OCULAR HYPOTENSIVE ACTIVITY OF THE ADENOSINE AGONIST (R)-PHENYLISOPROPYLADENOSINE IN RABBITS

Adenosine A1 agonists have been shown to induce a variety of pharmacolgical effects. In New Zealand White rabbits, the topical administration of 500-mu-g of the relatively selective adenosine A1 receptor agonist R(-) phenylisopropyl-adenosine (R-PIA) produced a biphasic response in IOP in the ipsilateral eye: an initial ocular hypertension (3.5 +/- 1.4 mm of Hg) at 0.5 hour, followed by significant reduction in IOP (5 to 8 mm of Hg) from 2 to 6 hours postadministration. The IOP response to 50 and 165-mu-g of R-PIA demonstrated that the ocular hypotensive response to R-PIA was dose-related; however, no initial hypertension was observed at these lower doses. The ocular response to R-PIA was dose-related; with only a small reduction in contra-lateral IOP at 1 hour observed in animals treated with 500-mu-g. No significant change in pupil diameter was observed with any dose of R-PIA. Pretreatment with the adenosine antagonist CPT (10 mg/kg; i.p.) significantly inhibited the ocular hypotensive response to R-PIA. However, pretreatment with the cyclooxygenase inhibitor indomethacin (50 mg/kg; i.p.) did not alter the change in IOP induced by R-PIA. The administration of R-PIA once a day for five days demonstrated that tolerance does not develop in rabbits with repeated administration. These data demonstrate that the adenosine A1 agonist R-PIA can lower IOP. The unilateral nature and the inhibition by CPT supports the idea that this response is mediated by adenosine receptors located in the eye. However, the biphasic response produced by 500-mu-g of R-PIA indicates that multiple receptor types or sites can be activated by large doses of R-PIA.