The effect of timolol maleate on the disruption of the blood-aqueous barrier in the rabbit eye

A disruption of the blood-aqueous barrier in rabbit eyes was elicited by use of topical prostaglandin E2(PGE2), infrared irradiation of the iris, or by subcutaneous alpha-melanocyte-stimulating hormone (alpha-MSH). The aqueous flare provoked was measured quantitatively with a photoelectric instrument. The effect of the (topical) beta-adrenergic antagonist timolol maleate on the breakdown of the blood-aqueous barrier was tested. Timolol applied topically in very large doses had no effect on exogenously administered PGE2. However, even in a very small concentration applied topically, timolol reduced the flare response to both infrared irradiation and alpha-MSH. These results support the theory that the effect of alpha-MSH and infrared irradiation on the blood-aqueous barrier is dependent on intact beta-adrenergic receptor sites.     

The effect of experimental uveitis on the uptake of prostaglandin E1 in the rabbit iris-ciliary body

Disruption of the blood-aqueous barrier in rabbits was elicited by infrared irradiation of the iris or by alpha-melanocyte stimulating hormone (alpha-MSH) given subcutaneously. One group of animals was pretreated with topical imidazole before the injection of alpha-MSH. The aqueous flare response was followed and the rabbits were killed at the expected height of the uveitis. The uptake of 3H-prostaglandin E1 in the iris with the ciliary body was then determined and found to be significantly decreased in the rabbits in which alpha-MSH had caused a severe damage of the blood-aqueous barrier. When alpha-MSH caused a more moderate aqueous flare response the prostaglandin uptake was on the contrary significantly increased. Pretreatment of the animals with topical imidazole enhanced parallelly the prostaglandin uptake and the aqueous flare response to alpha-MSH. Topical imidazole per se was found to increase the accumulation of prostaglandin. The prostaglandin uptake values were, however, unchanged in eyes in which infrared irradiation of the iris induced a moderate flare response.     

Capsaicin pretreatment prevents disruption of the blood-aqueous barrier in the rabbit eye

Capsaicin, the irritating agent of red pepper, produces ocular inflammation through a neurogenic mechanism. The present study is concerned with the long-term effects of capsaicin pretreatment on the capacity of the eye to respond to different inflammatory stimuli. Following retrobulbar injection of capsaicin to rabbits the aqueous flare response induced by subsequent infrared irradiation (IR) of the iris, subcutaneously administered alpha-melanocyte-stimulating hormone (alpha-MSH) and exogenously administered prostaglandin E2 (PGE2) was reduced greatly. In the case of IR and alpha-MSH the reduced responsiveness was manifest for several weeks after capsaicin pretreatment, involving first the capsaicin-treated eye, but later also the contralateral control eye. After 2-3 months the aqueous flare response was normal in both eyes. In the case of PGE2 the responsiveness was reduced for a shorter time; after 3 weeks the response was normal in both eyes. The results indicate that all three stimuli tested are at least partly dependent upon an intact sensory innervation to disrupt the blood-aqueous barrier, but that the mechanism of action of PGE2 is different from that of IR and alpha-MSH.     

The effect of polyphloretin phosphate on the aqueous flare response to alpha-melanocyte stimulating hormone

The breakdown of the blood aqueous barrier caused by topical prostaglandin E1 (PGE1), prostaglandin E2 (PGE2) or subcutaneous alpha-melanocyte stimulating hormone (alpha-MSH) was quantified by measurements of the aqueous flare seen in the anterior chamber. Polyphloretin phosphate (PPP) administration subcutaneously was found to effectively block the protein leakage caused by all three traumatic stimuli. The same dose of PPP given intravenously inhibited effectively the flare response to PGE1 and alpha-MSH, whereas the effect of PGE2 was only slightly decreased. Significant inhibition by subconjunctival PPP was not achieved for any of the three stimuli. Assuming that PPP is a specific PG-antagonist the present results support the eariler suggestion that PGs take part in the barrier damaging action of alpha-MSH. However, it cannot be excluded that PPP acts on a step subsequent to PG. This step might be common to PGs- and alpha-MSH-effects on the barrier, explaining why PPP inhibits both types of trauma.     

The effect of theophylline on the breakdown of the blood-aqueous barrier in the rabbit eye.

