title: Bimatoprost, prostamide activity, and conventional drainage.
abstract: 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.
authors.affiliation: Department of Ophthalmology and Vision Science, University of Arizona, Tucson, AZ 85711, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wan
authors.forename: David F
authors.initials: DF
authors.lastname: Woodward
authors.forename: Clive L
authors.initials: CL
authors.lastname: Cornell
authors.forename: Hans G
authors.initials: HG
authors.lastname: Fliri
authors.forename: José L
authors.initials: JL
authors.lastname: Martos
authors.forename: Simon N
authors.initials: SN
authors.lastname: Pettit
authors.forename: Jenny W
authors.initials: JW
authors.lastname: Wang
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Kharlamb
authors.forename: Larry A
authors.initials: LA
authors.lastname: Wheeler
authors.forename: Michael E
authors.initials: ME
authors.lastname: Garst
authors.forename: Kari J
authors.initials: KJ
authors.lastname: Landsverk
authors.forename: Craig S
authors.initials: CS
authors.lastname: Struble
authors.forename: W Daniel
authors.initials: WD
authors.lastname: Stamer
mesh_terms: 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
chemical_list: 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