Document Detail


Cellular basis for bimatoprost effects on human conventional outflow.
MedLine Citation:
PMID:  20435598     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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(2α). 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 μM, 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.
Authors:
W Daniel Stamer; David Piwnica; Thierry Jolas; Robert W Carling; Clive L Cornell; Hans Fliri; Jose Martos; Simon N Pettit; Jenny W Wang; David F Woodward
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-04-30
Journal Detail:
Title:  Investigative ophthalmology & visual science     Volume:  51     ISSN:  1552-5783     ISO Abbreviation:  Invest. Ophthalmol. Vis. Sci.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-29     Completed Date:  2010-10-19     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  7703701     Medline TA:  Invest Ophthalmol Vis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5176-81     Citation Subset:  IM    
Affiliation:
Department of Ophthalmology and Vision Science, The University of Arizona, Tucson, Arizona 85711, USA. dstamer@eyes.arizona.edu
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MeSH Terms
Descriptor/Qualifier:
Actins / metabolism
Adult
Aged
Amides / antagonists & inhibitors,  pharmacology*
Antihypertensive Agents / antagonists & inhibitors,  pharmacology*
Aqueous Humor / secretion*
Cells, Cultured
Ciliary Body / drug effects*,  metabolism
Cloprostenol / analogs & derivatives*,  antagonists & inhibitors,  pharmacology
Cornea / drug effects*,  metabolism
Dose-Response Relationship, Drug
Electric Impedance
Humans
Infant
Intraocular Pressure / drug effects
Middle Aged
Muscle, Smooth / drug effects*,  metabolism
Receptors, Prostaglandin / metabolism
Tissue Donors
Trabecular Meshwork / drug effects*,  metabolism
Grant Support
ID/Acronym/Agency:
EY12797/EY/NEI NIH HHS; EY17007/EY/NEI NIH HHS
Chemical
Reg. No./Substance:
0/Actins; 0/Amides; 0/Antihypertensive Agents; 0/Receptors, Prostaglandin; 0/bimatoprost; 0/prostaglandin F2alpha receptor; 40665-92-7/Cloprostenol
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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