Contributions of adenosine receptor activation to the ocular actions of epinephrine

PURPOSE. Epinephrine is an effective drug fur glaucoma treatment. However, the mechanisms responsible for the ocular hypotensive action of this compou nd are not completely understood. Adenosine is an autacoid released by all cells. This study evaluated the role of adenosine receptor activation in ep inephrine-induced changes in ocular Function. METHODS. Rabbits were pretreated topically with the moderately selective ad enosine A(1) antagonist 8-(p-sulfophenyl)theophyline (8-SPT) or the adenosi ne A(2) antagonist 3,7-dimethyl-1-propargylxanthine (DMPX). Epinephrine (50 0 mu g) was then administered, and intraocular pressures (IOPs), pupil diam eters (PDs), or total outflow facility was evaluated. In a separate group o f animal, epinephrine or vehicle was administered, and aqueous humor sample s obtained to evaluate changes in aqueous humor purine levels by means of h igh-performance liquid chromatography. RESULTS. In control animals, epinephrine produced a biphasic change in IOP: an initial rise in IOP of approximately 1 mm Hg from 1/2 to 1 hour followe d by significant reduction in IOP of 8 to 9 mm Hg from 3 to 5 hours postadm inistration. These animals also exhibited a significant increase in PD of 2 to 3 mm from 1/2 to 2 hours postadministration. Pretreatment with 8-SPT (1 000 mu g) enhanced the initial rise in IOP, while significantly inhibiting the ocular hypotensive response, Pretreatment with 8-SPT also significantly enhanced the epinephrine-induced increase in PD. Inhibition of the epineph rine-induced reduction in IOP by 8-SPT nas dose-related with an IC50 of 4.4 6 mu g. Administration of 8-SPT alone did nor significantly alter IOP or PD . The A(2) antagonist DMPX did not alter the epinephrine-induced change in IOP or PD. In rabbits pretreated with 8-SPT, the epinephrine-induced increa se in outflow facility was significantly reduced by 60% when compared with those in rabbits treated with epinephrine alone. In vehicle-treated rabbits , aqueous humor adenosine and inosine levels were 2.7 +/- 0.38 and 29 +/- 4 .2 ng/100 mu l respectively. Three hours after epinephrine administration. adenosine and inosine levels had significantly increased to 11 +/- 1.6 and 66 +/- 4.4 ng/100 mu l, respectively. CONCLUSIONS. These results support the idea that in rabbits epinephrine adm inistration stimulates adenosine release in the anterior segment. This rise in endogenous levels of adenosine then leads to the activation of ocular a denosine receptors and is in part responsible for the ocular hypotensive ac tion of epinephrine.