Abstract
Adenosine 5′ tetraphosphate, Ap4, is a natural nucleotide present in many biological systems. This nucleotide has been found as a constituent of the nucleotide pool present in the aqueous humor of New Zealand rabbits. HPLC analysis confirmed its identity and calculated its concentration levels to be 197 ± 21 nM. When applied topically to the rabbit eyes, this mononucleotide produced a reduction in the intraocular pressure, which was dose-dependent. The pD2 value calculated from the dose-response curve was 7.28 ± 0.47, which is equivalent to 52.48 nM. The time course of such intraocular pressure reduction presented a maximal decrease of IOP to 75.1 ± 2.3% compared with the vehicle control value (100%), and the effect lasted for more than 2 h. Cross-desensitization studies demonstrated that Ap4 effect was mediated via a P2X receptor in this system. P2 receptor antagonists suramin, pyridoxal phosphate 6-azophenyl-2′,4′-disulfonic acid (PPADS), and reactive blue 2 (RB-2) showed that only the latter was able to revert the effect of Ap4. Antagonists of adrenoceptors and cholinoceptors were able to partially reverse the effect of this nucleotide; this might indicate a connection with the neural mechanisms that control the intraocular pressure.
Footnotes
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This work has been supported by a research grant from Inspire Pharmaceuticals, from the Ministry of Science and Technology DGCYT SAF2003-00338 and Fondos Europeos FEDER UCMA-E017.
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DOI: 10.1124/jpet.103.058669.
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ABBREVIATIONS: Ap4, adenosine 5′-tetraphosphate; IOP, intraocular pressure; Ap4A, diadenosine tetraphosphate; ATP-γ-S, adenosine 5′-3-O-thiotriphosphate; α,β-me ATP, α,β-methylene-adenosine 5′ triphosphate; β,γ-meATP, β,γ-methylene-adenosine 5′ triphosphate; HPLC, high-performance liquid chromatography; PPADS, pyridoxal phosphate 6-azophenyl-2′,4′-disulfonic acid; RB-2, reactive blue 2; Ap5A, diadenosine pentaphosphate; ICI-118.551, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino].
- Received August 14, 2003.
- Accepted October 31, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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Adenosine Tetraphosphate, Ap4, a Physiological Regulator of Intraocular Pressure in Normotensive Rabbit Eyes
