The role of prostaglandin EP(2) receptors in the disruption of the blood-aqueous barrier was examined using EP(2) receptor-deficient mice. Eyes were topically treated with EP receptor agonists or subjected to paracentesis. Fluorescein angiography was performed after topical treatment with 2.0 icrog butaprost. The results show that EP receptor agonists, PGE( 2) and the EP(2) receptor-selective agonist butaprost, increased aqueous humor protein in EP(2) +/+ wild-type mice to 18.0 mg/ml and 12.0 mg/ml, respectively, from the control value of 2.7 mg/ml. The increase in aqueous humor protein concentration in response to these EP receptor agonists was reduced significantly in EP(2) receptor-deficient mice. Fluorescein leakage into the anterior chamber, two minutes after its injection, was significantly greater in butaprost-treated wild-type mice than in butaprost-treated knockout mice. Protein concentration, 15 min after paracentesis, increased from 2.2 mg/ml to 25.0 mg/ml in the aqueous humor of the eyes of wild-type mice, while the increase in knockout mice was 10.6 mg/ml. These results suggest that EP( 2) and EP(4) receptors mediate the disruption of the blood-aqueous barrier induced by EP receptor agonists and paracentesis.