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

Abstract

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.

MRP4-Mediated Regulation of Intracellular cAMP and cGMP Levels in Trabecular Meshwork Cells and Homeostasis of Intraocular Pressure

“…21,23 TM cells and tissues of the AH outflow pathway have been demonstrated to express both the cyclases and phosphodiesterases and they have been reported to participate in modulation of AH outflow in different species. 20,[24][25][26][27][28][29][30] From the…”

Role of cyclic AMP‐induced Cl conductance in aqueous humour formation by the dog ciliary epithelium

“…This implies that considerable elevation in IOP could result from P-adrenoceptor stimulation, considering that the basal rate of aqueous humour production is about 2.5 fl min-' (Guyton, 1991). However, in vivo, the consequences of elevated cyclic AMP in the eye are not confined to modulation of the rate of aqueous humour production, but may include the decreased resistance to outflow (Bartels et al, 1982) or the altered activity of the sympathetic nervous system (Potter et al, 1985). Recent experiments with in vivo fluorophotometry suggest that the P-antagonist, timolol, produces a significant reduction in the rate of aqueous flow in the dark, in which the cyclic AMP level in the aqueous humour is increased due to the increased activity of sympathetic nerves .…”

A Synopsis of Recent Developments in Antiglaucoma Drugs

“…Forskolin (10 yg, intracamerally), a direct activator of adenyl cyclase, lowered IOP in rabbits (197). Topical forskolin on rabbit (0.1%, 1%, and 4%), monkey (1%), and normal human (1%) eyes significantly reduced IOP (198,199).…”

“…Topical forskolin on rabbit (0.1%, 1%, and 4%), monkey (1%), and normal human (1%) eyes significantly reduced IOP (198,199). There was some disagreement as to whether the mechanism was an increase in outflow facility (197) or a decrease in AH formation (198,199). Tolerance did not develop in rabbits (198) but did in monkeys (199).…”