A disruption of the blood-aqueous barrier in rabbit eyes was elicited by topical prostaglandin E2, infrared irradiation of the iris, or subcutaneous alpha-melanocyte stimulating hormone (alpha-MSH). The course of the inflammatory reaction was followed by photoelectrical measurements of the aqueous flare in the anterior chamber. Pretreatment with intravenous theophylline, a phosphodiesterase inhibitor, significantly increased the protein leakage caused by prostaglandin E2 and alpha-MSH, but the response to infrared irradiation was slightly but not significantly enhanced. Intravenous theophylline given in higher doses caused per se an aqueous flare increase, which could not be inhibited by pretreatment with topical indomethacin. Our results indirectly indicate that accumulation of intraocular cAMP promotes a barrier damage and that cAMP might be the common effector of the barrier breakdown caused by prostaglandin as well as by nonprostaglandin agents.     

Interaction of adrenergic antagonists with prostaglandin E2 and tetrahydrocannabinol in the eye.

Both alpha- and beta-adrenergic antagonists have been utilized in an atempt to discern the site of action of prostaglandin (PG) and tetrahydrocannabinol (THC) in the eye. Both alpha- and beta-adrenergic antagonists (alpha-antagonists, phentolamine and phenoxybenzamine; beta-antagonists, propranolol and sotalol) cuased a dose-dependent reduction in intraocular pressure and blood pressure and increased total outflow facility. The results are consistent with the concept that both alpha- and beta-adrenergic receptors are present in the anterior uvea and that vasomotor tone is essential to the maintenance of normal intraocular pressure. No antagonist reduced the PG-induced elevation of intraocular pressure unless the blood pressure was severely lowered. All antagonists inhibit the normal PG-induced increase in total outflow facility, indicating that these agents protect the blood-aqueous barrier from breakdown without altering the vasodilatory response to PG. All antagonists reduced the fall in intraocular pressure produced by THC by approximately 50 per cent, except for sotalol which completely abolished the intraocular pressure fall. Only the alpha-adrenergic antagonists prevented the THC-induced increase in total outflow facility. The results indicate that true outflow facility may well be regulated exclusively by alpha-receptors. The data are consistent with the effect of THC being primarily a vasodilation of the efferent blood vessels of the anterior uvea. The partial inhibition by alpha-adrenergic antagonists may also suggest a lesser role of THC on the afferent vessels.     

Effects of tetramethylpyrazine on prostaglandin E(2)- and prostaglandin E(2) receptor agonist-induced disruption of blood-aqueous barrier in pigmented rabbits

PURPOSE: To evaluate the effect of tetramethylpyrazine on the elevation of aqueous flare and intraocular pressure (IOP) induced by prostaglandin (PG) E(2) and PGE(2) receptor (EP) agonists. METHODS: PGE(2) or EP agonists (11-deoxy PGE(1), EP(2) agonist; 17-phenyl trinor PGE(2), EP(1) and EP(3) agonist; or sulprostone, EP(1) and EP(3) agonist), 25 microg/mL, were transcorneally administered to pigmented rabbits. Animals were pretreated with tetramethylpyrazine intravenously (10 or 30 mg/kg) or topically (0.1% solution). Aqueous flare was measured using a laser flare-cell meter, and the intensity was expressed as the area under the curve (AUC). Intraocular pressure was measured using a noncontact tonometer. RESULTS: After administration of PGE(2), aqueous flare and IOP increased and then gradually decreased. The AUC of eyes pretreated with tetramethylpyrazine, 10 or 30 mg/kg, intravenously, or topical 0.1% solution, was significantly smaller than that of the controls. The mean Delta IOP of eyes pretreated with tetramethylpyrazine, 30 mg/kg intravenously, was significantly lower than that of the controls. After administration of 11-deoxy PGE(1), aqueous flare increased and then gradually decreased. 17-phenyl trinor PGE(2) and sulprostone did not disrupt the blood-aqueous barrier. The AUC of eyes pretreated with tetramethylpyrazine, 10 or 30 mg/kg, intravenously, before 11-deoxy PGE(1) application was significantly smaller than that of the controls. CONCLUSION: The results indicated that tetramethylpyrazine inhibited PGE(2)- or 11-deoxy PGE(1)-induced elevation of aqueous flare and IOP.     

