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的血流动力学不稳定和死亡密切相关。尽管如此，旨在抑制诱导型一氧化氮合酶(NOS)的药物，在增加血压的同时，会恶化脓毒症患者的预后。因此，目前正在研究抑制NO潜在有害影响的替代方法。一种这样的试剂是二乙基三氨基五乙酸铁(DTPA)。这种试剂是一种低分子量的游离NO清除剂，不会直接改变NOS的功能。静脉注射高致死量的大肠杆菌后，注射DTPA Iron III可降低血管内硝酸盐水平，提高存活率，但对血流动力学没有明显影响。我们研究了在血管外感染部位的动物模型中，同样的药物是否会有类似的有益效果。 通过支气管内或血管内途径给大鼠注射剂量的大肠杆菌，以产生高致死率。然后，他们接受了一系列剂量的DTPA Iron III或安慰剂的治疗。连续监测血压、心率和循环细胞介质24小时，观察生存期168小时。正如基于其清除NO的作用所预期的那样，增加DTPA Iron III的剂量会导致血压按剂量顺序增加。然而，无论是在支气管内还是血管内注射DTPA Iron III，都不能提高存活率，而且在大多数情况下存活率都会降低。因此，在这种脓毒症大鼠模型中，DTPA Iron III似乎与在脓毒症患者中使用NOS抑制剂观察到的效果非常相似。更多的实验现在已经完成，证实了这些发现。

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.