Acute renal response to LPS: impaired arginine production and inducible nitric oxide synthase activity

Abstract

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 μmol·min−1·kg−1iv) 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.