Effects of topical mydriatics and vasoconstrictors on prostaglandin-E2-induced aqueous flare elevation in pigmented rabbits

We evaluated the effects of topical instillation of mydriatics and vasoconstrictors on prostaglandin E2 (PGE2) induced aqueous flare elevation in pigmented rabbits. Transcorneal diffusion of PGE2 (25 microg/ml) by means of a glass cylinder produced aqueous flare elevation. Mydriatics (atropine sulfate, tropicamide, tropicamide plus phenylephrine hydrochloride, phenylephrine hydrochloride, and cyclopentolate hydrochloride) or vasoconstrictors (naphazoline nitrate and tramazoline hydrochloride) were topically administered before PGE2 application. Aqueous flare was measured with a laser flare-cell meter. One or two instillations of atropine sulfate 1.0%, tropicamide 0.4%, tropicamide 0.5% plus phenylephrine hydrochloride 0.5%, phenylephrine hydrochloride 5.0%, cyclopentrate hydrochloride 1.0%, and naphazoline nitrate 0.05% did not inhibit PGE2-induced aqueous flare elevation. Tramazoline hydrochloride 0.118% inhibited significantly (p < 0.05) PGE2-induced aqueous flare elevation. It is possible that vasoconstriction may be involved partly in inhibition of PGE2-induced aqueous flare elevation by some drugs in pigmented rabbits.     

Effects of adrenergic agents on transepithelial electrical measurements across the isolated iris-ciliary body.

Transmembrane electrical measurements were performed on the isolated rabbit iris-ciliary body to study direct effects of adrenergic drugs on the ciliary epithelium. Alpha-adrenergic agonists (epinephrine, norepinephrine, or phenylephrine) lowered the short-circuit current (SCC) in a dose-dependent fashion relative to which chamber side the drug was added: simultaneous addition to both chambers greater than blood side only greater than aqueous side only. Pretreatment (5 x 10(-5) M) with the non-selective beta-adrenergic antagonist timolol had no effect while the non-selective alpha-adrenergic antagonist, phentolamine, completely prevented the alpha agonist-induced decrease in SCC. The alpha-adrenergic response was mediated by the alpha 1 subtype since prazosin, but not yohimbine, blocked the induced reduction in SCC. The beta-adrenergic agonist isoproterenol caused a dose-dependent decrease in the SCC. The decrease was similar when the drug was added to only the blood side or to both sides of the chamber. Addition to only the aqueous chamber had no effect. Pretreatment with beta-adrenergic antagonists blocked the isoproterenol response: non-selective = selective beta 2 greater than selective beta 1. The isoproterenol-induced decrease in SCC was also blocked by non-selective alpha-adrenergic antagonists. The response was mediated by the alpha 1 subtype since prazosin, but not yohimbine, blocked the isoproterenol response. This suggests that isoproterenol interacted with the alpha 1-adrenergic sensitive pathway in the rabbit ciliary process.     

Effect of topical betaxolol on acute rise of aqueous flare induced by prostaglandin E(2) in pigmented rabbits.

PURPOSE: To evaluate the effects of topical betaxolol on experimental ocular inflammation. METHODS: Transcorneal diffusion of 25 microg/mL (7.09 x 10(-2) mmol/L) of prostaglandin E(2) (PGE(2)), placed in a glass cylinder, was employed to induce aqueous flare elevation in pigmented rabbits. Betaxolol was administered topically before PGE(2) application. Aqueous flare was measured with a laser flare cell meter. RESULTS: Four-, two-, and one-time topical instillations of betaxolol inhibited the PGE(2)-induced aqueous flare elevation by 44% +/- 8%, 32 +/- 7%, and 8 +/- 6%(mean +/- SD), respectively. The inhibition of flare elevation was dependent on the number of betaxolol instillations. CONCLUSION: Topical betaxolol has an inhibitory effect on PGE(2)-induced aqueous flare elevation in rabbit eyes.     

