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Abstract #27575 Published in IGR 12-4
Cellular basis for bimatoprost effects on human conventional outflow
Stamer WD; Piwnica D; Jolas T; Carling RW; Cornell CL; Fliri H; Martos J; Pettit SN; Wang JW; Woodward DFInvestigative ophthalmology & visual science 2010; 51: 5176-5181
PURPOSE: Bimatoprost is a widely used ocular hypotensive agent to treat glaucoma. It lowers intraocular pressure in humans by increasing both pressure-independent (uveoscleral) and pressure-dependent (conventional) aqueous humor outflow. The present study specifically examines bimatoprost effects on the cells that populate human outflow tissues. METHODS: The authors tested for prostamide receptor activation in primary cultures of human trabecular meshwork (TM), Schlemm's canal (SC), and ciliary smooth muscle (CSM) cells using cellular dielectric spectroscopy (CDS). RESULTS: The authors observed that bimatoprost produced an immediate and concentration-dependent increase in cell monolayer impedance for TM, SC, and CSM cells with EC(50) values of 4.3, 1.2, and 1.7 nM, respectively; corresponding to decreased cell contractility. Notably, in TM, SC, and CSM cells, bimatoprost was approximately equipotent to the selective FP receptor agonists fluprostenol and 17-phenyl PGF(2(alpha)). Bimatoprost effects were insensitive to cholera toxin and pertussis toxin but were abolished by phorbol 12-myristate 13-acetate pretreatment, suggesting Gq-involvement in cell signaling. The effects of bimatoprost on TM and SC cells were inhibited by the prostamide receptor antagonist AGN211334, with IC(50) values of 1.2 and 3.3 (mu)M, respectively. Interestingly, AGN211334 behaved as an apparent inverse agonist in CDS assays involving TM cells but as a neutral prostamide antagonist with SC cells. CONCLUSIONS: Taken together, results suggest that bimatoprost specifically activates receptors in both cell types of the human conventional outflow pathway to modify intraocular pressure. However, only TM cell monolayers appear to have autocrine, or agonist-independent, receptor signaling that is sensitive to a prostamide receptor antagonist.
W.D. Stamer. Department of Ophthalmology and Vision Science, The University of Arizona, Tucson, Arizona 85711, USA. dstamer@eyes.arizona.edu
Classification:
11.4 Prostaglandins (Part of: 11 Medical treatment)
2.6.2.1 Trabecular meshwork (Part of: 2 Anatomical structures in glaucoma > 2.6 Aqueous humor dynamics > 2.6.2 Outflow)
3.6 Cellular biology (Part of: 3 Laboratory methods)
