Effects of prostanoid EP agonists on mouse intraocular pressure.
OBJECTIVE
To investigate the ocular hypotensive effect and change of outflow facilities by prostaglandin E2 (PGE2) and selective agonists of PGE2 receptor subtypes (EP1, -2, -3, -4) using C57BL/6 (wild-type [WT]) mice or FP, EP1, -2, and -3 receptor-deficient mice.


METHODS
IOP was measured with a microneedle, and IOP reduction was evaluated by the difference in IOP between the treated eye and the contralateral control eye. The time course and dose dependency of IOP reduction with PGE2 and the four selective EP receptor agonists were assessed. Aqueous humor outflow facility was measured by a two-level constant-pressure perfusion


METHODS



RESULTS
PGE2, ONO-AE1-259-01 (EP2 agonist), and ONO-AE1-329 (EP4 agonist) significantly reduced IOP in a dose-dependent manner, whereas ONO-DI-004 (EP1 agonist) and ONO-AE-248 (EP3 agonist) had no effect. Peak IOP reduction at 2 hours with 0.1% ONO-AE1-259-01 (EP2 agonist) and ONO-AE1-329 (EP4 agonist) were 21.1% +/- 4.8% and 17.5% +/- 2.9%, respectively (P < 0.01). IOP reduction with ONO-AE1-259-01 (EP2 agonist) was completely eliminated in EP2 knockout mice, but IOP reduction in other knockout mice was similar to that observed in WT mice. The effects of ONO-AE1-259-01 (EP2 agonist) and ONO-AE1-329 (EP4 agonist) on the outflow facility were similar to those of their carrier.


CONCLUSIONS
EP2 and EP4 receptors mediated IOP reduction in mice, whereas the contribution of EP1 and EP3 receptors was insignificant. The EP2 and EP4 receptor-mediated mechanisms of IOP reduction were different from those mediated by the FP receptor.
Saeki
Tadashiro
T
Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
Ota
Takashi
T
Aihara
Makoto
M
Araie
Makoto
M
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001082:Aqueous Humor / Q000378:metabolism; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007429:Intraocular Pressure / Q000187:drug effects*; D000077338:Latanoprost; D008738:Methyl Ethers / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015814:Ocular Hypotension / Q000209:etiology; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013997:Time Factors; D014065:Tonometry, Ocular
C499423:9-deoxy-9-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydroprostaglandin E2; D000959:Antihypertensive Agents; D008738:Methyl Ethers; C461399:ONO-AE1-329; D011461:Prostaglandins F, Synthetic; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000077338:Latanoprost; D015232:Dinoprostone