Mechanism of production of intestinal secretion by elevated venous pressure.

A study was carried out to elucidate the physiological mechanisms responsible for the intestinal secretion produced by venous pressure elevation. In dogs, measurements were made of the rate and composition of small intestinal secretion, rate of flow and composition of intestinal lymph, plasma composition, and mucosal water content, all in response to elevations of intestinal venous pressure. Venous pressure elevations above a threshold value of 30-35 cm H2O produce secretion at a rate of approximately proportional to the value of the pressure minus the threshold value. Above the threshold value, there were large increases in the rates of lymph flow and net sustained transcapillary filtration. These rates were also roughly proportional to the incremental venous pressure. It is concluded that intestinal secretion produced by elevated venous pressure is almost surely secretory filtration, a passive process with the driving force for secretion an increase in mucosal tissue fluid pressures to values of only some 4-6 cm H2O. The increased tissue fluid pressure not only provides the driving force but also produces an increase in the hydraulic permeability of the epithelium without which the driving force would be ineffective. The transepithelial channels are large enough to permit insulin to pass freely and even plasma protein to pass in large amounts, and hence are most probably intercellular. Secretory filtration probably represents a general pathophysiological response of transporting epithelia to elevated tissue fluid pressure. It is proposed that the threshold value for secretion and associated changes is explained by dilution of the tissue fluid protein colloid osmotic pressure in a small subepithelial, juxtacapillary compartment.

Eicosanoids as a new class of ocular hypotensive agents. 2. Comparison of the apparent mechanism of the ocular hypotensive effects of A and F type prostaglandins.

It has recently been shown that derived prostaglandins (PGs) of the A and B types are much more potent ocular hypotensive agents than primary PGs of the E, F, or D type. The purpose of this study was to determine whether two representatives of these structurally different PGs, namely PGA2 and PGF2 alpha-1-isopropyl ester (PGF2 alpha IE), reduce intraocular pressure (IOP) of the feline eye by similar or dissimilar mechanisms. Aqueous humor flow rate was determined by a fluorophotometric technique, Schiotz electronic tonography was used to measure outflow facility and venomanometry was done to measure episcleral venous pressure. Although at the doses used, both PGF2 alpha IE (2.5 micrograms/eye) and PGA2 (5.0 micrograms/eye) caused significant IOP reduction within 2.5 hr after their topical application, neither caused a significant decrease in aqueous humor flow rate, a significant increase in outflow facility or a change in episcleral venous pressure. It was concluded, therefore, that both of these PGs reduce IOP by an apparently similar mechanism, presumably by increasing uveoscleral outflow.

Effect of oxygen on aqueous humor dynamics in rabbits.

A study was made in albino rabbits of the effect on aqueous humor dynamics of 100% oxygen, administered by face mask. A mean decrease in intraocular pressure of 4.9 mm Hg was found. This was accompanied by a decrease in episcleral venous pressure of 4.5 mm Hg. Anterior chamber aqueous humor flow decreased transiently after oxygen administration but returned to pre-oxygen levels after about 60 min. It was concluded that the sustained decrease in intraocular pressure which was caused by oxygen was secondary to the decrease in episcleral venous pressure and not to a decrease in the production of aqueous humor.

Dexamethasone, D-penicillamine, and glaucoma filter surgery in rabbits.

A study was made in rabbits of the effect of topical dexamethasone ointment, .05%, and either subconjunctival or intraperitoneal D-penicillamine on the duration of function of glaucoma filtering surgery. The drugs were tested alone and in combination. Intraperitoneal D-penicillamine was not effective, either alone or combined with topical dexamethasone. Topical dexamethasone ointment alone and subconjunctival D-penicillamine alone significantly prolonged the duration of function of the filter surgery; however, when combined, no additional effect was observed. It was concluded that the institution of therapy with both drugs immediately after glaucoma filtering surgery was not the optimal temporal sequence for combining the two modes of therapy.

Oxygen lowers intraocular pressure.

A significant decrease in intraocular pressure was demonstrated in 14 patients as atmospheric pressure was increased at intervals of 0.5 atmospheric pressure up to 3 atmospheres within a hyperbaric chamber. Nine of these patients had the identical protocol repeated in room air at atmospheric pressure without a significant change in intraocular pressure. Administration of 100% O2 at 15 L/min by partial rebreathing face mask to these patients using the same protocol at atmospheric pressure resulted in a significant decrease in intraocular pressure. The results in the oxygen and hyperbaric groups were not statistically different. While in the hyperbaric chamber, scleral rigidity increased uniformly, outflow facility decreased significantly, and keratometry readings remained unchanged. A significant decrease in intraocular prssure occurred in 20 rabbits that received 100% oxygen by partial rebreathing face mask for 180 minutes. Arterial blood gases were obtained at 0.90, and 180 min in seven rabbits. The pH and pCO2 did not change significantly; however, pO2 was markedly elevated. Increased oxygen concentration was felt to be responsible fot the decrease in intraocular pressure and the changes in other parameters observed in patients and rabbits.

