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Lindsay H. Millard, David F. Woodward, W. Daniel Stamer; The Role of the Prostaglandin EP4 Receptor in the Regulation of Human Outflow Facility. Invest. Ophthalmol. Vis. Sci. 2011;52(6):3506-3513. doi: 10.1167/iovs.10-6510.
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© ARVO (1962-2015); The Authors (2016-present)
Activation of prostaglandin (PG)-EP4 receptors by 3,7-dithiaPGE1 robustly lowers intraocular pressure in nonhuman primate eyes, which increases outflow facility but has no effect on aqueous secretion or uveoscleral outflow. Because of differences in PG efficacy in outflow function between nonhuman primates and humans, we tested the impact of 3,7-dithiaPGE1 on conventional outflow function in human donor eyes.
The expression pattern of PG-EP4 receptors was determined in corneoscleral tissues of human donor eyes and in cultures of human outflow cells by immunofluorescence microscopy and Western blot, respectively. The efficacy of 3,7-dithiaPGE1 was determined by assaying agonist-stimulated cAMP accumulation and β-arrestin mobilization in cultured human cells. Agonist effects on outflow facility were examined in paired human donor eyes that were perfused at 8 mm Hg of constant pressure, equivalent to 15 mm Hg in vivo.
The trabecular meshwork (TM) and Schlemm's canal (SC) cells expressed PG-EP4 receptors. Agonist-mediated effects on the PG-EP4 receptors were detected in SC (EC50 = 6.3 × 10−9 M, n = 4), but not TM (EC50 = 1.7 × 10−7 M, n = 5) cells. Effects in SC cells were blocked by the PG-EP4 receptor–selective antagonist GW627368 (EC50 = 1.09 × 10−2 M, n = 4), but not the PG-EP2 receptor–selective antagonist AH6809 (EC50 = 4.10 × 10−9 M, n = 5). Perfused into human eyes at a concentration that selectively activates PG-EP4 receptors, 3,7-dithiaPGE1 (10 nM) increased outflow facility by 51% ± 18% over baseline levels in individual drug-treated eyes after drug exchange (n = 6 eyes; P = 0.05) and by 69% ± 23% (P < 0.01) compared with that in contralateral eyes.
Activation of PG-EP4 receptors expressed by SC cells of the human conventional outflow pathway appears to contribute to PG regulation of outflow facility.
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