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Experiments were undertaken in normal albino rabbits to determine if cyclooxygenase inhibition by nonsteroidal anti-inflammatory drugs modified the ocular hypotensive activities of topically applied MK-507, MK-927 and L-662,583, three water-soluble carbonic anhydrase inhibitors (CAI). Cyclooxygenase was inhibited either by systemic indomethacin or by topically administered flurbiprofen, and epinephrine was included as a positive control. Both a 1-hr pretreatment with indomethacin (5 mg/kg i.p.) and topically applied 0.03% flurbiprofen antagonized the ocular hypotensive effect of one drop (50 microliters) of 1% epinephrine. Two percent solutions of the three CAIs were instilled three times with 10 min between each drop in order to obtain a meaningful and reproducible reduction in intraocular pressure (IOP). This dosage schedule elicited a peak decline in IOP ranging from 4.6 mm Hg to 6.2 mm Hg which was achieved via a local action within the eye. The ocular hypotensive effects of MK-507, MK-927 and L-662,583 were unaltered either by a 1-hr pretreatment with indomethacin (5 mg/kg i.p.) or by topically administered 0.03% flurbiprofen. These studies indicate that the IOP lowering actions of the three CAIs, unlike that of epinephrine, in rabbits are not mediated by endogenous prostaglandins and/or other prostanoids.

MK-927 (dl-5,6-dihydro-4-(2-methylpropylamino)-4H-thieno(2,3b)thiopyra n-2-sulfonamide-7,7-dioxide hydrochloride) is a water soluble, carbonic anhydrase inhibitor (CAI) possessing a Ki of 12.0 nM against purified human carbonic anhydrase II in vitro. The acute instillation of one drop (50 microliters) of 0.5%, 1% and 2% solutions of MK-927 maximally decreased the intraocular pressure (IOP) of ocular hypertensive, cynomolgus monkeys by 4.7, 5.9 and 9.6 mm Hg, respectively. The decline of 9.6 mm Hg represented a reduction of 27% from the corresponding vehicle-treated value of 35.3 mm Hg. Peak reductions in IOP were present at 2 to 4 hr after the instillation of the three doses and the ocular hypotensive effect was waning at 6 hr. The IOP of normotensive, monkey eyes was significantly lowered by 1% and 2% solutions of MK-927 with the effect being more transient in these eyes than in hypertensive eyes. The elevated IOP of alpha-chymotrypsinized rabbits was dose-dependently decreased by 0.01%, 0.1% and 0.5% solutions of MK-927. MK-927 modestly bound to rabbit ocular pigment in vitro and the concentrations of MK-927 in the iris + ciliary body of pigmented rabbits were higher than those in the same tissue of albino rabbits after dosing with 0.5% MK-927. The ocular hypotensive effect of 2% MK-927 was greater in magnitude and longer in duration in normal pigmented than in albino rabbits. The IOP lowering action of MK-927 was local as evidenced by results of ocular distribution studies and the observation that the unilateral instillation of 0.5% MK-927 into the contralateral eye was devoid of effect on the untreated, hypertensive eye of alpha-chymotrypsinized rabbits. MK-927 has been selected for topical evaluation in glaucoma patients.

3H-Prazosin and 3H-rauwolscine binding sites were identified in a membrane suspension prepared from albino rabbit iris + ciliary body. Scatchard analysis of saturation binding experiments demonstrated that both 3H-prazosin and 3H-rauwolscine bind to a single population of binding sites with KD values of 0.87 nM and 5.33 nM, respectively. Bmax values of 65.7 and 198 fmol/mg protein were obtained for 3H-prazosin and 3H-rauwolscine, respectively. Displacement studies by several adrenergic agonists and antagonists indicated that 3H-prazosin and 3H-rauwolscine labelled alpha 1- and alpha 2-adrenoceptors, respectively, in the iris + ciliary body. Epinephrine, norepinephrine and phenylephrine were able to stimulate the synthesis of 3H-inositol phosphates in ciliary processes labelled with 3H-inositol, with EC50 values of 2.4, 12 and 10 microM, respectively. The corresponding maximum stimulations of basal activity were 433, 430 and 283%, respectively. Phenylephrine behaved like a partial agonist in this assay. The norepinephrine response could be potently antagonized by prazosin (Ki = 27 nM), with rauwolscine being 285-fold less potent. An epithelial cell suspension was prepared from the ciliary process. Stimulation of phosphatidylinositol turnover by norepinephrine (0.1 mM) was observed, and this could be blocked by prazosin (10 microM), thus, indicating the presence of alpha 1-adrenoceptors, coupled to phosphatidylinositol turnover, in epithelial cells of the rabbit ciliary process.

The ocular distribution of the carbonic anhydrase inhibitors 6-hydroxybenzothiazide-2-sulphonamide (L-643,799) and 6-hydroxybenzothiophene-2-sulphonamide (L-650,719) has been investigated in albino rabbits after conjunctival administration of these compounds or related alkyl prodrugs. The ocular penetration of L-650,719 has been compared in ocular normotensive rabbits and in animals whose intraocular pressure has been experimentally elevated.