Presence of diadenosine polyphosphates in the aqueous humor: Their effect on Intraocular pressure

Adenine dinucleotides are present in many biological systems and may serve as physiological regulators of processes such as neurotransmitter release, vascular tone or corneal hydration. The presence of diadenosine polyphosphates was investigated in New Zealand White rabbit aqueous humor. Diadenosine tetraphosphate (Ap(4)A) and diadenosine pentaphosphate (Ap(5)A) were identified and quantified in the aqueous humor with concentrations of 0.34+/-0.1 and 0.08+/-0.01 muM, respectively. The effects of topical corneal application of diadenosine pyrophosphate (Ap(2)A), diadenosine triphosphate (Ap(3)A), Ap(4)A, and Ap(5)A on intraocular pressure in rabbits were also studied. Ap(2)A, Ap(3)A, and Ap(5)A increased intraocular pressure with threshold doses of approximately 0.1 to 1.0 mug.10 mul(-1). Ap(4)A decreased intraocular pressure with an IC50 value of 0.12 mug.10 mul(-1) (or 0.13 nmol). Cross-desensitization studies suggested the activation of a P2X receptor for the hypotensive effect of Ap(4)A and a P2Y receptor in the case of Ap(5)A. The ATP receptor antagonists (all 100 mug.10 mul(-1)), pyridoxal phosphate-6-azophenyl-2', 4'-disulfonic acid (PPADS), suramin, and reactive blue 2 (RB-2) alone had no effect on intraocular pressure but attenuated responses to diadenosine polyphosphates by approximately 80%. It is concluded that Ap(2)A, Ap(3)A, and Ap(5)A increase intraocular pressure, and Ap(4)A decreases intraocular pressure via mechanisms that involve P2 receptors, and that Ap(4)A present in aqueous humor may serve to regulate intraocular pressure. Furthermore, we suggest that topical application of Ap(4)A to the cornea has therapeutic potential for lowering intraocular pressure, a major risk factor for glaucoma.