Munger Karen A, Blantz Roland C, Lortie Mark J
Department of Internal Medicine, University of South Dakota School of Medicine, Sioux Falls, USA.
Am J Physiol Regul Integr Comp Physiol. 2006 Sep;291(3):R684-91. doi: 10.1152/ajpregu.00873.2005. Epub 2006 Apr 13.
We have previously shown in rats that lipopolysaccharide (LPS) causes both decreased renal perfusion and kidney arginine production before nitric oxide (NO) synthesis, resulting in a >30% reduction in plasma arginine. To clarify the early phase effects of LPS, we asked the following two questions: 1) is the rapid change in renal arginine production after LPS simply the result of decreased substrate (i.e., citrulline) delivery to the kidney or due to impaired uptake and conversion and 2) is the systemic production of NO limited by plasma arginine availability after LPS? Arterial and renal vein plasma was sampled at 30-min intervals from anesthetized rats with or without citrulline or arginine (2 micromol.min(-1).kg(-1) iv) a dose with no effect on MAP, renal function, or NO production. Exogenous citrulline was quickly converted to arginine by the kidney, resulting in plasma levels similar to equimolar arginine infusion. Also, the increase in citrulline uptake resulted primarily from increased filtered load and reabsorption. In a separate series, citrulline was infused after LPS administration, verifying that citrulline uptake and conversion persists during impaired kidney function. Last, in rats given LPS, the elevation of plasma arginine had no discernable impact on mean arterial pressure, kidney function, or systemic NO production. This work demonstrates how arginine synthesis is normally "substrate limited" and explains how impaired kidney perfusion quickly results in decreased plasma arginine. However, contrary to in vitro studies, the significant reduction in extracellular arginine during the early phase response to LPS in vivo is not functionally rate limiting for NO production.
我们之前在大鼠中发现，脂多糖（LPS）在一氧化氮（NO）合成之前会导致肾灌注减少和肾脏精氨酸生成减少，从而使血浆精氨酸降低超过30%。为了阐明LPS的早期作用，我们提出了以下两个问题：1）LPS后肾脏精氨酸生成的快速变化仅仅是底物（即瓜氨酸）输送到肾脏减少的结果，还是由于摄取和转化受损所致？2）LPS后全身NO的生成是否受血浆精氨酸可用性的限制？以30分钟的间隔从麻醉的大鼠采集动脉和肾静脉血浆，这些大鼠接受或未接受瓜氨酸或精氨酸（2 μmol·min⁻¹·kg⁻¹静脉注射），该剂量对平均动脉压、肾功能或NO生成无影响。外源性瓜氨酸被肾脏迅速转化为精氨酸，导致血浆水平与等摩尔精氨酸输注相似。此外，瓜氨酸摄取的增加主要源于滤过负荷和重吸收的增加。在另一个系列中，在给予LPS后输注瓜氨酸，证实了在肾功能受损期间瓜氨酸的摄取和转化持续存在。最后，在给予LPS的大鼠中，血浆精氨酸的升高对平均动脉压、肾功能或全身NO生成没有明显影响。这项工作证明了精氨酸合成通常是如何“受底物限制”的，并解释了肾脏灌注受损如何迅速导致血浆精氨酸减少。然而，与体外研究相反，体内对LPS早期反应期间细胞外精氨酸的显著减少在功能上并非NO生成的限速因素。
