Systemic administration of L-arginine alters renal haemodynamics in humans. We examined whether L-arginine-induced vasodilation of the renal vasculature is related to an increased production and release of NO by comparing the effects of L- and D-arginine on renal endothelium-dependent vasodilation. In a double-blind randomized cross-over study including 20 young, healthy male white subjects (age 26±2 years), we determined the effects of intravenous administration of L-arginine or its enantiomer D-arginine, at doses of 100 mg/kg body weight for 30 min or 500 mg/kg for 30 min, on renal haemodynamics. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by a constant-infusion input-clearance technique (using p-aminohippuric acid and inulin respectively). In addition, changes in blood pressure, heart rate, urinary sodium excretion (UNa) and urinary cGMP were measured. HPLC was used to determine L- and D-arginine concentrations. Intravenous infusion of L-arginine at 100 mg/kg for 30 min increased RPF from 641±87 to 677±98 ml/min (P = 0.019), whereas infusion of D-arginine did not (from 642±74 to 657±86 ml/min; not significant). The change in RPF was more marked during the infusion of L-arginine than during the infusion of D-arginine (+36±61 versus +16±57 ml/min; P = 0.037). Infusion of both L- and D-arginine at doses of 500 mg/kg for 30 min increased RPF from baseline [from 641±87 to 762±133 ml/min (P < 0.001) and from 642±74 to 713±120 ml/min (P = 0.004) respectively], but the change in RPF again was greater in response to L-arginine infusion than to infusion with D-arginine (+121±97 versus +71±94 ml/min; P = 0.018). In accordance, changes in renal vascular resistance (RVR) were higher in response to L-arginine compared with D-arginine for both doses (P < 0.05 and P< 0.001 respectively). UNa increased only with L-arginine (change in UNa, +0.33±0.26 mmol/min; P< 0.01) but not with D-arginine (change in UNa, +0.11±0.17 mmol/min; not significant). The change in UNa was more pronounced during infusion of L-arginine compared with infusion of D-arginine (P = 0.023). In parallel, urinary excretion of cGMP only increased in response to L-arginine (+676±272 pmol/l; P = 0.038) and not during D-arginine infusion (+185±153 pmol/l; not significant). L-Arginine-induced changes in RPF, RVR, UNa and cGMP excretion differed significantly from those induced by D-arginine. Thus although no direct measurements of NO synthesis were performed, putative markers of NO synthesis suggest that the renal vasodilatory response to L-arginine, at least in part, was due to increased production and release of NO. The dose of L-arginine at 100 mg/kg for 30 min emerged as the most suitable, because of the absence of systemic haemodynamic changes. The effects of infusion of L-arginine at 500 mg/kg for 30 min on renal endothelium-dependent vasodilation need to be corrected for the effects of D-arginine before conclusions can be drawn.