The intracellular pathway by which beta-adrenergic agonists and antagonists affect aqueous humor dynamics involves the intracellular mediator, cyclic AMP. We have therefore tested the activity of forskolin, a direct activator of adenylate cyclase, in rabbits. Following a 15 min in vitro incubation in the presence of forskolin (15 microM) and isobutylmethylxanthine, a 10 fold increase in cyclic AMP was found in both rabbit iris-ciliary body and scleral-trabecular rings relative to controls. Following an intracameral injection of forskolin (10 micrograms) a time-dependent decrease in intraocular pressure was observed, which reached a mean decrease of 5 mm Hg at 4 hr in unanesthetized rabbits. Outflow facility was measured in anesthetized rabbits by constant pressure perfusion before injection and 1 hr after injection of either forskolin (10 micrograms) or control vehicle. Forskolin caused an approximate doubling of outflow facility (0.41 microliter/min/mm Hg) compared to the preinjection mean value. Control vehicle, ethyl alcohol, caused a statistically insignificant increase in outflow facility. At this concentration of forskolin, the integrity of the blood-aqueous barrier was normal as measured by protein and fluorescein entry into the aqueous humor. These results indicate that agents which directly activate adenylate cyclase are effective at increasing outflow facility and decreasing IOP.

Forskolin was used to study cyclic AMP-mediated regulation of aqueous humor dynamics in rabbits. Crystalline forskolin was solubilized in oil and its pharmacological effects were studied both in vitro and following topical ocular administration. In vitro, using cultured corneal epithelial cells, forskolin rapidly stimulated cyclic AMP production and in vivo increased cyclic AMP concentration in the aqueous humor 10-fold following topical administration. The effect of topical forskolin on intraocular pressure and aqueous humor formation was determined in vivo using pneumatonometry and fluorophotometry, respectively. Forskolin caused a prolonged reduction of intraocular pressure and decreased aqueous humor formation. The ability of forskolin to potentiate the ocular hypotensive effect of epinephrine was investigated. Forskolin in combination with epinephrine caused a decrease in intraocular pressure of longer duration than either 0.1% epinephrine or 1% forskolin administered separately. Forskolin caused a small but significant increase in the permeability of the blood-aqueous barrier at the time of maximal intraocular pressure reduction. This effect on the blood-aqueous barrier may explain the inhibitory effect of forskolin on aqueous humor formation.