1. The mechanisms involved in the protective effect of amylin (administered into the brain ventricle, i.c.v.) on gastric ulcers induced by the oral administration of ethanol 50% (EtOH, 2 ml/rat) or indomethacin (indomethacin, 20 mg kg(-1), at a dosing volume of 5 ml) were investigated in rats. 2. The possible involvement of endogenous nitric oxide (NO) in the beneficial effect of amylin against EtOH-induced ulcers was examined. The inhibitor of NO-synthesis, NG-nitro-L-arginine methyl ester (L-NAME, 70 mg kg(-1), s.c.) was injected 30 min before amylin (2.2 microg/rat, i.c.v.) followed by EtOH after a further 30 min. Rats were sacrificed 1 h after EtOH. L-NAME completely removed the protective effect of amylin. 3. The interaction between amylin and gastric nonprotein sulfhydryl groups was studied. The rats were treated with N-ethyl-maleimide (NEM, 25 mg kg(-1), s.c.) 30 min before amylin (2.2 microg/rat, i.c.v.) followed by EtOH 30 min after or by indomethacin 5 min after amylin. Rats were sacrificed 1 h or 6 h respectively after EtOH or indomethacin. NEM counteracted the protective effect of amylin against EtOH-induced ulcers but not against those provoked by indomethacin. 4. To determine whether amylin was able to promote ulcer healing, the peptide was injected 5 min after EtOH or 1 h after indomethacin. In the case of EtOH, the beneficial effect of amylin was lost whereas it was still effective on indomethacin-induced ulcers. 5. The results indicate that: the mechanisms involved in the antiulcer effects of amylin are different in these two types of gastric lesions probably because of the different etiopathology of various types of ulcers. Endogenous NO and nonprotein sulfhydryl groups are involved in the mucosal protective effects of amylin on EtOH and not on indomethacin-induced ulcers. Furthermore the effectiveness of amylin against indomethacin-induced lesions when administered after the ulcerogenic process has started suggests that amylin is involved not only in the protection but also in the healing mechanisms in this type of ulcer.