Histamine dihydrochloride (40 or 80 mg/kg, dissolved in 10% gelatin) subcutaneously administered to fasted rats induced few lesions in the gastric mucosa within 4 h. Pretreatment with subcutaneously administered 16,16-dimethyl prostaglandin E2 (dmPGE2; greater than or equal to 10 micrograms/kg) dose-dependently worsened mucosal injury induced by histamine, mostly with severe hemorrhage in the corpus mucosa along the greater curvature, although dmPGE2 alone did not induce any macroscopic damage. The mucosal vascular permeability as measured using Evans blue was slightly but significantly augmented by either dmPGE2 (30 micrograms/kg) or histamine (80 mg/kg) alone, but was markedly increased by histamine in the presence of dmPGE2. The increased vascular permeability occurred within 2 h, and preceded the appearance of hemorrhagic mucosal injury. Both the mucosal injury and the increased vascular permeability caused by histamine (80 mg/kg) in the presence of dmPGE2 (30 micrograms/kg) were significantly reduced by pretreatment with tripelennamine (30 mg/kg) and prednisolone (3 mg/kg), but not affected by atropine sulfate, cimetidine, methysergide, or indomethacin. The stimulation of acid secretion caused by histamine was significantly inhibited by dmPGE2 (30 micrograms/kg). Repeated administration of histamine (40 or 80 mg/kg) in the same area of the stomach in the presence of dmPGE2 (30 micrograms/kg), once or twice daily for 4 days to fed rats, induced more pronounced damage than single-dose treatment. These results suggest that dmPGE2 may aggravate gastric mucosal injury induced by histamine in rats probably due to potentiation of the increased vascular permeability caused by histamine through stimulation of H1-receptors.