The effect of H1-blocking antihistamines on intraocular pressure in rabbits

H1-blocking antihistamines were administered topically to rabbits to determine their effects on intraocular pressure. Chlorcyclizine which is in the piperazine class of H1-inhibitors was found to elevate intraocular pressure. This effect was prevented by the systemic administration of indomethacin and is probably a prostaglandin induced change. Of the other agents tested, antazoline which is in the ethylenediamine class, was the only drug found to lower intraocular pressure. The antazoline-induced lowering of intraocular pressure was associated with no changes in outflow facility, episcleral venous pressure, systemic blood pressure, or ocular blood flow. Tonographic and aqueous humor ascorbate humor ascorbate data suggested a decreased (41% and 33% respectively) rate of aqueous flow as the mechanism for the decrease in intraocular pressure. The systemic administration of the alpha-adrenergic blocker phentolamine prevented the decrease in intraocular pressure but systemically administered blockers of cholinergic (atropine) or beta-adrenergic (propranolol) activity had no effect.     

Responses of intraocular pressure and the pupil of feline eyes to prostaglandin EP1 and FP receptor agonists.

PURPOSE: Previous studies suggested that FP receptors do not mediate the relaxation of the ciliary muscle and reduction of intraocular pressure in cats by prostaglandin (PG) F2alpha. The present study was undertaken to determine whether the reduction of intraocular pressure in cats induced by PGF2alpha is mediated by FP or other prostaglandin receptors. METHODS: One eye of each cat was treated topically with prostaglandin F2alpha, fluprostenol (FP receptor agonist), or 17-phenyl trinor PGE2 (EP1 receptor agonist) in a dose range of 12.5 to 50 microg. The effects of SC19220 and SC51089 (EP1 receptor antagonists), BWA868c, and SQ29548 (DP and TP receptor antagonists, respectively) on the intraocular response to PGF2alpha were also examined. At intervals up to 6 hours after treatment, intraocular pressure was measured with a pneumotonometer, and pupil diameters were measured with a millimeter ruler. RESULTS: In the dose ranges used, PGF2alpha and 17-phenyl trinor PGE2 decreased intraocular pressure and pupil diameter. The greatest reduction of intraocular pressure by 50.0 microg PGF2alpha was 5.0+/-1.4 mm Hg, whereas that by 50 microg 17-phenyl trinor PGE2 was 6.2+/-1.5 mm Hg. The isopropyl ester of PGF 2alpha at a dose of 1.25 microg reduced intraocular pressure by 3.75+/-0.25 mm Hg at 2 hours. At doses up to 100 microg, fluprostenol did not decrease intraocular pressure but did reduce pupil diameter. SC19220, a weak but selective EP1 receptor antagonist, inhibited the intraocular pressure response to both PGF2alpha and 17-phenyl trinor PGE2. The more potent EP1 receptor antagonist SC51089 had a greater inhibitory effect than SC19220 on the intraocular pressure response to PGF2alpha. Both of these antagonists had a small but non-dose dependent and statistically insignificant effect on the pupil response to PGF2alpha. These observations suggest that in cats, intraocular pressure and pupil responses to PGF2alpha, are mediated by EP1 and FP receptors, respectively. However, SC19220 significantly and dose-dependently inhibited the pupil response to 17-phenyl trinor PGE2alpha suggesting that EP1 receptors mediate pupil response to this agonist. DP and TP receptor antagonists at doses 5- to 20-fold greater than the IC50 values had no effect on the ocular hypotensive response to PGF2alpha. The concurrent administration of 12.5 microg of each of PGF2alpha and 17-phenyl trinor PGE2 did not produce an additive effect on intraocular pressure, indicating that in cats PGF2alpha and 17-phenyl trinor PGE2 act on the same receptor type. CONCLUSIONS: These results suggest that a significant proportion of the ocular hypotensive action of PGF2alpha in cats is mediated by EP1 but not by FP receptor. Evidence was also provided to show that 17-phenyl trinor PGE2 is an ocular hypotensive agent in cats.     

