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VOL. 72 (3), 519-538, 2006 NEW PERSPECTIVES IN OCULAR PHARMACOLOGY...

used in order to reduce the resistance to aqueous outflow (37-39).
Compounds that do not interfere with the nervous system have been
used to reduce IOP. These include carbonic anhydrase inhibitors
(decreasing aqueous production) or more recently the use of
prostaglandin analogues such as latanoprost (Xalatan).

Until the year 2000, the only purines tested for their ability to
modify IOP were adenosine and derivatives that demonstrated
relevant physiological effects on IOP (40). Adenosine acting through
adenosine A2 receptors produces an increase in IOP when topically
applied to rabbit eyes, while A1 produce a decrease in IOP (41, 42).

The application of mono- and dinucleotides depicted a clear

pattern of modulators on IOP. Thus, mononucleotides were classified

under two main groups: on the one hand those elevating IOP and on

the other those reducing it. Among the first, 2-MeSATP, ATP-?-S and
the natural compound ATP presented a clear increase on IOP, which

was maximal 2-3 h after the compound instillation. This profile fits

well with P2Y receptor pharmacology, although the destruction

of these nucleotides by means of ectonucleotidases and the

corresponding adenosine formation cannot be discarded (43). In this

sense, a recent work by Farahbakhsh and Cilluffo (35) described the

presence of P2Y1 and P2Y2 receptors in the rabbit ciliary body
epithelial cells, which may be responsible for the action of 2-

MeSATP, ATP-?-S, as well as other P2Y agonists. On the contrary,
ß?-meATP and aß-meATP produced a clear and marked reduction
in rabbit IOP. The time course to obtain the maximal effect was

similar to the one obtained for the hypertensive compounds (3 h).

Concentration-response analysis presented IC50 values of 1.52 mg/
mL and 0.55 mg/mL and a maximal reduction in IOP of 35.66% and

45.04% for aß-meATP and ß?-meATP respectively. The hypotensive
effect produced by these two mononucleotides were blocked by

the P2 antagonist PPADS but were unaffected by the adenosine

antagonists DPCPX (43). ß?-meATP and aß-meATP, activate P2
receptors, presumably P2X2 receptors, present in cholinergic
terminals that are in the trabecular meshwork. The activation of this

P2X2 receptor would generate an increase in acetylcholine release,
which facilitates both the relaxation of trabecular meshwork cells

and the elimination of aqueous humour (Figure 3).

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