Topical timolol and epinephrine: biochemical actions and interactions in the rabbit eye in vivo

The effects of topical 0.5% timolol maleate and 1% or 2% levo-epinephrine hydrochloride on aqueous humor cyclic-AMP and intraocular pressure were assessed in 97 normotensive New Zealand white rabbits in vivo. The study was conducted using three experimental protocols: (A) timolol and epinephrine individually, (B) timolol and epinephrine in coadministration, and (C) timolol and epinephrine in crossover, applied either in a single dose, twice a day for two days, and/or twice a day for six days. These studies demonstrated that timolol has complex biochemical actions, one of which is beta-adrenergic antagonism. By itself, timolol had no effect on cyclic-AMP levels. However, when used in both single-dose coadministration and in pretreatment in six-day crossover with epinephrine, it significantly diminished the cyclic-AMP elevation produced by a single dose of epinephrine. In the six-day crossover protocol, pretreatment with timolol also significantly reduced the ocular hypotensive effect of a single dose of epinephrine, thereby correlating biochemical cause with clinical effect. Yet, timolol alone had no ocular hypotensive effect. Therefore, timolol's biochemical actions in this animal model cannot explain its marked clinical efficacy in man, which appears to depend on more complex pharmacologic actions.