BACKGROUND L-Arginine has been shown to induce fluid secretion in human jejunum. Nitric oxide, a derivative of L-arginine is thought to have an important role as an intestinal secretagogue. OBJECTIVE To determine the effect of L-arginine and the nitric oxide synthase inhibitor, nitro L-arginine methyl ester (L-NAME), on fluid and electrolyte movement in rat jejunum. METHODS A 25 cm segment of rat jejunum was perfused in situ with iso-osmotic solutions containing either (1) saline, (2) D-arginine 20, (3) L-arginine 20, (4) L-NAME 0.1, 1, or 20 mmol/l, or (5) a combination of L-arginine 20 and L-NAME 0.1, 1, or 20 mmol/l. In further groups the effect of a subcutaneous injection of L-NAME 100 mg/kg was examined in rats pretreated with either D-or L-arginine 500 mg/kg. RESULTS L-Arginine, unlike D-arginine, induced fluid secretion despite being better absorbed (mean -7.3 v 17.0 microliters/min/g; p < 0.01). L-NAME at 0.1 mmol/l had no effect on basal fluid movement but reversed L-arginine induced secretion (7.8; p < 0.05). L-NAME at 1 and 20 mmol/l induced fluid secretion (-15.4 and -28.4, respectively), which was enhanced by the addition of L-arginine (-30.0 and -41.0, respectively; both p < 0.05). A subcutaneous injection of L-NAME resulted in marked fluid secretion (-39.9) and histological evidence of intestinal ischaemia. These changes were attenuated or reversed by pretreatment with subcutaneous L- but not D-arginine. CONCLUSIONS L-arginine induces intestinal fluid secretion through production of nitric oxide. There is a delicate balance between the effect of nitric oxide as a secretagogue and its effect on maintaining blood flow and thus preventing intestinal ischaemia.