Increase In Outflow Facility Research Articles

Pigment release.

Guttae phenylephrine 10% produced a significant decrease in intraocular pressure and increase in facility of outflow in eyes with untreated ocular hypertension. If at the same time pigment was released into the aqueous, the pressure and outflow effect was nullified. Guttae pilocarpine 2% also reduced pressure and increased outflow, but if phenylephrine was added to the pilocarpine 2 responses appeared. If no pigment was released, pressure decreased and outflow increased; if pigment was released, there was no significant change in either. An identical response was shown by eyes with treated open-angle glaucoma. In eyes with treated exfoliation glaucoma pilocarpine and phenylephrine combined produced a significant increase in pressure and decrease in outflow because of pigment release. Finally, 18 eyes are described in which pigment release produced a mean increase in intraocular pressure of 14 mmHg. An acute release of pigment has an outflow-blocking effect that can be readily demonstrated. It provides an explanation for some of the paradoxical responses that occur after the instillation of autonomic drugs. It also provides a sufficient explanation for glaucoma associated with pigment dispersion.

Guanethidine--adrenaline eye drops in glaucoma simplex production and outflow of the aqueous humour during a long-term treatment.

A comparative tonographic study was performed in 10 primary open angle glaucoma patients (15 eyes) and 7 patients with suspected glaucoma (14 eyes) during a 7-months' period. The patients were treated twice daily with guanethidine 3% and adrenaline 0.5% (GA). The fall in intraocular pressure (IOP) of 44% in primary open angle glucoma patients was mainly due to an inhibition of aqueous humour production (54%; p < 0.005) and to a lesser extent an increase in outflow facility. In the suspected glaucoma patients, the fall in IOP of 43% was due to an inhibition of the aqueous rate (46%; p < 0.005) and to an increase in outflow facility (64%; p < 0.005). The increase in outflow facility during treatment was significantly different between both groups of patients. It suggests degeneration of the receptors mediating outflow mechanism in the patients with open angle glaucoma. For both groups of patients it is shown that during treatment with GA there is not only a supersensitivity for adrenaline 0.5% of the mechanisms that mediate the inhibition of the aqueous rate, but also of the mechanisms that mediate outflow facility.

The combination of guanethidine 1% and epinephrine 0.2% in one eye drop (GA-weak) in the treatment of glaucoma.

Thirty-one patients (58 eyes) with either primary open angle glaucoma (19 patients with 34 eyes) or suspected glaucoma (12 patients with 24 eyes) were treated for a period of 7 months with only guanethidine 1% and epinephrine 0.2% in one eyedrop (GA-weak) twice daily. The intraocular pressure (IOP) was controlled in 64% of all eyes with an average pressure decrease of 8.4 mm Hg or 31% (p < 0.005). Tonography revealed that the decrease in IOP was due both to inhibition of aqueous humour production (26%, p < 0.005) and to an increase in outflow facility (32%, p < 0.005), showing supersensitivity to inflow and outflow for epinephrine 0.2%, 8 patients were eliminated from the study due to tolerance for the drug. The side-effects were mild and did not lead to cessation of treatment. GA-weak was found to be an effective agent in the management of glaucoma. The treatment was well tolerated by the patients.

2. Epinephrine

Epinephrine is reported to reduce intraocular pressure by decreasing aqueous formation and increasing outflow facility. Because epinephrine is devoid of accommodative and miotic effects, is administered twice a day, and is accompanied by relatively minor complications, it can be used as the initial therapy for primary open angle glaucoma, as an additive to current therapy, and as part of maximal medical therapy for glaucoma. Epinephrine is contraindicated for angle-closure glaucoma and should be used with caution in patients with narrow angles. Although there is a potential for serious systemic side effects, most of the recognized side effects are not serious and are reversible with drug discontinuation. The development of dipivalyl epinephrine (DPE) as a molecule with greater ocular penetration promises to maintain this drug's therapeutic effect with a reduction in external and extraocular side effects.

