Marvin Sears

Cyclic-AMP in the aqueous humor: The effects of adrenergic agents

Adrenergic agents, which reduced intraocular pressure when applied topically to the rabbit eye, increased the cyclic-AMP concentration in the aqueous humor. The order of potency for both reducing intraocular pressure and increasing cyclic-AMP was: epinephrine > norepinephrine > isoproterenol. Intravenous phenoxybenzamine partially blocked the decrease in intraocular pressure and the increase in cyclic-AMP. Intravenous propranolol was ineffective. Topically applied aminophylline, theophylline, and dibutyryl cyclic-AMP were also ineffective. The time course for the epinephrine induced mydriasis was different from the time course for the decrease in intraocular pressure and the increase in cyclic-AMP. The pupil dilated rapidly and then slowly returned to baseline values over the next 4 hr. The intraocular pressure and cyclic-AMP responses peaked at approximately the same time (1·5 hr) and were sustained for at least 5 hr. Substantial tissue levels of cyclic-AMP were found in the cornea, iris-ciliary body and retina-choroid. However, no differences in tissue level could be demonstrated in the control versus epinephrine-treated eye. Thus the site of production of the increased cyclic-AMP in the aqueous humor is not yet resolved. Intracameral injection of high concentrations of cyclic-AMP (estimated final concentration in anterior chamber: 4 × 10−4m) caused a marked decrease in intraocular pressure. Similar injections of 5′AMP into the other eye of the same animal were ineffective. The experiments indicate that cyclic-AMP plays a central role in mediating the action of catecholamines on aqueous humor dynamics. The role of the increase in the aqueous humor and possible sites of production and action of the cyclic-AMP are discussed.

Forskolin lowers intraocular pressure in rabbits, monkeys, and man.

Topical ocular application of forskolin, a diterpene that increases intracellular cyclic adenosine monophosphate by stimulating adenylate cyclase directly without cell surface mediation, lowered intraocular pressure (IOP) in rabbits, monkeys, and volunteers who were free from eye disease. In man 50 microliters of a topical suspension of 1% forskolin significantly lowered IOP in 1 h, the effect reaching a peak at 2 h but remaining significant for at least 5 h. Outflow pressure fell by 70% on average. Forskolin and its analogues represent a new class of drugs active against glaucoma which differ in their molecular actions from any previously used drug.

Quantitative Evaluation of the Optic Nerve Head in Patients with Unilateral Visual Field Loss from Primary Open-angle Glaucoma

Measurable structural alterations of the optic nerve head may precede visual field abnormalities in early open-angle glaucoma. The authors studied the optic nerve heads of 10 patients with unilateral visual field loss from primary open-angle glaucoma, and 12 age- and sex-matched normal subjects. Topographic optic nerve head parameters were measured with a system of computerized image analysis (Rodenstock Analyzer, G. Rodenstock Instrumente GMBH, Munich, W. Germany). In patients with asymmetric primary open-angle glaucoma, eyes with normal visual fields had a slightly larger mean (+/- standard error of the mean) disc rim area (0.90 +/- 0.04 mm2) than eyes with glaucomatous visual field defects (0.78 +/- 0.05 mm2). However, both sets of eyes in the asymmetric primary open-angle glaucoma patients had smaller mean disc rim areas (P less than 0.0007) than did the control group (1.27 +/- 0.09 mm2). These findings support the hypothesis that loss of the optic disc rim can be detected before perimetric abnormalities develop in primary open-angle glaucoma.

Leber's Congenital Amaurosis

An early stage of Lebers congenital amaurosis, characterized by white spots or lines in the fundus, occurred in two children. Light microscopic examination of eyes obtained from one child, a 16-month-old Japanese girl, revealed subretinal deposits corresponding to the white spots and lines in the fundus deposits. Light and electron microscopic examination of the eye showed distinctive changes in the outer retinal layers and choroid, while the inner retinal layers were nearly normal. Characteristic early lesions of congenital amaurosis appeared to be produced by deposits consisting of loose outer segments and apical processes of the pigmental epithelial cell and macrophages. Undifferentiation in the nuclei of the photoreceptor cell, the inner segment, the pigment epithelial cell, and the choriocapillaris were likely characteristics of the early changes of congenital amaurosis.

Patterns of Early Visual Field Loss in Open-Angle Glaucoma

We examined two groups of patients with primary open-angle glaucoma with distinctly different patterns of early visual field loss using two visual field indices: mean defect and loss variance. Patients were selected on the basis of visual field criteria only. Eight patients were selected for diffuse depression of the differential light sensitivity without localized scotomas (mean defect greater than 3.0 decibels, loss variance less than 10.0 decibels). Seven patients were selected for localized scotomas without diffuse depression of the differential light sensitivity (mean defect less than or equal to 3.0 decibels, loss variance greater than or equal to 20.0 decibels). Patients with diffuse depression manifested intraocular pressures that were higher (mean peak pressure +/- S.E.M., 27.6 +/- 1.2 mm Hg) than those with localized defects (22.4 +/- 1.4 mm Hg). The optic disk rim area of the localized loss group (mean +/- S.E.M., 1.02 +/- 0.15 mm2) was significantly smaller (P less than .05) than the disk rim area of the diffuse loss group (1.33 +/- 0.07 mm2). This difference was largely because of thinner temporal disk rims in the localized loss group. Different patterns of visual field loss may be caused by different mechanisms of glaucomatous optic nerve damage.

