Prostaglandin F-2 alpha and its analogs induce release of endogenous prostaglandins in iris and ciliary muscles isolated from cat and other mammalian species

Prostaglandin F-2 alpha (PGF(2 alpha)) and its analog latanoprost are effective in lowering intraocular pressure (IOP) in both animal and human subjects. There is mounting experimental evidence now which indicates that the IOP-lowering effect of these PGs occurs through an increased uveoscleral outflow of aqueous humor. The ciliary muscle constitutes the main resistance in this pathway. Work from several laboratories, including our own, has shown that in this smooth muscle PGF(2 alpha) has little effect on cAMP accumulation or on Ca2+ mobilization. In the present study, we hypothesized that some of the effects of PGF(2 alpha) and its analogs may be mediated through the release of endogenous PGs. The purpose of this work was to determine whether or not PGF(2 alpha) and its analogs can enhance the release of endogenous PGs in iris and ciliary muscles isolated from different species. This report documents for the first time that exogenous PGF(2 alpha) and its analogs, PhXA85 and latanoprost, stimulate the formation of PGE(2), PGD(2) and PGF(2 alpha) in iris and ciliary muscles isolated from cat, bovine, rabbit, dog, rhesus monkey and human. PG-induced PG release was demonstrated by means of both radioimmunoassay and radiochromatography. Kinetic studies on cat iris revealed that PGF(2 alpha)-induced PGE(2) release is time (t(1/2) = 1.7 min) and dose-dependent (EC(50) = 45 nM). The increase in PGE(2) release was blocked by indomethacin (Indo) and by dexamethasone in a dose-dependent manner with IC(50)s of 9.2 nM and 2.6 mu M, respectively. Furthermore, dexamethasone inhibited arachidonic acid (AA) release, suggesting the involvement of phospholipase A(2) in PGF(2 alpha)-induced PG release. The data presented demonstrate that PGF(2 alpha) and its analogs interact with the PG receptor to stimulate phospholipase A(2) and release AA for PG synthesis. Relaxation of ciliary muscle by PGF(2 alpha) and its analogs, via release of endogenous PGE(2), a potent activator of the adenylate cyclase system, could in part explain how these PGs may increase uveoscleral outflow and consequently lower IOP. (C) 1996 Academic Press Limited