 67±4 mmHg，p < 0.05），但不会加重乳酸酸中毒。然而，再次观察到黏膜氧合有进一步恶化。1400W可促进血压稳定（注射60分钟后为88±5 vs. 67±4 mmHg，p < 0.05），与L-NMMA类似，可降低血浆亚硝酸盐和硝酸盐水平，且不会加重乳酸酸中毒。此外，该药物不会导致黏膜氧合恶化。因此，我们得出结论，在内毒素休克大鼠模型中，选择性iNOS抑制剂在治疗实验性感染性休克的大循环和微循环异常方面优于非特异性NOS抑制剂，尤其优于去甲肾上腺素。
