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INFLAMMATION AND CYTOKINES

Production of arginine by the kidney is impaired in a model of sepsis: early events following LPS

¹Division of Nephrology and Hypertension, School of Medicine, and ⁴Department of Neurosciences, University of California-San Diego, San Diego 92093; ²Veterans Affairs San Diego Healthcare System, and ³Veterans Medical Research Foundation, San Diego, California 92161

Submitted 3 June 2004 ; accepted in final form 5 August 2004

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 60 µmol·h^–1·kg^–1, corresponding to an apparent plasma half-life of 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.

inducible nitric oxide synthase; sepsis; lipopolysaccharide; ornithine

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