Influences of cyclic nucleotides on outflow facility in the vervet monkey

Analogues of adenosine 3′,5′-monophosphate (cyclic AMP), such as 8-methylthio cyclic AMP or dibutyryl cyclic AMP, administered into the anterior chamber of the vervet monkey eye, in vivo, cause a two-fold increase in outflow facility which lasts approximately 1 hr. Isoproterenol, given intracamerally, increases outflow facility, as demonstrated previously by other investigators. Intracameral pretreatment with isoproterenol prevents a further increase in outflow facility following a cyclic AMP analogue, perfused through the anterior chamber. Topical epinephrine also increases outflow facility as shown previously by other investigators. Topical pretreatment with epinephrine prevents a further increase in outflow facility following a cyclic AMP analogue, given intracamerally. These findings indicate that the primary action of catecholamines on outflow facility in the primate is mediated by cyclic AMP. To determine if the cholinergic action on outflow facility is mediated by an intracellular messenger, a potent analogue of guanosine 3′,5′-monophosphate was tested and found to be ineffective. Perfusion of 8-methylthio cyclic AMP through the anterior chamber of the enucleated vervet monkey eye causes a decrease in outflow facility. These results, in vitro, are opposite to those observed in vivo and may be due to cyclic AMP-induced relaxation of the ciliary muscle.

Some effects of progestogens, oestrogens and androgens on the ocular tension of rabbits and owl monkeys

Topically applied progestogens; progesterone, quingestanol acetate and norethisterone acetate, were shown to reduce the ocular tension of conscious rabbits. Quingestanol acetate and norethisterone acetate also reduced the ocular tension of conscious owl monkeys. It was found that quingestanol acetate did not increase outflow facility in anaesthetized rabbits, but it significantly reduced the clearance of [ 14C]inulin from the anterior chamber suggesting a reduction in aqueous flow. Androgens and oestrogens were not found to exert hypotensive effects in either species.

PILOCARPINE‐INDUCED SUBSENSITIVITY TO CARBACHOL AND PILOCARPINE OF CILIARY MUSCLE IN VERVET AND CYNOMOLGUS MONKEYS

Vervet monkeys were given unilateral treatment for two weeks with one 2% pilocarpine eye drop three times daily between 8 a.m. and 6 p.m. (night interval 14h) and were then subjected to anterior chamber perfusion 20 mug pilocarpine intracamerally caused similar and substantial increases in outflow facility in both eyes. Cynomolgus monkeys were unilaterally treated with continuous release of 33 mug/h of pilocarpine for 5-6 days. The facility response to 1 mg/kg pilocarpine iv was small or absent on the treated side. Iridectomized cynomolgus monkeys responded with 12.6+/-5.2 (SD) diopters accommodation to 1.5 mg/kg pilocarpine im, with very similar responses in the two eyes. During continuous release of 30 mug/h pilocarpine, accommodation of the treated eye dropped grdually and after 4-8 days treatment the accommodative response was markedly reduced to pilocarpine 1.5 mg/kg im or 100 mug topically. The degree of subsensitivity was much less when tested with either systemic or topical carbachol. This was also the case in a few vervet experiments. Recovery of full pilocarpine sensitivity took several weeks in the cynomolgus monkey. As an explanation for the excessive subsensitivity and large interindividual differences found with pilocarpine, an individually variable, nonmuscarinic relaxant action counteracting the muscarinic excitatory action is suggested. Clinical implications of this hypothesis are discussed.

Some effects of topically applied (−)-adrenaline bitartrate on the rabbit eye

A 2·5% solution of thymoxamine hydrochloride applied topically to the eyes of conscious rabbits did not affect ocular tension. When 2·5% thymoxamine was administered prior to 0·5% adrenaline, a decline in ocular tension commenced 1–2 hr after adrenaline, in contrast to the observation with 0·5% adrenaline alone in which tension remained unchanged for 2 hr after administration. Topical adrenaline solutions of several concentrations were shown to reduce penetration of tritiated water from the blood into the aqueous humour of conscious rabbits and also to reduce the clearance of [ 14C]inulin injected into the anterior chambers of conscious and anaesthetized rabbits. However, these effects were short-lived, being negligible after approximately 2 hr and absent after 4 hr. Another early effect of adrenaline observed in conscious rabbits was a concentration-related decrease in the anterior chamber depth. Experiments performed on anaesthetized rabbits showed a correlation to exist between the magnitudes of facility increases and ocular tension reductions observed after the topical administration of 0·5% adrenaline. The discussion suggests that the reduction of ocular tension present 4–5 hr after topical administration of adrenaline in the rabbit is mainly due to increased outflow facility. It is further suggested that the delay in onset of the hypotension is due to a hypertensive mechanism which temporarily negates the potentially hypotensive effects of increased facility and decreased aqueous inflow.

