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PROSTAGLANDINS, NONSTEROIDAL ANTI-INFLAMMATORY AGENTS and EYE DISEASE* by Steven M

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PROSTAGLANDINS, NONSTEROIDAL ANTI-INFLAMMATORY AGENTS and EYE DISEASE* by Steven M PROSTAGLANDINS, NONSTEROIDAL ANTI-INFLAMMATORY AGENTS AND EYE DISEASE* BY Steven M. Podos, MD DURING THE LAST DECADE AN EVER-INCREASING NUMBER OF INVESTIGATIONS HAVE been carried out on the prostaglandins and their inhibitors. It has become clear that the prostaglandins are an important group of compounds. One function ofthese compounds is the mediation ofcertain aspects ofthe inflammatory response. Moreover, a host of nonsteroidal anti-inflam- matory agents that inhibit the action of the prostaglandins have been elucidated. It is the purpose of this report to review the interrelationships of the prostaglandins, their inhibitors, and their role in disorders of the ocular system and to present the results ofstudies designed to answer some ofthe questions about their actions and inhibition with respect to the eye. PROSTAGLANDINS AND THE EYE Mechanical irritation of the iris produces miosis, increased vascular per- meability, and elevation of intraocular pressure in rabbits.' Rabbit iris contains a substance which contracts smooth muscles and mimics the effects of stroking the iris. This substance is an unsaturated hydroxy fatty acid which Ambache named irin.2 After paracentesis, irin appears in secondary aqueous humor.3 Acidic lipids extracted from human vesicular glands, which von Euler called prostaglandins, contract smooth muscle.4 The prostaglandins are 20 carbon, unsaturated fatty acids.§ Arachidonic acid (5, 8, 11, 14- eicosatetraenoic acid) and dihomo-y-linolenic acid (8, 11, 14-eicosatri- enoic acid) are the precursors of prostaglandin E2 (PGE2) and prosta- glandin E, (PGE,), respectively. Other prostaglandins are reported *From the Departments of Ophthalmology, Mount Sinai School of Medicine of The City University of New York, New York, and Washington University School of Medicine, St. Louis, Missouri. Supported in part by research grants EY-00004, EY-01333, and EY-01661 from the National Eye Institute, Bethesda, Maryland. TR. AM. OPHTH. Soc., vol. LXXIV, 1976 638 Podos such as the A, F, and B series. The activity of the prostaglandin syn- thesis system varies among different tissues of the body. The prostaglandins exist in virtually ever.y organ system and their ac- tions are diverse.6 They are involved in inflammation, pain, fever, smooth muscle contraction, gastric secretion, lipid and carbohydrate metabolism, cardiovascular responses, renal physiology, and blood coagulation, for example. Suggested therapeutic implications of this family of compounds include their use as bronchial dilators, gastric antisecretogogues, abor- tifacients, and antihypertensive agents. Different members of the family may have different actions on the same system. The iris of rabbits and sheep contains PGE2 and prostaglandin Fa (PGF2,) which are felt to be the vasoactive agents of irin.7 Moreover, the iris of the pig eye, in vitro, is able to convert fatty acid precursor to prostaglandin.8 Thus, the eye contains these compounds and the machinery to manufacture them. The effects of prostaglandins on the eye have been reviewed.9'10 Prostaglandins, administered topically, systemically, or intracamerally, elevate intraocular pressure in the rabbit, cat, and monkey. 11-17 Very small doses of prostaglandin produce this effect. With topical applica- tion of0.55,g or greater of PGE 1, a significant rise in intraocular pressure occurs with a maximum elevation within the first 30 minutes. 16 This is followed by a gradual decrease. Two hours after 50 ,.ug of PGE1 the intraocular pressure still remains above baseline values. The PGEs in- duce the greatest pressure response while PGF2a, PGA, and PGF1. are respectively less effective. 12 Differences between species of animals are noted. The mechanism of the intraocular pressure response appears to be increased aqueous humor production. No decrease of outflow facility oc- curs after intracameral injections of PGE1 in cannulated eyes of anes- thetized rabbits. 14 In awake, non-cannulated rabbits, tonography reveals an increase in total facility of outflow after topical PGE1.16 The intra- ocular pressure response is less in the monkey after equivalent doses of PGE but a rise of outflow facility also occurs. 17 PGE1 increases trans- epithelial short circuit current in isolated ciliary body preparations,18 implying increased active transport. A breakdown of the blood aqueous barrier and increased pseudofacility caused by PGE may provide other possible explanations for its pressure effects. After topical application of PGE, extravasation of thorotrast particles occurs in the stroma of the ciliary and iris processes.19 After injection of PGE1 into the vitreous humor there is alteration of the tight junctions of the non-pigmented epithelium allowing for leakage of protein into the anterior chamber in Prostaglandins 639 rabbits.20 In addition, anterior segment fluorescein angiography shows increased vascular permeability in rabbit eyes.21 A marked increase of aqueous-humor protein is a concomitant feature in cat, monkey, and rabbit eyes after treatment with PGE1 or PGE2. 