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Vol. 300, Issue 1, 291-297, January 2002

Effects of Diadenosine Polyphosphates on Tear Secretion in New Zealand White Rabbits

J. Pintor, A. Peral, C. H. V. Hoyle, C. Redick, J. Douglass, I. Sims and B. Yerxa

Escuela Universitaria (E.U.) Optica, Universidad Complutense de Madrid, Madrid, Spain (J.P.); Departmento de Bioquimica, E.U. Optica, Universidad Complutense, Madrid, Spain (A.P.); University College, London, United Kingdom (C.H.V.H.); and Inspire Pharmaceuticals, Inc., Durham, North Carolina (C.R., J.D., I.S., B.Y.)

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.

0022-3565/02/3001-0291$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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