Recent observations concerning the effects of cholinergic drugs on outflow facility in monkeys

Several major areas of work by the author and his international collaborators are reviewed. (1) The ciliary muscle in the non-human primate eye was disinserted at the scleral spur. Pilocarpine was then ineffective in increasing outflow facility, indicating that ciliary muscle contraction mediated the IOP-lowering effect of muscarinic cholinergics. (2) Compounds such as cytochalasins, H-7 and latrunculin A/B, which alter the actin cytoskeleton, cellular contractility and cellular adhesions in cultured trabecular meshwork cells, relaxed trabecular pathway cells and consequently the meshwork itself so as to decrease IOP and enhance trabecular outflow facility in non-human primates. Gene transfer approaches utilizing C3 and caldesmon over-expression by viral vectors to target specific steps in the cellular contractility/cytoskeleton/cell adhesion cascades characteristically altered trabecular meshwork cell morphology and increased outflow facility in organ-cultured anterior segments. (3) Prostaglandin F2α analogues enhanced matrix metalloproteinase production by ciliary muscle cells and scleral fibroblasts, leading to remodeling of the extracellular matrix of the ciliary muscle and sclera and consequently to increased uveoscleral outflow and decreased IOP in primates. (4) The rhesus monkey was an excellent model for human presbyopia, losing the accommodative response to cholinergic stimulation in the same timeframe relative to lifespan. No changes were found in ciliary muscle enzymes involved in acetylcholine biosynthesis or degradation or in muscarinic receptor numbers or affinity. Contractility of isolated ciliary muscle did not diminish with age, but posterior ciliary muscle attachments stiffened, suggesting a possible role in restricting muscle and consequently lens movement during accommodation. A model to reproducibly stimulate accommodation through central stimulation of the Edinger–Westphal nucleus was developed. Goniovideography and ultrasound biomicroscopic techniques allowed real-time recording and analysis of the accommodation-relevant structures. Surgical ablation of the intraocular structures involved in the accommodation response has led to further understanding of their roles and changes with age related to presbyopia. (5) Global collaborations such as those involved in these studies will be essential in the future, as science becomes “bigger”.

Changes in the facility of aqueous outflow induced by lens depression and intraocular pressure in excised human eyes.

The effects of intraocular pressure on aqueous outflow facility and mechanical tension on the iridocorneal angle were evaluated in 44 excised postmortem human eyes. Mechanical tension on the iridocorneal angle was induced by depression of the crystalline lens posteriorly in a quantitative manner to simulate the effect of cyclotonia on the facility of aqueout outflow. In eyes perfused at constant intraocular pressure but with stepwise increases in lens depression, the increase in facility of outflow produced by the increased tension on the iridocorneal angle was minimal at low levels of intraocular pressure (2.5 and 5 mm Hg) and greatest at higher levels of intraocular pressure (10 to 25 mm Hg). Conversely, in pairs of eyes perfused over a graded series of increasing intraocular pressure, and subjected to maximal lens depression, facility of outflow remained constant until intraocular pressure exceeded 20 mm Hg; in the fellow eyes, perfused without lens depression, facility of outflow diminished linearly with increasing intraocular pressure.

Recordings of applanating force at constant intraocular pressure. V. Intraocular volume changes due to changes in the content of aqueous humour.

Facility of outflow of aqueous humour estimated at two Pt‐levels suggests a pressure‐dependence within the eye with a lower facility of outflow at a higher pressure level. A rise in the intraocular pressure by 15 mmHg, before the measurement of the facility of outflow, resulted in larger values. No age‐dependent difference in the facility of outflow between eyes of selected young and elderly subjects with normal ocular tension was found. Nor could any difference be established between subjects with normal ocular tension and those with ocular hypertension. In young subjects accommodation induced an increase in the facility of outflow. Thirty minutes after a single‐dose of pilocarpine, no significant decrease in intraocular pressure, but an increase in facility of outflow was found. Two hours after a single‐dose of acetazolamide, a decrease in intraocular pressure but no significant change in facility of outflow was found.