Effect of cold air on aqueous humor dynamics in humans.

Several parameters of aqueous humor dynamics were measured in 11 human subjects before and after exposure of one eye to a continuous stream of cold air. In the treated eye, I.O.P. was found to decrease significantly from a mean +/- SD pre-treatment value of 14.1 +/- 2.3 mmHg to a post-treatment value of 12.6 +/- 2.6 mmHg. Episcleral venous pressure was found to decrease significantly from a pre-treatment value of 6.2 +/- 1.3 mm Hg. No significant changes were found in aqueous flow or total outflow facility, indicating that cold air exposure decreased I.O.P. by causing a decrease in episcleral venous pressure.

Fluorophotometric study of intravenous carbonic anhydrase inhibitors in rabbits.

The ability of fluorophotometry to measure the time course of changes in aqueous humor flow in rabbits was evaluated by measuring the effect of intravenous carbonic anhydrase inhibitors on aqueous humor flow determinations. The abrupt changes in aqueous humor flow which were found by fluorophotometry agreed well with the expected changes in aqueous humor flow calculated from the time course of the intraocular pressure. Therefore, it was concluded that fluorophotometry could measure the time course of changes in aqueous humor flow in rabbits. Furthermore, it was suggested that the initial abrupt changes in aqueous humor flow after the administration of a carbonic anhydrase inhibitor were induced by the base content of the drug, followed by a more gradual decrease in aqueous humor flow caused by the direct effect of the drug on aqueous humor formation.

Timolol maleate: efficacy and safety.

A randomized, double-masked trial of various concentrations of timolol maleate ophthalmic solution (0.1%, 0.25%, 0.5%, and 1.0%) vs placebo demonstrated that all concentrations of timolol effectively lowered intraocular pressure (IOP). A 0.5% solution of timolol was as effective in reducing IOP as the 1.0% concentration. Blood pressure, visual acuity, and pupillary diameter were not altered significantly by any concentration of timolol tested during this study. There was a dose-dependent decrease in resting pulse rate with increasing concentrations of timolol. No objective signs of drug intolerance were found on external ocular examination, nor were any subjective symptoms elicited on questioning the subjects. Timolol applied topically twice daily in concentrations of 0.1% to 0.5% appeared to be an effective and safe ocular hypotensive agent.

Fluorophotometric study of epinephrine and timolol in human subjects.

The action and interaction of topical 2% epinephrine hydrochloride and 0.5% timolol maleate therapy were studied in 12 normal and 16 ocular hypertensive subjects. Measurements of intraocular pressure, outflow facility, and aqueous secretion by fluorophotometry were made. Uveoscleral outflow values were calculated. Epinephrine, applied topically twice daily for one week, resulted in a decrease in IOP of 3.3 +/- 0.9 mm Hg and an increase in outflow facility of 0.05 +/- 0.01 microL/min/mm Hg, as well as an increase in the rate of aqueous production of 0.32 +/- 0.09 microL/min. Uveoscleral outflow showed an increase of 0.83 +/- 0.23 microL/min. Timolol, applied topically twice daily for one week, reduced the IOP 3.9 +/- 1.0 mm Hg and decreased aqueous flow 0.84 +/- 0.23 microL/min, but produced no change in outflow facility or uveoscleral flow. When epinephrine and timolol are given in combination, the effects in lowering IOP may not be completely additive.

Cataracts induced by topical dexamethasone in diabetics.

Eleven diabetic patients were treated with unilateral topical dexamethasone for 14 to 36 months in an attempt to control their retinopathy. Cataracts developed in the treated eye of nine patients, compared with only one cataract in an untreated eye.

Effects of brimonidine on aqueous humor dynamics in human eyes.

OBJECTIVE: To evaluate the mechanism by which brimonidine, a selective alpha 2-adrenergic agonist, lowers intraocular pressure (IOP) in humans. SUBJECTS: Twenty-one volunteers with ocular hypertension. METHODS: Brimonidine tartrate (0.2%) was given topically twice daily for 1 week to one eye in a randomized, double-masked study. The fellow eye was similarly treated with brimonidine vehicle. Before (baseline) and after 1 week (day 8) of dosing, IOP, aqueous flow, episcleral venous pressure, and tonographic outflow facility were directly measured. Fluorophotometric outflow facility and uveoscleral outflow were calculated. Brimonidine-treated eyes were compared with vehicle-treated contralateral control eyes and with baseline measurements after 1 week of dosing. RESULTS: Brimonidine significantly (P < .001, Student's two-tailed t test) reduced IOP mean +/- SE of 4.7 +/- 0.7 and 4.2 +/- 0.4 mm Hg compared with the baseline day and with the vehicle-treated contralateral control eyes, respectively. Compared with the baseline day, aqueous flow was reduced by 20% (P = .002) and uveoscleral outflow was increased (P = .04). A slight contralateral decrease in IOP of 1.2 +/- 0.6 mm Hg (P = .05) and in aqueous flow of 12% (P = .05) was noted. No significant difference was seen in the outflow facility values or episcleral venous pressure compared with the baseline day or with the contralateral control eye. CONCLUSIONS: The brimonidine-induced reduction in IOP in humans is associated with a decrease in aqueous flow and an increase in uveoscleral outflow. The decrease in IOP and aqueous flow in the contralateral control eye on day 8 compared with the baseline day suggests a mild contralateral effect.

