advertisement
Abstract #12589 Published in IGR 7-3
Effects of dinucleoside polyphosphates on trabecular meshwork cells and aqueous humor outflow facility
Soto D; Pintor J; Peral A; Gual A; Gasull XJournal of Pharmacology and Experimental Therapeutics 2005; 314: 1042-1051
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 (Ap4 A) and pentaphosphate (Ap5 A) in the AH. Topic application of Ap4 A to the cornea decreased IOP, whereas Ap5 A increased it. Because dinucleoside polyphosphates stimulate P2Y purinergic receptors, we studied their presence in trabecular meshwork (TM) cells. Additionally, the effects of diadenosine polyphosphates (Apn As; n = 3-5) and Up4 U (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, Ap3 A, Ap4 A, and Ap5 A induced discrete intracellular calcium concentration ([Ca2+ ]i ) mobilizations compared with higher and more sustained [Ca2+ ]i mobilizations after Up4 U application. In bovine ocular anterior segments perfused at constant pressure, 1 μM Ap3 A or Ap4 A increased outflow facility, whereas Up4 U or Ap5 A did not modify it. 2-MeSADP, a selective P2Y1 agonist, induced outflow facility increases similar to those obtained after Ap3 A and Ap4 A, 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 Ap4 A 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.
Dr. X. Gasull, Laboratori de Neurofisiologia, Facultat de Medicina-U.B., Casanova 143, E-08036 Barcelona, Spain
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
