Marked Differential Effects of Prostanoid Metabolites on Rabbit Intraocular Pressure

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Abstract
A comparison of the effects of the major metabolites of prostaglandins E2, F2.alpha., and D2 (PGF2, PGF2.alpha. and PGD2) on rabbit intraocular pressure (IOP) revealed differences in potency relative to each other and the parent prostanoid. 15-Keto PGE2.alpha. 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% PGF2.alpha. indicating a 10-fold difference in potency between PGF2.alpha. and its 15-keto metabolite. 13,14-Dihydro PGF2.alpha. appeared slightly less active than 15-keto PGF2.alpha., whereas 13,14-dihydro-15-keto PGF2.alpha. was almost 100-fold less potent than PGF2.alpha.. 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 PGF2.alpha. 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 PGF2.alpha. metabolites was of shorter duration than responses produced by the respective parent prostanoid. Although PGD2 was equipotent with PGE2 and PGF2.alpha., the 11-ketoreductase-derived metabolite (9.alpha.,11.beta.-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 PGF2.alpha. may produce marked changes in IOP: 15-keto PGF2.alpha. 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.