Effect of EP2–agonists on the outflow of aqueous humor in the cynomolgus monkey

Abstract

Abstract: : Purpose: To investigate the effects of two prostaglandin E₂–receptor agonists, AH13205 and butaprost, on the outflow of aqueous humor. Methods: Physically restrained cynomolgus monkeys received unilateral topical treatment with AH13205 or butaprost (25 µl), whereas vehicle was administered to the contralateral eye. Total outflow facility was determined with the two–level constant pressure method, during anesthesia with a combination of ketamine and diazepam. In one group of animals (n=6), the determination of outflow facility was made 4–6 hours after the 9^th dose of AH13205 (0.1%; BID for 5 days) and in another group (n=6) outflow facility was determined 4–6 hours after a single drop of butaprost (0.1%). One year later, the animals in the latter group were treated once daily with butaprost (0.1%) for 5 days, and uveoscleral outflow was determined 4–6 hours after the last dose. The determination was made in anesthetized monkeys by perfusion of the anterior chamber with FITC–labeled dextran (70 kDa) during 30 min, at a fixed intraocular pressure of ∼15 mmHg. Results: There was no significant difference in total outflow facility between the drug and vehicle treated eye, in any of the groups. In the AH13205 group, total outflow facility was 0.71±0.14 and 0.66±0.08 µl min^–1 mmHg^–1, in the treated and control eye, respectively. The corresponding values for the butaprost group were 0.76±0.22 and 0.66±0.13 µl min^–1 mmHg^–1, respectively. Uveoscleral outflow was significantly higher in the butaprost treated eye than in the contralateral vehicle treated eye, 1.03±0.20 compared with 0.53±0.18 µl min^–1 (P≤0.01; student’s paired t–test). Conclusions: The lack of effect on the total outflow facility and the increase in uveoscleral outflow caused by butaprost, suggest that EP₂–receptor agonists lower intraocular pressure by increasing the uveoscleral outflow of aqueous humor. These findings are in good agreement with the enlargement of the uveoscleral pathways that has been observed after long–term treatment with AH13205, in cynomolgus monkeys.

Keywords: outflow: ciliary muscle • outflow: trabecular meshwork • eicosanoids