Nitric Oxide Inhibition With DTPA/Fe3--Rat Model Sepsis

一氧化氮（NO）的过量产生与脓毒症和感染性休克时血流动力学的不稳定和死亡密切相关。尽管如此，旨在抑制诱导型NO合酶（NOS）的药物，同时增加血压，恶化了脓毒症患者的结局。因此，目前正在研究抑制NO潜在有害作用的替代方法。一种这样的试剂是二乙基三胺五乙酸（DTPA）铁III。该试剂是游离NO的低分子量清除剂，其不直接改变NOS功能。在用高致死剂量的静脉内E.大肠杆菌降低血管内硝酸盐水平，提高生存率，但对血液动力学没有明显影响。我们研究了这种相同的药物是否会在采用血管外感染部位的动物模型中具有类似的有益效果。 用E.大肠杆菌通过支气管内或血管内途径设计，以产生高致死率。然后，他们接受DTPA铁III在一定剂量范围内或安慰剂治疗。连续测量血压、心率和循环细胞介质24小时，观察存活168小时。正如基于其对NO的清除所预期的那样，增加剂量的DTPA铁III导致血压的剂量顺序升高。然而，没有剂量的DTPA铁III，无论是支气管内或血管内E。大肠杆菌提高了存活率，在大多数情况下，存活率降低。因此，在该脓毒症大鼠模型中，DTPA铁III似乎与脓毒症患者中使用NOS抑制剂观察到的效果非常相似。现在已经完成了更多的实验来证实这些发现。

Excessive nitric oxide (NO) production has been closely associated with the hemodynamic instability and death occurring during sepsis and septic shock. Despite this, agents designed to inhibit the inducible form of NO synthase (NOS), while increasing blood pressure, worsened outcome in patients with sepsis. Alternative methods for inhibiting the potentially harmful effects of NO are therefore now under study. One such agent is diethyltriaminepentacetate (DTPA) Iron III. This agent is a low molecular weight scavenger of free NO which does not directly alter NOS function. Administration of DTPA Iron III in baboons challenged with a highly lethal dose of intravenous E. coli reduced intravascular nitrate levels and improved survival but did not have observable effects on hemodynamics. We studied whether this same agent would have similar beneficial effects in an animal model employing an extravascular site of infection. Rats were challenged with doses of E. coli via either intrabronchial or intravascular routes designed to produce high lethality rates. They were then treated with DTPA Iron III over a range of doses or placebo. Blood pressure, heart rate and circulating cellular mediators were measured continuously for 24 hours and survival was observed for 168 hours. As would be expected based on its scavenging of NO, increasing doses of DTPA Iron III resulted in dose ordered increases in blood pressure. However, no dose of DTPA Iron III, with either intrabronchial or intravascular E. coli improved survival rates, and in most cases survival rates were reduced. Thus in this rat model of sepsis, DTPA Iron III appeared to have very similar effects to those observed with NOS inhibitors in patients with sepsis. Additional experiments have now been completed substantiating these findings.