title: Modulation of conventional outflow facility by the adenosine A1 agonist N6-cyclohexyladenosine.
abstract: OBJECTIVE
  Studies have shown that the activation of adenosine A(1) receptors lower intraocular pressure primarily by increasing total outflow facility. The purpose of this study was to investigate the actions of the adenosine A(1) agonist N(6)-cyclohexyladenosine (CHA) on conventional outflow facility.
  
  
  METHODS
  Conventional outflow facility was evaluated in isolated bovine anterior segments, perfused at a constant pressure of 10 mm Hg. After overnight perfusion to establish a stable baseline, the concentration- and time-dependent changes in outflow facility induced by CHA were determined. To confirm the involvement of adenosine A(1) receptors and matrix metalloproteinases (MMP) in any change in facility, the responses to CHA were evaluated in preparations treated with the adenosine A(1) receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT), or the nonselective MMP inhibitor GM-6001.
  
  
  RESULTS
  The administration of CHA (10 microM) to perfused anterior segments produced a 28% increase in outflow facility over basal levels. This response was relatively slow to develop with no significant change in outflow facility measured until after 60 minutes of CHA infusion. The peak response to CHA infusion occurred between 3 and 4 hours after CHA administration. Analysis of the CHA concentration-response curves demonstrated that this increase in outflow facility was concentration-dependent, with an EC(50) of 0.28 microM. Pretreatment with the adenosine A(1) receptor antagonist CPT (10 microM) or the nonselective MMP inhibitor GM-6001 (10 microM) blocked the response to CHA (1 microM). When compared with control eyes, no significant change in baseline facility was measured in eyes perfused with CPT or GM-6001.
  
  
  CONCLUSIONS
  These studies demonstrate that the adenosine agonist CHA significantly increases conventional outflow facility in the perfused bovine eye. Analysis of the CHA concentration-response curve and inhibition of the CHA-induced increase in outflow facility by the adenosine A(1) antagonist confirms that this response is mediated by the activation of adenosine A(1) receptors. The inhibition of the CHA-induced increase in outflow facility by the MMP inhibitor GM-6001 provides evidence that the secretion and activation of MMPs within the conventional outflow pathway play a central role in the ocular hypotensive action of adenosine A(1) agonists.
authors.affiliation: Hewitt Laboratory of the Ola B. Williams Glaucoma Center, Department of Ophthalmology, Medical University of South Carolina, Charleston, 29425, USA. crossonc@musc.edu
authors.forename: Craig E
authors.initials: CE
authors.lastname: Crosson
authors.forename: Carl F
authors.initials: CF
authors.lastname: Sloan
authors.forename: Philip W
authors.initials: PW
authors.lastname: Yates
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D000869:Anterior Eye Segment / Q000187:drug effects* / Q000378:metabolism; D001082:Aqueous Humor / Q000378:metabolism*; D002417:Cattle; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D043682:Receptor, Adenosine A1; C053907:8-cyclopentyl-1,3-dimethylxanthine; C027513:N(6)-cyclohexyladenosine; D013806:Theophylline; D020782:Matrix Metalloproteinases; D000241:Adenosine