Bimatoprost, prostamide activity, and conventional drainage.
OBJECTIVE
Despite structural similarity with prostaglandin F(2 alpha), the ocular hypotensive agent bimatoprost (Lumigan; Allergan, Inc., Irvine, CA) shows unique pharmacology in vitro and functional activity in vivo. Unfortunately, the precise mechanisms that underlie bimatoprost's distinctive impact on aqueous humor dynamics are unclear. The purpose of the present study was to investigate the effects of bimatoprost and a novel prostamide-selective antagonist AGN 211334 on human conventional drainage.


METHODS
Two model systems were used to test the consequences of bimatoprost and/or AGN 211334 treatment on conventional drainage. Human anterior segments in organ culture were perfused at a constant flow rate of 2.5 microL/min while pressure was recorded continuously. After stable baseline facilities were established, segments were treated with drug(s), and pressure was monitored for an additional 3 days. In parallel, the drugs' effects on hydraulic conductivity of human trabecular meshwork (TM) cell monolayers were evaluated. Pharmacological properties of AGN 211334 were characterized in isolated feline iris preparations in organ culture and heterologously expressed G-protein-coupled receptors were examined in vitro.


RESULTS
Bimatoprost increased outflow facility by an average of 40% +/- 10% within 48 hours of treatment (n = 10, P < 0.001). Preincubation or coincubation with AGN 211334 significantly blunted bimatoprost's effects by 95% or 43%, respectively. Similar results were obtained in cell culture experiments in which bimatoprost increased hydraulic conductivity of TM cell monolayers by 78% +/- 25%. Pretreatment with AGN 211334 completely blocked bimatoprost's effects, while coincubation decreased its effects on average by 74%. In both models, AGN 211334 alone significantly decreased fluid flux across trabecular tissues and cells.


CONCLUSIONS
The findings indicate that bimatoprost interacts with a prostamide receptor in the trabecular meshwork to increase outflow facility.
Wan
Zhou
Z
Department of Ophthalmology and Vision Science, University of Arizona, Tucson, AZ 85711, USA.
Woodward
David F
DF
Cornell
Clive L
CL
Fliri
Hans G
HG
Martos
José L
JL
Pettit
Simon N
SN
Wang
Jenny W
JW
Kharlamb
Alexander B
AB
Wheeler
Larry A
LA
Garst
Michael E
ME
Landsverk
Kari J
KJ
Struble
Craig S
CS
Stamer
W Daniel
WD
D000368:Aged; D000369:Aged, 80 and over; D000577:Amides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001082:Aqueous Humor / Q000378:metabolism; D000069580:Bimatoprost; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002415:Cats; D018929:Cell Culture Techniques; D003008:Cloprostenol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D007429:Intraocular Pressure / Q000502:physiology; D007498:Iris / Q000187:drug effects; D008055:Lipids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects; D009924:Organ Culture Techniques; D010080:Oxazoles / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins; D014129:Trabecular Meshwork / Q000187:drug effects* / Q000378:metabolism
C523387:AGN 211334; D000577:Amides; D000959:Antihypertensive Agents; D008055:Lipids; D010080:Oxazoles; D017482:Receptors, Thromboxane; D011994:Recombinant Proteins; C493494:prostaglandin F2alpha ethanolamide; D003008:Cloprostenol; D015237:Dinoprost; D015232:Dinoprostone; D000069580:Bimatoprost; D002118:Calcium