Department of Anesthesiology, The University of Texas Medical Branch and Shriners Hospitals for Children, Galveston, Texas, USA.
Anesthesiology. 2010 Dec;113(6):1376-84. doi: 10.1097/ALN.0b013e3181fc5588.
Recent evidence suggests that nitric oxide produced via the neuronal nitric oxide synthase is involved mainly in the early response to sepsis, whereas nitric oxide derived from the inducible nitric oxide synthase is responsible during the later phase. We hypothesized that early neuronal and delayed inducible nitric oxide synthase blockade attenuates multiple organ dysfunctions during sepsis.
Sheep were randomly allocated to sham-injured, nontreated animals (n = 6); injured (48 breaths of cotton smoke and instillation of Pseudomonas aeruginosa into the lungs), nontreated animals (n = 7); and injured animals treated with a neuronal nitric oxide synthase inhibitor from 1 to 12 h and an inducible nitric oxide synthase inhibitor from 12 to 24 h postinjury (n = 6).
The injury induced arterial hypotension, vascular leakage, myocardial depression, and signs of renal and hepatic dysfunctions. The treatment significantly attenuated, but did not fully prevent, the decreases in mean arterial pressure and left ventricular stroke work index. Although the elevation of creatinine levels was partially prevented, the decreases in urine output and creatinine clearance were not affected. The injury-related increases in bilirubin levels, international normalized ratio, and lipid peroxidation in liver tissue were significantly attenuated. Although plasma nitrite/nitrate levels were significantly increased versus baseline from 12-24 h in controls, plasma nitrite/nitrate levels were not increased in treated animals.
The combination treatment shows potential benefit on sepsis-related arterial hypotension and surrogate parameters of organ dysfunctions in sheep. It may be crucial to identify the time course of expression and activation of different nitric oxide synthase isoforms in future investigations.
最近的证据表明，神经元型一氧化氮合酶产生的一氧化氮主要参与脓毒症的早期反应，而诱导型一氧化氮合酶产生的一氧化氮则在后期起作用。我们假设早期神经元型和延迟诱导型一氧化氮合酶阻断可减轻脓毒症期间的多器官功能障碍。
绵羊被随机分为假损伤、未治疗动物（n=6）；损伤（48 次棉烟雾呼吸和假单胞菌肺部滴注）、未治疗动物（n=7）；和损伤动物从损伤后 1 至 12 小时给予神经元型一氧化氮合酶抑制剂，从 12 至 24 小时给予诱导型一氧化氮合酶抑制剂（n=6）。
损伤引起动脉低血压、血管渗漏、心肌抑制以及肾功能和肝功能障碍的迹象。治疗显著减轻，但不能完全预防平均动脉压和左心室每搏功指数的降低。尽管肌酐水平的升高部分得到预防，但尿排量和肌酐清除率的降低不受影响。损伤相关的胆红素水平、国际标准化比值和肝组织脂质过氧化的升高明显减轻。尽管与对照组相比，血浆亚硝酸盐/硝酸盐水平从 12 至 24 小时显著升高，但治疗动物的血浆亚硝酸盐/硝酸盐水平并未升高。
联合治疗对绵羊脓毒症相关的动脉低血压和器官功能障碍的替代参数显示出潜在的益处。在未来的研究中，确定不同一氧化氮合酶同工型的表达和激活的时间过程可能至关重要。