12-14,16 The protein level in rabbit aqueous humor is ten to fifteen times as high one hour after the topical application of 5 ug of PGE1 as compared to aqueous humor from untreated or control eyes. 16 The reason for the increased aqueous humor production is not entirely resolved. Other related features of the effect of prostaglandins on the eye are of interest. Most investigators report concomitant miosis. 11-13 A consensual response in the fellow eye after treating one eye with intracameral pros- taglandin is reported. 12 The secondary messenger cyclic adenosine-3',5' -monophosphate (cyclic AMP, c-AMP) is involved in the actions of prostaglandins.22'23'24 Adenyl cyclase, the enzyme which generates cyclic AMP, and c-AMP phospho- diesterase, which converts cyclic AMP to the metabolically inactive adenosine-5'-monophosphate, exist in ciliary processes and iris tissue. 25,26 Cyclic AMP is present in aqueous humor, iris, ciliary body, and other ocular tissues.27 Adrenergic agents increase the amount of anterior but not posterior chamber aqueous humor c-AMP,28'29 and c-AMP in- creases outflow facility.30 Ciliary process adenyl cyclase is responsive to PGE,25 as is the cyclic AMP of rabbit iris and ciliary body in vitro. 27 The following studies were carried out to delineate the effect oftopically applied PGE2 on aqueous humor cyclic AMP in rabbits in vivo. MATERIALS AND METHODS 3H-c-AMP (38.4 Ci/mMole) was obtained from New England Nuclear, c-AMP from Sigma, and scintillation fluid (3a40) from Research Products International Corporation. c-AMP-dependent protein kinase was purified from rabbit skeletal muscle by the method of Wastila and associates.31 The protein kinase inhibitor was purified through the trichloracetic acid precipitation step from rabbit skeletal muscle by the method of Walsh and co-workers.32 Charcoal (3 gm, Nutural A from Sigma) was suspended in 250 ml of 50 mM potassium phosphate buffer, pH 4.0, and stirred for 30 minutes at 4°C. Bovine serum albumin (0.5 gm, Sigma) and dextran (0.3 gm, mol. wt. 8200, Sigma) were dissolved in 250 ml of the same buffer and stirred for at least 30 minutes. The dextran and bovine serum albumin solution was then added to the charcoal suspension and was allowed to stir overnight at 4°C. This was made up fresh each week and was stirred for 30 minutes before each use. 640 Podos Cyclic AMP was measured by a modification of the protein-binding method of Gilman.33 All procedures were carried out in an ice bath except where indicated. All components of the reaction mixture except the protein kinase were made up or diluted in 50 mM sodium acetate buffer, pH 4.0. Protein kinase was diluted in 10 mM potassium phos- phate, pH 7.0. The concentration of the components of the reaction mixture was adjusted so that there was enough 3H-c-AMP to give 25,000 counts per minute, enough protein kinase to bind between 12 and 20% of the c-AMP, and a maximal effective concentration ofprotein kinase inhibitor. Volumes normally used were 110 ul sodium acetate buffer, 20 ,1u 3EH-c- AMP, 20 ul protein kinase inhibitor, and 50 ul binding protein. Test tubes containing the air dried aqueous humor samples were stirred vigorously with buffer on a vortex mixer to insure all c-AMP was in solu- tion. The reaction was initiated by the addition of protein kinase. After two hours the reaction was stopped by the addition of 1 ml charcoal and the test tube was quickly stirred on a vortex mixer and centrifuged for five minutes at 1300 X g. Centrifugation was done at room temperature. The aqueous phase was decanted off the charcoal and counted in 10 ml scintillation fluid. A standard curve of0.25 to 16 p moles c-AMP was run with each experi- ment and duplicates were run at each concentration. Each milligram of PGE2 was dissolved in 0.1 ml of 95% ethanol and 0.9 ml of 0.02% sodium carbonate aqueous solution. Baseline intraocular pressure was measured in awake, wrapped animals under topical 0.5% proparacaine anesthesia with the Mackay-Marg tonometer. PGE2, 5 ,ug in 5 ,ul, was applied to one eye and 5 ,ul of diluent to the other eye. Other rabbits received just the diluent. Thirty minutes later, intraocular pressure was remeasured and 0.1 ml of anterior chamber aqueous humor was removed with a tuberculin syringe. Duplicate sam- ples of 100 ,1 aqueous humor were immediately pipetted into 1.5 ml absolute ethanol in 12 X 75 mm polystyrene test tubes. These were placed in boiling water until the ethanol boiled and were then cooled in an ice bath. They were then dried under a stream ofair and the c-AMP assay was run in the same test tube. RESULTS At 30 minutes after instillation ofPGE2, the cyclic AMP in aqueous humor was significantly higher in the treated eyes than in the fellow eyes (Table I).
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