Decreased beta-adrenergic responsiveness in cornea and iris-ciliary body following topical timolol or epinephrine in albino and pigmented rabbits.

The ability of topical timolol and epinephrine to decrease the 0-adrenergic responsiveness of the cornea and iris-ciliary body of albino and pigmented rabbits is reported. The time course of the decrease in responsiveness was determined by comparing in vitro, /?-adrenergic stimulated cyclic AMP synthesis in these tissues from in vivo drug treated and contralateral, untreated eyes. In the cornea, loss of #-adrenergic responsiveness was maximal within the first hour after a single dose of topical 0.5% timolol and returned to control values within 3-6 hrs. In pigmented iris-ciliary body, however, a greater than 80% decrease of /?-adrenergic responsiveness remained at 6 hrs after topical 0.5% timolol and a 60% decrease remained at 12 hrs. Repeated administration of 0.5% timolol, caused a decrease of /9-adrenergic responsiveness in the iris-ciliary body that persisted for up to 24 hrs. Thus, the long duration of action of timolol observed in pigmented iris-ciliary bodies compared to the much shorter time course observed in nonpigmented tissue in previous studies indicate that pigment may act as a slow releasing depot for this drug. Topical epinephrine was found to decrease jd-adrenergic responsiveness of both the cornea and iris-ciliary body. In albino rabbits, a single topical administration of 2% epinephrine decreased /3-adrenergic responsiveness of the cornea by 42% and of the iris-ciliary body 39% 6 hrs after administration. Pretreatment with topical 1% timolol lessened the effect of epinephrine on the cornea but not on the iris-ciliary body. In pigmented rabbits, a single topical administration of 2% epinephrine desensitized the iris-ciliary body for up to 24 hrs. Repeated topical administration of 2% epinephrine twice-a-day for 7 days in albino rabbits decreased the 0adrenergic responsiveness of the iris-ciliary body for up to 72 hrs after the last drug treatment. The results of this study indicate that in addition to its high receptor affinity for /?-adrenergic receptors, topical timolol may bind reversibly to ocular pigment, prolonging its bioavailability as a /8-adrenergic antagonist. In addition, topical epinephrine has two time-related effects: initial /?-adrenergic/adenylate cyclase stimulation followed by /9-adrenergic/adenylate cyclase desensitization. We conclude that decreased /3-adrenergic responsiveness, the common pharmacologic effect in the iris-ciliary body following either topical timolol or epinephrine, may be responsible for the decrease in aqueous humor formation observed in glaucoma patients using these medications. Invest Ophthalmol Vis Sci 24:718724, 1983