Effects of selective beta 1- and beta 2-adrenoreceptor agonists and antagonists on intraocular pressure in the cat.

Ocular tension of cats was measured after topical administration of the selective beta 1-adrenergic agonist CGP 7760B, the selective beta 1-adrenergic antagonist atenolol, the selective beta 2-adrenergic agonist salbutamol, the selective beta 2-adrenergic antagonist H 35/25, and the mixed beta 1- and beta 2-adrenergic antagonist timolol. Although atenolol did not alter intraocular pressure, CGP 7760B produced a modest decrease amounting to 3 to 4 mm Hg. Salbutamol, H 35/25, and timolol each produced a dose-dependent lowering of ocular tension, with maximal reductions amounting to 7, 5, and 5 mm Hg, respectively. Sympathetically denervated cat eyes showed supersensitivity to the pressure-lowering effect of salbutamol. In contrast, sympathectomy markedly reduced the effects of H 35/25 and timolol on ocular tension. Eyes rendered subsensitive to the pressure-lowering effects of cholinomimetics by chronic echothiophate treatment likewise showed diminished responsiveness to H 35/25 and timolol. Pretreatment with timolol (3 hr) completely abolished the pressure-lowering effect of salbutamol, and pretreatment with atenolol likewise completely antagonized the effect of CGP 7760B. These results suggest that beta-adrenergic receptors in the anterior segment of the cat eye are predominantly beta 2. Although beta-adrenergic antagonists apparently exert their effects on ocular tension by action at beta-adrenergic receptors, a cholinergic mechanism may be involved as well.

Effects of selective inhibition of type A and type B monoamine oxidase on intraocular pressure in the cat and the rabbit.

Ocular tension of conscious cats and rabbits was measured after topical application of clorgyline, a selective inhibitor of type A monoamine oxidase, or deprenyl, a selective inhibitor of line (1,4 and 12%) showed a dose-related reduction of intraocular pressure, with maximal lowerings amounting to 6 to 7 mm Hg. Pretreatment of eyes with clorgyline, 1%, markedly potentiated the pressure lowering response to epinephrine, 0.1%, applied topically. Sympathetic denervation almost completely abolished the effect of clorgyline. In contrast, deprenyl (2 to 8%) did not lower intraocular pressure after topical application to cat or rabbit eyes. beta-Phenylethylamine (2 to 16%) a specific substrate for the B form of monoamine oxidase, likewise did not lower ocular tension when given either alone or after pretreatment with deprenyl. These findings suggest that the intraocular pressure lowering effect of monoamine oxidase inhibitors is due primarily to inhibition of the A form of the enzyme and is dependent on intact sympathetic innervation.

Responsiveness of the rabbit eye to adrenergic and cholinergic agonists after treatment with 6-hydroxydopamine or alpha-methyl-para-tyrosine: part II--intraocular pressure changes.

The influence of adrenergic and cholinergic drugs on intraocular pressure after chemical sympathectomy produced by 6-hydroxydopamine has been examined in rabbits. For comparison, ocular tension in response to these same drugs has been measured after chronic treatment of rabbits with the norepinephrine synthesis inhibitor alpha-methyl-para-tyrosine. The results indicated that the effects of these 2 treatments were both qualitatively and quantitatively similar. In both cases, supersensitivity to the pressure-lowering effects of alpha and beta adrenergic amines developed. After administration of cholinergic drugs, however, ocular tension became elevated to values ranging from 3 to 7 mm Hg above the baseline levels.

Responsiveness of the rabbit eye to adrenergic and cholinergic agonists after treatment with 6-hydroxydopamine or alpha-methyl-para-tyrosine: Part I--Pupillary changes.

The responses of rabbit pupils to graded doses of both adrenergic and cholinergic drugs after chemical sympathectomy with 6-hydroxydopamine have been examined. For comparison, similar data were obtained in rabbits treated chronically with the norepinephrine synthesis inhibitor, alpha-methyl-para-tyrosine. While quantitative differences were apparent, the effects of these 2 treatments were qualitatively similar. In both cases, a marked reduction in the responsiveness of the iris to cholinergic agonists accompanied the development of supersensitivity to adrenergic amines.

Enhanced ocular penetration of the methyl ester of (+/-) alpha-methyl-para-tyrosine after lontophoresis.

A comparative study of ocular penetration of the methyl ester of (+/-) alpha-methyl-para-tyrosine after the intraperitoneal route of administration versus that after the more localized subconjunctival and iontophoretic routes has been undertaken. Levels of alpha-methyl-para-tyrosine in the aqueous humor of rabbits were measured both 2 and 6 hr affter drug administration. Changes in norepinephrine levels in iris and ciliary processes at these time points were also determined. The results indicated that the highest concentrations of the drug in aqueous were reached 2 hr after iontophoresis (40 mg/ml, positive pole, 3 mamp for 5 min), at which time norepinephrine tissue levels were reduced by 20%. While norepinephrine levels 2 hr after the intraperitoneal route (100 mg/kg) remained unchanged, those after subconjunctival injection (5 mg in 0.3 ml saline) were slightly but significantly elevated. By 6 hr after alpha-methyl-para-tyrosine administration by each route, only small amounts of the drug were detected in aqueous humar. Norepinephrine levels in iris and ciliary processes after iontophoresis, however, were still depleted by 20%. Norepinephrine stores after the intraperitoneal route likewise were reduced by 20%, while those after subconjunctival injection did not differ from control. These results suggest that iontophoresis, in addition to confining the site of drug action, actually enhances ocular penetration.

Alterations in adrenergic sensitivity of the rabbit iris after variation of environmental lighting conditions.

After variation of the environmental lighting conditions, pupillary diameters of albino rabbits in response to progressively increasing doses of the sympathomimetics norepinephrine, epinephrine, and isoproterenol were measured. After maintenance of the rabbits under conditions of constant light for one week, an increased sensitivity of the iris dilator to the mydriatic effects of these adrenergic agents became evident. After maintenance of the rabbits in constant dark for one week, on the other hand, there was no change in the sensitivity of the iris upon administration of the same sympathomimetics. Norepinephrine levels measured in iris and ciliary processes after one week of either constant light of constant dark, moreover, did not differ significantly from those determined under normal lighting conditions. These results indicate that the sensitivity of the iris dilator can be altered by variation of the physiologic stimulus, light. In addition, the chronic interruption of contact between the normal neurotransmitter norepinephrine and its effector cells leading to supersensitivity in the dilator appears to be due to the removal of a trophic influence of norepinephrine, rather than its absolute loss.