TY - JOUR T1 - Effects of Diadenosine Polyphosphates on Tear Secretion in New Zealand White Rabbits JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 291 LP - 297 DO - 10.1124/jpet.300.1.291 VL - 300 IS - 1 AU - J. Pintor AU - A. Peral AU - C. H. V. Hoyle AU - C. Redick AU - J. Douglass AU - I. Sims AU - B. Yerxa Y1 - 2002/01/01 UR - http://jpet.aspetjournals.org/content/300/1/291.abstract N2 - Extracellular diadenosine polyphosphates play important signaling functions in a number of physiological responses. Here we show that diadenosine polyphosphates are normal constituents of tear fluid and are potent stimulators of tear secretion through their interaction with P2Y receptors. Diadenosine tetraphosphate (Ap4A) and Ap5A were found in rabbit tears under basal conditions at concentrations of 2.92 and 0.58 μM, respectively. Single applications of UTP, ATP, and Ap4A increased tear secretion to 160 ± 8% (n = 16) (P < 0.001), 131 ± 6% (P < 0.05), and 162 ± 11% (P < 0.05) of placebo values, respectively. Ap4A, Ap5A, and Ap6A, but not Ap2A and Ap3A, were able to stimulate tear secretion in a dose-dependent manner. Concentration-response studies produced pD2 values of 5.56 ± 0.03, 5.75 ± 0.12, and 5.50 ± 0.09 for Ap4A, Ap5A, and Ap6A, respectively, with Ap4A showing the greatest efficacy. Diadenosine polyphosphates also stimulated P2Y1 and P2Y2 receptors expressed in 1321N1 cells with no apparent effect on the other P2Y receptors tested. Nonselective P2 antagonists did not modify the tear secretion induced by UTP or Ap4A in rabbit eyes in vivo or in cloned receptors, except for a weak but significant reduction in stimulated tear secretion by reactive blue 2. These results suggest that diadenosine polyphosphates stimulate tear secretion via a P2Y receptor-mediated mechanism. Comparing the effects of diadenosine polyphosphates applied to the rabbit eye and to cloned P2Y receptors, it appears that the P2Y2 receptor subtype is responsible for the prosecretory effects of these compounds. ApnAdiadenosine polyphosphatePPADSpyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acidRB-2reactive blue 2HPLChigh-performance liquid chromatographyICI 118,551±-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3[(1-methylethyl)amino]-2-butanol ER -