Marked Differential Effects of Prostanoid Metabolites on Rabbit Intraocular Pressure

Abstract

A comparison of the effects of the major metabolites of prostaglandins E₂, F_2α, and D₂ (PGE₂, PGF_2α and PGD₂) on rabbit intraocular pressure (IOP) revealed differences in potency relative to each other and the parent prostanoid. 15-Keto PGF_2α produced significant, dose-dependent decreases in IOP at 0.1 and 1 % doses; responses of a similar magnitude were achieved with 0.01 and 0.1% PGF_2α indicating a 10-fold difference in potency between PGF_2α and its 15-keto metabolite. 13,14-Dihydro PGF_2α appeared slightly less active than 15-keto PGF_2α, whereas 13,14-dihydro-15-keto PGF_2α was almost 100-fold less potent than PGF_2α PGE₂ was approximately 100-fold more potent as an ocular hypotensive than its 15-keto and 13,14-dihydro-15-keto metabolites. 19(R)-OH PGF_2α did not alter IOP, whereas 19(R)-OH PGE₂ was essentially equipotent to PGE₂ as an ocular hypertensive without producing the typical subsequent decrease in IOP. The decrease in IOP evoked by active PGE₂ and PGF_2α metabolites was of shorter duration than responses produced by the respective parent prostanoid. Although PGD₂ was equipotent with PGE₂ and PGF_2α, the 11-ketoreductase-derived metabolite (9α, l lβ-PGF₂) exhibited little effect on IOP, and 13,14-dihydro-15-keto PGD₂ was inactive. The thromboxane A₂ (TxA₂)-mimetic U-46619 and TxB₂ did not significantly alter IOP. Thus, it appears that the natural metabolites of PGE₂ and PGF_2α may produce marked changes in IOP: 15-keto PGF_2α appears to be only 10-fold less active than the parent prostanoid in terms of ocular hypotension, and 19(R)-OH PGE₂ is virtually equipotent to PGE₂ as an ocular hypertensive but lacks significant hypotensive activity.