Effects of topical antiglaucoma eye drops on prostaglandin E(2)-induced aqueous flare elevation in pigmented rabbits

PURPOSE: To evaluate the role of topical instillation of some antiglaucoma agents on experimental elevation of aqueous flare induced by prostaglandin E(2) (PGE(2)) in pigmented rabbits. METHODS: Transcorneal diffusion of PGE(2) (25 microg/mL or 7.09 x 10(-2) mM) with the use of a glass cylinder was achieved to produce aqueous flare elevation in pigmented rabbits. An antiglaucoma agent was topically administered before application of PGE(2). Aqueous flare was measured with a laser flare cell meter. RESULTS: A single instillation of apraclonidine 1.15%, two instillations of epinephrine 1.25%, two instillations of dipivefrin 0.1%, and two instillations and one instillation of dipivefrin 0.04% eye drops inhibited 98%, 96%, 87%, 73%, and 47% of PGE(2)-induced aqueous flare elevation, respectively. Timolol 0.5%, nipradilol 0.25%, dorzolamide 1%, and pilocarpine 2% eye drops had no effects on the increase of PGE(2)-induced flare. CONCLUSIONS: Apraclonidine, epinephrine, and dipivefrin eye drops inhibit PGE(2)-induced elevation of aqueous flare in pigmented rabbits.     

Effects of isopropyl unoprostone, latanoprost, and prostaglandin E(2) on acute rise of aqueous flare in pigmented rabbits

PURPOSE: To evaluate the effect of isopropyl unoprostone, latanoprost, and prostaglandin E(2) (PGE(2)) on aqueous flare elevation. METHODS: Isopropyl unoprostone (0.12%) or latanoprost (0.005%) was topically instilled. Transcorneal diffusion of PGE(2), 25 microg/ml, using a glass cylinder, was achieved in pigmented rabbits. Aqueous flare was measured with a laser flare cell meter. RESULTS: Topical instillation of isopropyl unoprostone induced aqueous flare elevation in rabbit eyes. Also, topical isopropyl unoprostone additionally induced aqueous flare elevation in eyes with transcorneal diffusion of PGE(2). Latanoprost did not induce flare elevation. CONCLUSION: Isopropyl unoprostone induced aqueous flare elevation in rabbits, and latanoprost did not produce aqueous flare elevation.     

Effects of topical corticosteroids and nonsteroidal anti-inflammatory drugs on prostaglandin e2-induced aqueous flare elevation in pigmented rabbits

We evaluated the effects of anti-inflammatory potency of corticosteroids and nonsteroidal anti-inflammatory drugs on prostaglandin E2 (PGE2)-induced aqueous flare elevation in pigmented rabbits. Transcorneal diffusion of PGE2, 25 microg/ml (7.09 x 10(-2) mmol/l), with the use of a glass cylinder was achieved to produce aqueous flare elevation. Anti-inflammatory drugs were topically administered once before PGE2 application. Aqueous flare was measured with a laser flare-cell meter. Topical single instillation of dexamethasone sodium metasulfobenzoate 0.1%, dexamethasone sodium phosphate 0.1%, and fluorometholone 0.1% 6 h before PGE2 application inhibited 56, 59, and 43% of flare elevation, respectively. Topical single instillation of bromfenac sodium 0.1% and pranoprofen 0.1% 1 h before PGE2 application inhibited 33 and 15% of flare elevation, respectively. Indomethacin 0.5% did not inhibit flare elevation. Corticosteroid eyedrops needed several hours from topical instillation to exhibit inhibition of flare elevation. Most nonsteroidal anti-inflammatory drug eyedrops inhibited aqueous flare elevation when instilled 1 h before PGE2 application.     

Effect of topical iganidipine on experimental elevation of aqueous flare induced by prostaglandin E(2) and EP agonists in pigmented rabbits

We evaluated the role of topical iganidipine on experimental aqueous flare elevation in rabbits. Transcorneal diffusion of prostaglandin E(2) (PGE(2)), 25 microg/ml or 7.09 x 10(-2) mmol/l, or highly selective agonists for prostaglandin E(2) receptor subtypes (EP), 25 microg/ml, was achieved with the use of a glass cylinder to produce aqueous flare elevation in pigmented rabbits. Iganidipine was topically administered before application of PGE(2) or EP agonists. Aqueous flare was measured with a laser flare cell meter. Topical instillation of 0.1% iganidipine once or twice inhibited 64 +/- 8% (p < 0.01) and 84 +/- 9% (p < 0.01) of PGE(2)-induced aqueous flare elevation, respectively. Two instillations of 0.1% iganidipine inhibited 95 +/- 5% (p < 0.01) of EP2-agonist(ONO-AE1-259-01)-induced flare elevation and 98 +/- 3% (p < 0.01) of EP4-agonist(ONO-AE1-392)-induced flare rise. Topical iganidipine may have anti-inflammatory activity in the eye.     

