Lortie Mark J, Satriano Joseph, Gabbai Francis B, Thareau Sonia, Khang Ser, Deng Aihua, Pizzo Donald P, Thomson Scott C, Blantz Roland C, Munger Karen A
Division of Nephrology and Hypertension, School of Medicine, University of California-San Diego, San Diego, CA 92093, USA.
Am J Physiol Regul Integr Comp Physiol. 2004 Dec;287(6):R1434-40. doi: 10.1152/ajpregu.00373.2004. Epub 2004 Aug 12.
Lipopolysaccharide (LPS) is used experimentally to elicit the innate physiological responses observed in human sepsis. We have previously shown that LPS causes depletion of plasma arginine before inducible nitric oxide synthase (iNOS) activity, indicating that changes in arginine uptake and/or production rather than enhanced consumption are responsible. Because the kidney is the primary source of circulating arginine and renal failure is a hallmark of septicemia, we determined the time course of changes in arginine metabolism and kidney function relative to iNOS expression. LPS given intravenously to anesthetized rats caused a decrease in mean arterial blood pressure after 120 min that coincided with increased plasma nitric oxide end products (NOx) and iNOS expression in lung and liver. Interestingly, impairment of renal function preceded iNOS activity by 30-60 min and occurred in tandem with decreased renal arginine production. The baseline rate of renal arginine production was approximately 60 micromol.h(-1).kg(-1), corresponding to an apparent plasma half-life of approximately 20 min, and decreased by one-half within 60 min of LPS. Calculations based on the systemic production and clearance show that normally only 5% of kidney arginine output is destined to become nitric oxide and that <25% of LPS-impaired renal production was converted to NOx in the first 4 h. In addition, we provide novel observations indicating that the kidney appears refractory to iNOS induction by LPS because no discernible enhancement of renal NOx production occurred within 4 h, and iNOS expression in the kidney was muted compared with that in liver or lung. These studies demonstrate that the major factor responsible for the rapid decrease in extracellular arginine content following LPS is impaired production by the kidney, a phenomenon that appears linked to reduced renal perfusion.
脂多糖（LPS）在实验中用于引发人类败血症中观察到的先天性生理反应。我们之前已经表明，LPS在诱导型一氧化氮合酶（iNOS）活性出现之前会导致血浆精氨酸耗竭，这表明精氨酸摄取和/或生成的变化而非消耗增加是其原因。由于肾脏是循环精氨酸的主要来源，且肾衰竭是败血症的一个标志，我们确定了精氨酸代谢和肾功能相对于iNOS表达的变化时间进程。给麻醉大鼠静脉注射LPS后120分钟，平均动脉血压下降，这与肺和肝脏中血浆一氧化氮终产物（NOx）增加以及iNOS表达增加同时发生。有趣的是，肾功能损害比iNOS活性提前30 - 60分钟出现，并且与肾脏精氨酸生成减少同时发生。肾脏精氨酸生成的基线速率约为60微摩尔·小时⁻¹·千克⁻¹，对应于约20分钟的表观血浆半衰期，在LPS注射后60分钟内下降了一半。基于全身生成和清除的计算表明，正常情况下只有5%的肾脏精氨酸输出会转化为一氧化氮，并且在最初4小时内，LPS损害的肾脏生成中<25%转化为NOx。此外，我们提供了新的观察结果，表明肾脏似乎对LPS诱导iNOS不敏感，因为在4小时内肾脏NOx生成没有明显增强，并且与肝脏或肺相比，肾脏中的iNOS表达受到抑制。这些研究表明，LPS后细胞外精氨酸含量迅速下降的主要因素是肾脏生成受损，这一现象似乎与肾脏灌注减少有关。
