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The role of the prostaglandin EP4 receptor in the regulation of human outflow facility.

Publication ,  Journal Article
Millard, LH; Woodward, DF; Stamer, WD
Published in: Invest Ophthalmol Vis Sci
June 1, 2011

PURPOSE: Activation of prostaglandin (PG)-EP(4) receptors by 3,7-dithiaPGE(1) 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-dithiaPGE(1) on conventional outflow function in human donor eyes. METHODS: The expression pattern of PG-EP(4) 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-dithiaPGE(1) 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. RESULTS: The trabecular meshwork (TM) and Schlemm's canal (SC) cells expressed PG-EP(4) receptors. Agonist-mediated effects on the PG-EP(4) receptors were detected in SC (EC(50) = 6.3 × 10(-9) M, n = 4), but not TM (EC(50) = 1.7 × 10(-7) M, n = 5) cells. Effects in SC cells were blocked by the PG-EP(4) receptor-selective antagonist GW627368 (EC(50) = 1.09 × 10(-2) M, n = 4), but not the PG-EP(2) receptor-selective antagonist AH6809 (EC(50) = 4.10 × 10(-9) M, n = 5). Perfused into human eyes at a concentration that selectively activates PG-EP(4) receptors, 3,7-dithiaPGE(1) (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. CONCLUSIONS: Activation of PG-EP(4) receptors expressed by SC cells of the human conventional outflow pathway appears to contribute to PG regulation of outflow facility.

Duke Scholars

Published In

Invest Ophthalmol Vis Sci

DOI

EISSN

1552-5783

Publication Date

June 1, 2011

Volume

52

Issue

6

Start / End Page

3506 / 3513

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Trabecular Meshwork
  • Tissue Donors
  • Sulfonamides
  • Sclera
  • Receptors, Prostaglandin E, EP4 Subtype
  • Ophthalmology & Optometry
  • Microscopy, Fluorescence
  • Isoindoles
  • Intraocular Pressure
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Millard, L. H., Woodward, D. F., & Stamer, W. D. (2011). The role of the prostaglandin EP4 receptor in the regulation of human outflow facility. Invest Ophthalmol Vis Sci, 52(6), 3506–3513. https://doi.org/10.1167/iovs.10-6510
Millard, Lindsay H., David F. Woodward, and W Daniel Stamer. “The role of the prostaglandin EP4 receptor in the regulation of human outflow facility.Invest Ophthalmol Vis Sci 52, no. 6 (June 1, 2011): 3506–13. https://doi.org/10.1167/iovs.10-6510.
Millard LH, Woodward DF, Stamer WD. The role of the prostaglandin EP4 receptor in the regulation of human outflow facility. Invest Ophthalmol Vis Sci. 2011 Jun 1;52(6):3506–13.
Millard, Lindsay H., et al. “The role of the prostaglandin EP4 receptor in the regulation of human outflow facility.Invest Ophthalmol Vis Sci, vol. 52, no. 6, June 2011, pp. 3506–13. Pubmed, doi:10.1167/iovs.10-6510.
Millard LH, Woodward DF, Stamer WD. The role of the prostaglandin EP4 receptor in the regulation of human outflow facility. Invest Ophthalmol Vis Sci. 2011 Jun 1;52(6):3506–3513.

Published In

Invest Ophthalmol Vis Sci

DOI

EISSN

1552-5783

Publication Date

June 1, 2011

Volume

52

Issue

6

Start / End Page

3506 / 3513

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Trabecular Meshwork
  • Tissue Donors
  • Sulfonamides
  • Sclera
  • Receptors, Prostaglandin E, EP4 Subtype
  • Ophthalmology & Optometry
  • Microscopy, Fluorescence
  • Isoindoles
  • Intraocular Pressure