Nitric oxide can exert either protective or damaging effects on the gastric mucosa. To further explore the role of nitric oxide in the modulation of gastric mucosal defense, the effects of intra-arterial administration of the precursor, L-arginine, on susceptibility of the gastric mucosa to damage induced by topically applied 20% ethanol was examined in the rat. L-Arginine administration prior to application of ethanol produced a dose-dependent increase in the extent of damage (P < 0.01 at 300 and P < 0.001 at 500 mg/kg). L-Arginine administration did not increase the extent of damage at a dose of 300 mg/kg, but did at a dose of 500 mg/kg. Pretreatment with NG-nitro-L-arginine-methyl-ester (L-NAME, 25 mg/kg), but not NG-nitro-D-arginine-methyl-ester (D-NAME, 25 mg/kg) significantly attenuated the exacerbation of injury induced by L-arginine (300 mg/kg). L-Arginine significantly reduced gastric blood flow relative to controls, while D-arginine had no effect. L-NAME induced a dose-dependent decrease in gastric blood flow and did not affect the response to L-arginine. These results suggest that L-arginine can significantly increase gastric injury through a mechanism that appears to be partly nitric oxide-dependent and partly nitric oxide-independent. Changes in gastric blood flow do not appear to be the sole mechanism responsible for the augmentation of injury caused by L-arginine.