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. Since 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 IV to anesthetized rats caused a decrease in MAP after 120 min that coincided with increased plasma nitric oxide end products (NOx) and iNOS expression in lung & 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 ~60 µmol/h/kg, corresponding to an apparent plasma half life of ~20 min, and decreased by 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 NO and that less than 25% of LPS impaired renal production was converted to NOx in the first 4h. In addition, we provide novel observations indicating that the kidney appears refractory to iNOS induction by LPS since no discernable enhancement of renal NOx production occurred within 4h and iNOS expression in the kidney was muted as compared to 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 which appears linked to reduced renal perfusion.