Dipivefrin and echothiophate. Efficacy of combined use in human beings.

In a previous study, pretreatment of rabbit eyes with echothiophate iodide prevented the ocular hypotensive effect of dipivefrin. The present masked study, using inpatient volunteers and nurse-administered drops, investigated whether a similar antagonism of action occurred in human beings. Eight volunteers received 0.25% echothiophate iodide twice a day in both eyes for three weeks. During the second week of therapy, one eye also received 0.25% dipivefrin twice a day and the contralateral eye received 2% epinephrine hydrochloride twice a day. During the third week of therapy, the eyes receiving dipivefrin and epinephrine were reversed. In four volunteers, dipivefrin plus echothiophate produced a significantly greater reduction in intraocular pressure than epinephrine plus echothiophate. As a group the eight eyes treated with dipivefrin plus echothiophate had significantly lower IOPs than the eyes treated with epinephrine plus echothiophate during the second week of therapy. Epinephrine plus echothiophate was never superior to dipivefrin plus echothiophate. Dipivefrin seemed to be effective during combination therapy with echothiophate.

Dipivefrin use in patients with intolerance to topically applied epinephrine.

Twelve patients who had previously demonstrated an intolerance to topically applied epinephrine received dipivefrin 0.1% in one eye and epinephrine 2% in the other eye. An adverse reaction occurred in only one eye (8%) receiving dipivefrin, but in ten (83%) on epinephrine. Topical dipivefrin 0.1% proved useful for lowering intraocular pressure in patients intolerant to topically applied epinephrine.

Topical nylidrin and aqueous humor dynamics in rabbits and monkeys.

Topical administration of nylidrin hydrochloride lowered intraocular pressure in both albino rabbits and cynomologus monkeys. The maximum decrease occurred two hours following drug application and was unilateral. The response lasted four hours in monkeys and at least six hours in rabbits. Outflow facility, episcleral venous pressure, and aqueous humor flow measured by fluorophotometry were unaltered in both species. In rabbits in the treated eyes, ocular blood flow was increased, and anterior and posterior chamber ascorbate concentrations were unchanged. The mechanism of IOP reduction appears to be increased aqueous humor outflow via uveoscleral outflow routes that are not pressure dependent.

Effects of exogenous prostaglandins on aqueous humor dynamics and blood-aqueous barrier function.

Topical prostaglandins (PGs) are very effective at reducing intraocular pressure (IOP) in a variety of animals and in humans with relatively few side effects. The mechanisms of action of several PGs, their prodrugs and analogues have been studied in rabbits, cats, monkeys and humans. PGF2 alpha and its analogues evaluated in monkeys include PGF2 alpha-tromethamine salt, PGF2 alpha -isopropylester (-IE), S-1033, PhXA34, PhDH100A and latanoprost (PhXA41). Aqueous flow and outflow facility are either increased or remain unchanged by these agents. PGF2 alpha-IE, PHXA34, PhDH100A and latanoprost increase uveoscleral outflow, accounting for most of the IOP reduction. PGA2 in cats increases aqueous flow and outflow facility, but it reduces IOP primarily by stimulating uveoscleral outflow. The PGD2 analogue BW245C is unique in that it is the only PG that decreases aqueous flow. Mechanistic studies in humans have been performed with PGF2 alpha -IE, unoprostone, PhXA34 and latanoprost. In two clinical studies with latanoprost, a significant increase in uveoscleral outflow was found which, as in animals, accounts for most of the IOP reduction. A slight but inconsistent increase in outflow facility may also be involved. The doses tested had minimal effects on the permeability of the blood-aqueous barrier (BAB). In vitro studies of human tissue have been conducted to elucidate the PG effect on outflow facility and uveoscleral outflow. Studies of isolated human anterior segment preparations show that PGE2 increases outflow facility whereas PGF2 alpha has no measurable effect on this parameter. Studies of human ciliary muscle cells in tissue culture indicate that PGs may directly modulate extracellular matrix metabolism, which may be related to the increased uveoscleral drainage. This review summarizes in vitro and in vivo studies of the effects of PGs on aqueous humor dynamics and BAB integrity in humans, cats and monkeys.

