Matejovic Martin, Krouzecky Ales, Martinkova Vendula, Rokyta Richard, Kralova Hana, Treska Vladislav, Radermacher Peter, Novak Ivan
Intensive Care Unit, 1st Medical Department, Charles University, Plzen, Czech Republic.
Shock. 2004 May;21(5):458-65. doi: 10.1097/00024382-200405000-00010.
We have recently demonstrated that selective inducible nitric oxide (NO) synthase (iNOS) inhibition with 1400W attenuated the hemodynamic and metabolic alterations affiliated with hyperdynamic porcine endotoxemia. In contrast to endotoxemia, limited evidence is available to document a relationship between NO and organ dysfunction in large animal bacteremic models. Therefore, using the same experimental setup, we investigated the role of selective iNOS blockade in porcine bacteremia induced and maintained for 24 h with a continuous infusion of live Pseudomonas aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n = 8) or continuous infusion of selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysine (L-NIL; n = 8). Measurements were performed before, and 12, 18, and 24 h after P. aeruginosa infusion. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite concentrations and prevented hypotension without affecting cardiac output. Despite comparable hepatosplanchnic macrocirculation, L-NIL blunted the progressive deterioration in ileal mucosal microcirculation and prevented mucosal acidosis. L-NIL largely attenuated mesenteric and hepatic venous acidosis, significantly improved P. aeruginosa-induced impairment of hepatosplanchnic redox state, and mitigated the decline in liver lactate clearance. Furthermore, the administration of L-NIL reduced the hepatocellular injury and prevented the development of renal dysfunction. Finally, treatment with L-NIL significantly attenuated the formation of 8-isoprostane concentrations, a direct marker of lipid peroxidation. Thus, selective iNOS inhibition with L-NIL prevented live bacteria from causing key features of metabolic derangements in porcine hyperdynamic sepsis. Underlying mechanisms probably include reduced oxidative stress with improved microcirculatory perfusion and restoration of cellular respiration.
我们最近证明,用1400W选择性诱导型一氧化氮(NO)合酶(iNOS)抑制可减轻与高动力型猪内毒素血症相关的血流动力学和代谢改变。与内毒素血症不同,在大型动物菌血症模型中,关于NO与器官功能障碍之间关系的证据有限。因此,我们使用相同的实验装置,研究了选择性iNOS阻断在持续输注活的铜绿假单胞菌诱导并维持24小时的猪菌血症中的作用。脓毒症12小时后,动物接受载体(对照组,n = 8)或持续输注选择性iNOS抑制剂L-N6-(1-亚氨基乙基)-赖氨酸(L-NIL;n = 8)。在铜绿假单胞菌输注前以及输注后12、18和24小时进行测量。L-NIL抑制了脓毒症诱导的血浆硝酸盐/亚硝酸盐浓度升高,并预防了低血压,而不影响心输出量。尽管肝脾大循环相当,但L-NIL减轻了回肠黏膜微循环的进行性恶化,并预防了黏膜酸中毒。L-NIL在很大程度上减轻了肠系膜和肝静脉酸中毒,显著改善了铜绿假单胞菌诱导的肝脾氧化还原状态损害,并减轻了肝脏乳酸清除率的下降。此外,L-NIL的给药减少了肝细胞损伤,并预防了肾功能障碍的发生。最后,用L-NIL治疗显著减轻了8-异前列腺素浓度的形成,8-异前列腺素是脂质过氧化的直接标志物。因此,用L-NIL选择性抑制iNOS可防止活菌在猪高动力型脓毒症中引起代谢紊乱的关键特征。潜在机制可能包括氧化应激降低、微循环灌注改善和细胞呼吸恢复。