Effects of topical clonidine on prostaglandin-E(2)-induced aqueous flare elevation in pigmented rabbits

We evaluated the role of topical clonidine on experimental ocular inflammation. Transcorneal diffusion of prostaglandin (PG) E(2), 7. 09 x 10(-2) mmol/l, with the use of a glass cylinder was employed to produce aqueous flare elevation in pigmented rabbits. Clonidine was topically administered and yohimbine was injected intravenously. Aqueous flare was measured with a laser flare cell meter. Topical instillation of 0.25% clonidine inhibited 89% of PGE(2)-induced aqueous flare elevation. Instillation of clonidine at 60 or 30 min before and 10 min after PGE(2) inhibited flare significantly. Pretreatment with intravenous yohimbine decreased the clonidine-induced inhibition of the flare elevation in a dose-dependent manner. It is possible that the anti-inflammatory action of topical clonidine may be mediated partly by alpha(2)-receptors.     

Prostanoids in rabbit aqueous humor: effect of laser photocoagulation of the iris

The authors measured concentrations of prostanoids (prostaglandin-like substances) in aqueous humor from normal pigmented rabbit eyes and from those subjected to argon laser photocoagulation of the iris. The predominant prostanoids quantitatively were prostaglandin E2 (PGE2), PGF2 alpha, and PGD2 with minor amounts of 6-keto-PGF1 alpha and thromboxane B2. In all cases, concentrations of prostanoids in laser-treated eyes were substantially greater than those in normal eyes. This finding was particularly striking in the case of PGE2 which increased 60-fold from 87 pg/ml to 5.5 ng/ml after irradiation. Concentrations of prostanoids following photocoagulation were related to the number of administered laser lesions and prostanoid release was associated with an initial hypertensive response and disruption of the blood-aqueous barrier.     

Effect of topical betaxolol on the acute rise of aqueous flare induced by highly selective agonists for prostaglandin E2 receptor subtypes in pigmented rabbits

PURPOSE: To evaluate the role of topical betaxolol on experimental ocular inflammation in rabbits. METHOD: Transcorneal diffusion of highly selective agonists for prostaglandin E2 receptor subtypes (EP), 25 microg/ml, with the use of a glass cylinder, was performed to produce aqueous flare elevation in pigmented rabbits. Betaxolol was topically administered before EP agonist application. Aqueous flare was measured with a laser flare cell meter. RESULTS: Performing topical instillation of 0.5% betaxolol 4 times inhibited 52 +/- 9% of EP2-agonist (ONO-AE1-259-01)-induced aqueous flare elevation. The inhibition of flare elevation was dependent on the number of betaxolol instillations. Betaxolol did not suppress the elevation induced by an EP4 agonist (ONO-AE1-392). CONCLUSION: Betaxolol inhibited EP2-agonist-induced aqueous flare elevation in pigmented rabbits.     

Topical prostaglandins inhibit trauma-induced inflammation in the rabbit eye

Topical administration of prostaglandin E1 (PGE1) and prostaglandin F2 alpha (PGF2 alpha) prior to ocular trauma can reduce the ocular inflammatory response in rabbits. In the present study, the ocular trauma consisted of puncture of the cornea, without aspiration of aqueous. Corneal puncture, which causes and inflammatory response, a breakdown of the blood-aqueous barrier, and a biphasic response of the intraocular pressure (IOP), yields a valid model of a mild inflammatory response. Pretreatment with PGE1 and PGF2 alpha led to a lower rise in the aqueous prostaglandin E2 (PGE2) concentration and a reduced inflammatory response after corneal puncture; in addition, the increase in the aqueous protein concentration was smaller and the aqueous ascorbate level was higher. The lower increase in the aqueous PGE2 concentration after pretreatment with PGs correlated with the reduced changes in IOP. It is suggested that PGE1 and PGF2 alpha reduced the trauma-induced inflammatory response by decreasing the formation of endogenous prostaglandins, as reflected by their concentration in aqueous. This study also indicates that the results of studies that require perforation of the cornea or cannulation of the anterior chamber may be affected by profound changes in the levels of cyclo-oxygenase products in the tissues surrounding the aqueous.