Sympathetic denervation effects of avian eye development and aqueous fluid dynamics.

Sympathetic denervation of the eye in experimental mammals, either by surgical means (1, 2) , or pharmacologically (3), has been reported to cause a decrease in intraocular pressure (IOP), an increase in outflow facility (C) (1, 2), no change (4) or a decrease (5) in aqueous secretion, no change in episckral venoaq pressure (4, mydriasis (6) or miosis (7) , suparsensitivity to alphaadrenergic drugs (7), decreased vascular tone and increased blood flow to the anterior segment of the eye (4, 8). Many of these effects are transient, the peak response occurring about 1 day after anterior cervical ganglionectomy. This “24-hr ganglionectomy effect” has been attributed to the release of stored catecholamines, primarily norepinephrine, from degenerating postganglionic nerve terminals (1, 9). This hypothesis was strengthened by Eakins and Eakins (10), and by Sears et al. (11), who showed that catecholamine stores in the weal tissues were depleted over a time period which coincided with postganglionectomy changes i...

Effects of atropine on aqueous humor dynamics in the vervet monkey ( Cercopithecus ethiops)

The effects of various doses of atropine on aqueous humor dynamies in vervet monkeys were studied by methods giving data for intraocular pressure, recipient venous pressure, gross facility of outflow, bulk flow of anterior chamber fluid into the general circulation and bulk flow into uveoscleral routes. Atropine (3 μg/ml) perfused through the anterior chamber enhanced uveoscleral flow by 0·41±0·08 μl/min and produced a corresponding reduction in flow into the general circulation. In control eyes, after the induction of anesthesia, there was an increase in the gross facility of outflow of 0·33±0·09 μl. min−1. mmHg−1. In atropine-treated eyes there was no significant increase in facility. Atropine (3 μg/ml) did not significantly change the rate of aqueous humor production, the intraocular pressure or the recipient venous pressure. Pseudofacility was not appreciably influenced by atropine.

The 24-hour-ganglionectomy effect in rabbits the influence of partial iridectomy and of acetazolamide

The influence of chronic or acute lowering of intraocular pressure on the 24-hr-ganglionectomy effect in rabbits was studied, using the manometric pressure-decay curve technique. The experiments were designed to test whether the 24-hr-ganglionectomy effect (lowering of intraocular pressure and increase in outflow facility 24 hr after superior cervical ganglionectomy) could be abolished or diminished by the use of partial iridectomy and cyclectomy to produce a chronic lowering of intraocular pressure and, by implication, aqueous humour formation rate; and intravenous acetazolamide to produce an acute lowering of intraocular pressure and aqueous humour formation rate. Both these procedures diminished the 24-hr-ganglionectomy effect on outflow facility.

Outflow facility after guanethidine sulfate administration.

Tonographic studies done on 20 normal eyes and 23 eyes with open-angle glaucoma confirm that the main mechanism by which guanethidine sulfate lowers the intraocular pressure is by reducing aqueous humour production. This effect is probably the consequence of the sympathetic blockade produced by the drug. In addition, there has been also demonstrated an early and transient increase of outflow facility corresponding to the phase of peripheral sympathetic stimulation probably due to intraocular release of norepinephrine.

Mydriasis and the increase in outflow of aqueous humor from the rabbit eye after cervical ganglionectomy in relation to the release of norepinephrine from the iris

Tritiated norepinephrine administered intravenously in small single doses to albino rabbits is taken up and retained by the iris, then lost into the anterior chamber. In the early hours after cervical ganglionectomy the iris retention phenomenon exhibits a progressive decline while the release of the radioactively labeled norepinephrine is enhanced. The time course of these events could well explain the transient mydriasis and increase in outflow facility noted in the eyes of these animals after cervical ganglionectomy.