Hormonal regulation of intraocular pressure

A detailed review of the hormonal effects on intraocular pressure is presented. There is evidence that corticotropin, vasopressin, thyroxin, insulin, glucocorticoids and mineralocorticoids may play a role in the physiologic regulation of intraocular pressure. Growth hormone, melanocyte stimulating hormone, progesterone, estrogen, chorionic gonadotropin and relaxin may influence intraocular pressure when administered in pharmacologic doses. Whether the key to understanding primary open-angle glaucoma lies in recognizing abnormal endocrine mechanisms, especially involving glucocorticoids, remains unclear at the present time.

Regulation of Aqueous Flow by the Adenylate Cyclase Receptor Complex in the Ciliary Epithelium

The answer to how the beta-adrenergic receptor mediates a fall in intraocular pressure has been elusive. Methods of measurement have not been refined sufficiently. The separate changes after adrenergic treatment frequently are small, and the tissue effects are multiple. On a molecular basis, stimulation of the beta-adrenergic receptor activates intracellular adenylate cyclase to produce increased cyclic adenosine monophosphate. Acting by different cell-receptor mechanisms, but nonetheless potent, nonadrenergic stimulators of adenylate cyclase in the ciliary epithelium, such as cholera toxin and organic fluorides, have been studied in experimental animals. They reduce intraocular pressure by reducing net aqueous flow. When forskolin, a diterpene and potent stimulator of adenylate cyclase, became available, it was used in noninvasive topical form in the human eye to clarify the question of whether increased cyclic adenosine monophosphate reduces intraocular pressure and aqueous flow. Noninvasive studies in human eyes have demonstrated a 35% reduction in outflow pressure after the administration of forskolin in a 1% topical suspension, matched by a corresponding reduction in aqueous flow. Tonographic outflow facility was unaltered. Thus, the entire reduction in intraocular pressure can be accounted for by a reduction in net aqueous flow.

The site of action of prostaglandin E2 on the disruption of the blood-aqueous barrier in the rabbit eye

Abstract The protein content of the anterior chamber and posterior chamber was determined soon after trauma to the eye. The trauma was topical administration of prostaglandin E 2 or paracentesis of the anterior chamber in untreated rabbits or rabbits treated with aspirin. The results are consistent with the hypothesis that the site of action of prostaglandin E 2 is on the tight junctions of the non-pigmented epithelial cells of the ciliary body. The possible routes of flow of plasmoid aqueous humor into the anterior chamber after trauma is discussed.

Cervical ganglionectomy alters the circadian rhythm of intraocular pressure in New Zealand White rabbits.

A circadian rhythm of intraocular pressure in rabbits could provide a useful model for understanding the daily rhythm of intraocular pressure in humans and for studying mechanisms which regulate intraocular pressure. Our results confirm earlier work showing that New Zealand White rabbits housed in an environment with a lighting cycle of 12 hours light and 12 hours dark have a rhythm of intraocular pressure, and that this rhythm persists in constant dark. We show further that the cycle of light and dark is the zeitgeber for entrainment of the rhythm of intraocular pressure, and therefore persistence of this rhythm in constant dark establishes it as a circadian rhythm. Cervical ganglionectomy demonstrated that intact sympathetic innervation to the eye is required for maintenance of the normal circadian rhythm of intraocular pressure in rabbits. Intraocular pressure in sympathectomized eyes is no different from control eyes during the light, but is significantly reduced during the dark.

Interaction between alpha2-and beta2-adrenergic receptors in rabbit ciliary processes

The interaction between the alpha 2- and beta 2-adrenergic receptors of ciliary processes has been studied by examining dose-response curves for adrenergic agonist stimulation of cyclic AMP production by intact, excised rabbit ciliary processes. Stimulation of cyclic AMP production by 1-isoproterenol is maximum from 0.1 to 1.0 microM; at higher concentrations stimulation decreases and approaches basal levels. Decreased cyclic AMP production at high concentrations of isoproterenol is blocked by the specific alpha 2-adrenergic antagonist, yohimbine, but not by the alpha 1-adrenergic antagonist, prazosin. Ciliary processes from animals after bilateral cervical ganglionectomy also show reduced cyclic AMP production at high concentrations of isoproterenol and this reduction is blocked by yohimbine, but not prazosin. This experiment suggests that the inhibition at high concentrations of isoproterenol is mediated by postsynaptic alpha 2-adrenergic receptors. Cyclic AMP production is relatively insensitive to epinephrine and norepinephrine, but their responses are potentiated by yohimbine. Catecholamines and clonidine, a specific alpha 2-adrenergic agonist, exhibit dose-dependent inhibition of forskolin-stimulated cyclic AMP production by ciliary processes. I50s from the dose-response curves are consistent with the characteristic binding affinities of these adrenergic agonists for alpha 2-adrenergic receptors: clonidine = epinephrine greater than norepinephrine greater than isoproterenol. Inhibition of forskolin-stimulated cyclic AMP production by clonidine is blocked by yohimbine but not by prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)