A new portable applanation tonometer.

A portable applanation tonometer consisted of a Goldmann applanation doubling prism mounted on a dynamometer. Results obtained on 100 consecutive eyes showed a good correlation with the standard slit-lamp mounted applanation tonometer. This portable tonometer is small and easy to use, utilizing the same end point as the standard Goldmann tonometer. In addition, the patient may assume almost any position.

A new fundus lens ophthalmodynamometer.

I devised a new ophthalmodynamometer by means of which a measured force is applied to a fundus lens, while the disk vessels are viewed at the slit-lamp microscope. In my hands, the new device was superior to the Bailliart ophthalmodynamometer when tested in normal volunteers. With the fundus lens ophthalmodynamometer, the diastolic end point differed between the two eyes by a mean of 2.3%, compared to 6.4% with the Bailliart. The new device showed a better correlation with systemic diastolic blood pressure than did the Bailliart instrument. The effect of intraocular pressure on the reading with the fundus lens device was significant, although variable.

A fluorophotometric study of the effect of argon laser trabeculoplasty on aqueous humor dynamics.

Fluorophotometry and tonography were used before and after argon laser trabeculoplasty to measure aqueous humor dynamics in 15 eyes of 14 patients. A new fluorophotometric method used to measure true outflow facility showed that it increased from a mean pretreatment value of 0.016 microliter/min/mm Hg to a mean posttreatment value of 0.075 microliter/min/mm Hg. Similarly, total outflow facility, measured tonographically, increased from 0.112 microliter/min/mm Hg to 0.151 microliter/min/mm Hg. Uveoscleral flow decreased after laser therapy; however, this was secondary to the decrease in intraocular pressure. No effect was found on the rate of aqueous humor production. We concluded that the primary effect of argon laser trabeculoplasty was to increase true outflow facility, thereby decreasing intraocular pressure.

Acute versus chronic effects of brimonidine on aqueous humor dynamics in ocular hypertensive patients.

PURPOSE: To report the acute vs chronic effects of brimonidine, a selective alpha2-adrenergic receptor agonist, on aqueous humor dynamics in ocular hypertensive patients. METHODS: Brimonidine 0.2% was given topically twice daily for 29 days to one eye each of 28 ocular hypertensive volunteers in a randomized double-masked study. The fellow eye was similarly treated with vehicle. Aqueous flow (Fa) and outflow facility (Cfl) were determined with fluorophotometry. Intraocular pressure, outflow facility (Cton), and episcleral venous pressure (Pev) were measured with pneumatonometry, tonography, and venomanometry, respectively. Uveoscleral outflow (Fu) was calculated from intraocular pressure, Fa, Pev, and Cfl values. All measurements were taken on baseline day, day 8, and day 29 of treatment. Intraocular pressure and Fa only were measured after instillation of 1 drop of brimonidine on day 1. RESULTS: When measured 3 hours after instillation on days 1, 8, and 29 of treatment, brimonidine significantly (P < .001) reduced intraocular pressure by at least 5.0 +/- 0.7 mm Hg (mean +/- SEM) compared with baseline day, and by 2.7 +/- 0.5 mm Hg compared with the vehicle-treated contralateral control eyes. The greatest decrease (6.0 +/- 0.6 mm Hg) was observed at 3 hours after the first drop. Aqueous flow was reduced by 29% (P < .001) after the first application but was not significantly different from baseline when measured at day 29 of treatment. Uveoscleral outflow was increased 60% at day 8 (P < .06) and day 29 (P < .05) compared with baseline. There was no significant difference in outflow facility or episcleral venous pressure at day 8 or day 29 of treatment. CONCLUSIONS: The brimonidine-induced reduction in intraocular pressure in humans is associated initially with a decrease in aqueous flow, and after chronic treatment with an increase in uveoscleral outflow.

Prognostic significance of optic disk cupping in ocular hypertensive patients.

The stereoscopic photographs of 102 patients with increased intraocular pressure (IOP) and normal visual fields were graded for cup:disk ratio. All patients were followed up for a five-year period, during which time 27 patients developed glaucomatous visual field loss and 75 patients did not. The patients who subsequently developed glaucomatous visual field loss had significantly larger cup:disk ratios than did the patients who did not develop glaucomatous visual field loss. Patients with a mean IOP greater than or equal to 28 mm Hg and a vertical contour cup:disk ratio greater than or equal to 0.6 had a 100% incidence of the development of glaucomatous visual field loss as compared to a 2% incidence in those with a mean IOP less than 28 mm Hg and a vertical cup:disk ratio less than 0.6. Disk:cup asymmetry and progressive increase in the area of the disk occupied by the cup was more common in the group that developed glaucomatous visual field loss.