The amino acid arginine is the sole precursor for nitric oxide (NO) synthesis. We have now studied the role of acutely reducing circulating arginine on whole body NO production in mice. Measurements were performed in 4 groups of mice, treated with saline (SAL) or arginase (ASE), and SAL or bacterial endotoxin (LPS). After 5 h, a 57% reduction in circulating arginine was obtained by intravenous injections of arginase (SAL/SAL: 138+/-7; ASE/SAL: 59+/-10 microM, P<0.05). Reduced circulating arginine caused a reduction in plasma arginine flux (SAL/SAL: 82+/-6; ASE/SAL: 63+/-5 nmol/(10 g b.w. min), P<0.05), but did not change whole body NO production. LPS treatment caused an increase in NO production (SAL/SAL: 1.3+/-0.3 SAL/LPS 2.3+/-0.4 nmol/(10 g b.w. min), P<0.05), presumably by NOS-2 and was unaffected by reducing circulating arginine. Also, intestinal citrulline and renal arginine production were not increased in LPS-challenged mice with reduced circulating arginine levels. The present study indicates that an acute decrease in circulating arginine does not compromise whole body NO production and provides evidence against a role for renal arginine production to counteract an acute reduction of circulating arginine.