The 24-hour ganglionectomy effect in rabbits: The influence of adrenergic blockade, adrenalectomy and carotid ligation

The pharmacological response of the intraocular pressure and outflow facility in albino rabbit eyes to endogenous catecholamines released as a result of sympathetic denervation was studied by the manometric pressure-decay curve technique. The experiments were designed to test whether the 24-hr ganglionectomy effect (lowering of intraocular pressure and increase in outflow facility 24 hr after ganglionectomy) could be abolished by specific α- or β-adrenergic blocking agents, and whether blood-borne adrenal medullary hormone contributed to the ganglionectomy effect. Propranolol (the β-adrenergic blocking agent) failed to influence the ganglionectomy effect, whereas intravitreous phentolamine (α-adrenergic blocking agent) reduced it by about 50%. Adrenalectomy, with adrenal cortical replacement therapy, failed to diminish the ganglionectomy effect. It was concluded from these experiments that (1) β-adrenergic receptors were not involved in the outflow of aqueous humor, nor did they play a role in the ganglionectomy effect; (2) an α-adrenergic mechanism accessible via the aqueous circulation (such as the release of endogenous accounted for only a part of the ganglionectomy effect; and (3) circulating adrenal hormone did not enter the aqueous humor in quantities sufficient to affect outflow facility 24 hr after ganglionectomy. Reduction of blood flow to the denervated eye by means of ipsilateral common carotid artery ligation abolished the 24-hr increase in outflow facility usually observed.

The effect of sympathetic nerve stimulation on the aqueous humor dynamics of the cocaine pretreated rabbit

The effect of electrical stimulation of the cervical sympathetic nerve on the outflow facility of aqueous humor in normal and cocaine pretreated rabbits is reported. Outflow facility was determined using the pressure decay curve technique. A significant increase in outflow facility resulting from stimulation in the cocaine pretreated animals was observed; the increase could be prevented by an intravitreous injection of phentolamine. The results of this study provide further evidence for the presence of an alpha-adrenergic mechanism involved in the outflow of aqueous humor in the rabbit eye.

Effects of some steroids on aqueous humor dynamics

We have performed tonographic and histological studies in rabbits, using several locally applied steroid preparations, with a view to analyzing the progression of an ocular hypertensive state. Two of the preparations tested (6α-methylprednisolone 21-acetate and dexamethasone 21-phosphate) induced a dual intraocular pressure response. The third preparation, aldosterone, induced a sustained hypotension. When dexamethasone 21-phosphate was applied topically, a quick drop in pressure, accompanied by an increase in outflow, was observed. This was followed by a small, but significant, rise in intraocular pressure after 2 weeks. Aldosterone was applied subconjunctivally and topically to separate groups of rabbits daily for 14 days. Sustained decreases in intraocular pressure occurred. The administration of 6α-methylprednisolone 21-acetate twice weekly for 2 weeks caused a prolonged hypotensive effect. Single doses of the same drug produced a lowering of the intraocular pressure 3 hr after administration, reaching a maximum effect in 2–4 days. This drop in intraocular pressure was accompanied by a large increase in facility of outflow. Almost identical ocular responses, with no signs of toxicity, were evoked with lower doses of 6α-methylprednisolone 21-acetate. Again, the initial hypotensive response was followed by a hypertensive phase. The response to this steroid was the same on eight occasions in five separate groups of animals. It occurred in old, middle-aged and young animals, it was not invoked by the vehicle or by any premedication used, and it was not produced by changes in ocular rigidity. Tonography suggested that the drop in intraocular pressure was caused by some structural change in the filtration angle. Attempts were made to evaluate these structural changes on the basis of histological findings.

Transient increase in outflow facility after superior cervical ganglionectomy in rabbits.

The ocular hypotony observed by Linnér and Prijot¹to occur 24 hours after excision of the superior cervical ganglion in rabbits was shown by Langham and Taylor²and by Sears and Bárány³to be due to a marked increase in facility of outflow. The phenomenon (henceforth called the ganglionectomy effect) has been tentatively explained by Sears and Bárány as being partly due to the release of a facility-increasing α-adrenergic substance from degenerating nerve endings in the eye and partly to a decrease in a facility-decreasing β-adrenergic substance. The present paper reports a number of further experiments regarding this question. <h3>Methods</h3><h3>Technique.</h3> —With unimportant exceptions, the technique used was that employed by Sears and Bárány.³Briefly, albino rabbits, mainly males, weighing between 2 and 2.5 kg., underwent superior cervical ganglionectomy under a short-acting barbiturate. For measurement of facility and pressure (in the standard experiment 24 hours later)