Forskolin stimulates cyclic AMP synthesis, lowers intraocular pressure and increases outflow facility in rabbits

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.