TY - JOUR T1 - Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1042 LP - 1051 DO - 10.1124/jpet.105.085274 VL - 314 IS - 3 AU - David Soto AU - Jesús Pintor AU - Assumpta Peral AU - Arcadi Gual AU - Xavier Gasull Y1 - 2005/09/01 UR - http://jpet.aspetjournals.org/content/314/3/1042.abstract N2 - The most important risk factor for the development of glaucoma is elevated intraocular pressure (IOP). Hypotensive drugs decrease IOP, preventing optic nerve damage and further vision loss. The balance between aqueous humor (AH) production and drainage determines IOP, and problems in AH outflow pathways are associated with open-angle glaucoma development. Previous studies have shown the presence of diadenosine tetraphosphate (Ap4A) and pentaphosphate (Ap5A) in the AH. Topic application of Ap4A to the cornea decreased IOP, whereas Ap5A increased it. Because dinucleoside polyphosphates stimulate P2Y purinergic receptors, we studied their presence in trabecular meshwork (TM) cells. Additionally, the effects of diadenosine polyphosphates (ApnAs; n = 3–5) and Up4U (P1,P4-(diuridine 5′)-tetraphosphate; INS365) in outflow facility were tested. P2Y1, P2Y2, and P2Y4 receptors were detected in TM cells by Western blot and immunocytochemistry. In TM cells, Ap3A, Ap4A, and Ap5A induced discrete intracellular calcium concentration ([Ca2+]i) mobilizations compared with higher and more sustained [Ca2+]i mobilizations after Up4U application. In bovine ocular anterior segments perfused at constant pressure, 1 μM Ap3A or Ap4A increased outflow facility, whereas Up4U or Ap5A did not modify it. 2-MeSADP, a selective P2Y1 agonist, induced outflow facility increases similar to those obtained after Ap3A and Ap4A, and these were prevented by addition of the selective P2Y1 receptor antagonist MRS-2179 (2′-deoxy-N6-methyladenosine-3′,5′-diphosphate). Our results demonstrate that the hypotensive effect of Ap4A and other dinucleotides is mediated, at least in part, by increasing trabecular outflow facility through activation of P2Y1 receptors. The latter would seem to be an interesting target in the development of antiglaucomatous drugs to selectively increase AH outflow. The American Society for Pharmacology and Experimental Therapeutics ER -