Original article
Effects of Prostaglandins on the Aqueous Humor Outflow Pathways

https://doi.org/10.1016/S0039-6257(02)00306-5Get rights and content

Abstract

Topical treatments with certain prostaglandins (PGs), including FP receptor agonists, lower intraocular pressure by increasing uveoscleral outflow. Although the precise mechanism for the increased uveoscleral outflow is not known, there appears to be activation of a molecular transduction cascade and an increase in the biosynthesis of certain metalloproteinases. This leads to reduction of extracellular matrix components within the ciliary muscle, iris root, and sclera. It is possible that this reduction of extracellular matrix present within portions of the uveoscleral pathway may contribute to the mechanism of increased uveoscleral outflow. Additional mechanisms that may contribute to the PG-mediated increase of uveoscleral outflow include relaxation of the ciliary muscle, cell shape changes, cytoskeletal alteration, or compaction of the extracellular matrix within the tissues of the uveoscleral outflow pathway. Future studies should clarify the importance of these various responses that may contribute to increased uveoscleral outflow. At present, there is no compelling evidence for a substantial facility-increasing effect on the trabecular meshwork outflow for any of these compounds.

Section snippets

Prostaglandin Effects on Intraocular Pressure

Certain PGs are potent and effective topical ocular hypotensive agents. For example, PGF isopropyl ester can reduce IOP in the normotensive monkey to less than 5 mm Hg at pharmacologic (μg) doses (Fig. 1).21 Latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinor-PGF isopropyl ester), an FP-selective agonist that specifically activates the FP-PG receptor, is a highly effective ocular hypotensive drug in humans,64, 102 but some evidence suggests it is less effective in monkeys.71 Fluprostenol,

Physiologic Mechanism of the Ocular Hypotensive Effect of Prostaglandins

The ocular hypotensive effect of PGs is accomplished by a several-fold enhancement of uveoscleral outflow, with little or no effect on aqueous humor formation or episcleral venous pressure, and either no effect or a modest increase in trabecular outflow facility. The many supporting studies have been summarized previously.83

Pg receptor activation

An understanding of the cellular and molecular actions of PGs and PG analogs provides insight about the mechanism of IOP lowering. The effects of PGF or its analogs topically applied to the eye are likely mediated by activation of PG receptors. Binding studies with labeled PGs observed specific PGF binding in the human ciliary body and portions of the iris.50 The PG receptor with greatest affinity for PGF is the FP receptor, although moderate affinity also is seen by EP3 receptors.16, 38

Conclusion

Topical treatments with FP-receptor agonists that lower IOP by increasing uveoscleral outflow activate a molecular transduction cascade. This cascade includes induction of the nuclear transcription factors c-Fos and c-Jun, and an increase in the biosynthesis of MMP-1, MMP-2, MMP-3, and MMP-9, leading to reduction of ECM components within the ciliary muscle, iris root, and sclera. Uveoscleral outflow is known to flow from the anterior chamber into the extracellular spaces of the ciliary muscle

References (102)

  • M Karin et al.

    AP-1 function and regulation

    Curr Opin Cell Biol

    (1997)
  • S Lake et al.

    Cloning of the rat and human prostaglandin F2 alpha receptors and the expression of the rat prostaglandin F2 alpha receptor

    FEBS Lett

    (1994)
  • J.D Lindsey et al.

    Prostaglandin action on ciliary smooth muscle extracellular matrix metabolismimplications for uveoscleral outflow

    Surv Ophthalmol

    (1997)
  • E Lutjen-Drecoll et al.

    Morphological study of the anterior segment of cynomolgus monkey eyes following treatment with prostaglandin F2 alpha

    Exp Eye Res

    (1988)
  • J.C Millar et al.

    PGF2 alpha/pilocarpine interactions on IOP and accommodation in monkeys

    Exp Eye Res

    (1995)
  • W.L Miller et al.

    Biological activities of 17-phenyl-18,19,20-trinorprostaglandins

    Prostaglandins

    (1975)
  • S.F Nilsson et al.

    Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2 -1-isopropylester in the cynomolgus monkey

    Exp Eye Res

    (1989)
  • A Ocklind

    Effect of latanoprost on the extracellular matrix of the ciliary muscle. A study on cultured cells and tissue sections

    Exp Eye Res

    (1998)
  • K.L Pierce et al.

    Cloning of a carboxyl-terminal isoform of the prostanoid FP receptor

    J Biol Chem

    (1997)
  • K Sakamoto et al.

    Molecular cloning and expression of a cDNA of the bovine prostaglandin F2 alpha receptor

    J Biol Chem

    (1994)
  • J.B Serle et al.

    A comparative study of latanoprost (Xalatan) and isopropyl unoprostone (Rescula) in normal and glaucomatous monkey eyes

    Jpn J Ophthalmol

    (1998)
  • S.D Shapiro et al.

    Induction of macrophage metalloproteinases by extracellular matrix. Evidence for enzyme- and substrate-specific responses involving prostaglandin-dependent mechanisms

    J Biol Chem

    (1993)
  • J Stjernschantz et al.

    Microvascular effects of selective prostaglandin analogues in the eye with special reference to latanoprost and glaucoma treatment

    Prog Retin Eye Res

    (2000)
  • Y Sugimoto et al.

    Cloning and expression of a cDNA for mouse prostaglandin F receptor

    J Biol Chem

    (1994)
  • C.B Toris et al.

    Effects of PhXA41, a new prostaglandin F2 alpha analog, on aqueous humor dynamics in human eyes

    Ophthalmology

    (1993)
  • C.B Toris et al.

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

    Surv Ophthalmol

    (1997)
  • C.B Toris et al.

    Uveoscleral outflow using different-sized fluorescent tracers in normal and inflamed eyes

    Exp Eye Res

    (1987)
  • C.B Toris et al.

    Aqueous humor dynamics in the aging human eye

    Am J Ophthalmol

    (1999)
  • C.B Toris et al.

    Prostaglandin A2 increases uveoscleral outflow and trabecular outflow facility in the cat

    Exp Eye Res

    (1995)
  • R.N Weinreb et al.

    Prostaglandin production by cultured cynomolgus monkey trabecular meshwork cells

    Prostaglandins Leukot Essent Fatty Acids

    (1989)
  • A Alm et al.

    PhXA34, a new potent ocular hypotensive drug. A study on dose-response relationship and on aqueous humor dynamics in healthy volunteers

    Arch Ophthalmol

    (1991)
  • T Anthony et al.

    Prostaglandin F2 receptors in the human trabecular meshwork

    Invest Ophthalmol Vis Sci

    (1998)
  • E Bárány

    Simultaneous measurement of changing the intraocular pressure and outflow facility in the vervet monkey by constant pressure infusion

    Invest Ophthalmol Vis Sci

    (1964)
  • Bárány E, Rohen J: Localized contraction and relaxation within the ciliary muscle of the vervet monkey Cercopithecus...
  • A Berg et al.

    Effect of PGE1, PGI2, and PGF2 alpha analogs on collagen gel compaction in vitro and interstitial pressure in vivo

    Am J Physiol

    (1998)
  • A Bill

    Uveoscleral drainage of aqueous humorphysiology and pharmacology

    Prog Clin Biol Res

    (1989)
  • A Bill

    Blood circulation and fluid dynamics in the eye

    Physiol Rev

    (1975)
  • A Bill

    Effects of atropine and pilocarpine on aqueous humour dynamics in cynomolgus monkeys (Macaca irus)

    Exp Eye Res

    (1967)
  • A Bill

    Aspects of the drainage of aqueous humor in cats

    Arch Ophthalmol

    (1962)
  • Camras C: Safety and side-effects of latanoprost, in Weinreb R, Kitazawa Y, Krieglstein G (eds): Glaucoma in the 21st...
  • C.B Camras et al.

    Maintained reduction of intraocular pressure by prostaglandin F2 alpha- 1-isopropyl ester applied in multiple doses in ocular hypertensive and glaucoma patients

    Ophthalmology

    (1989)
  • R.A Coleman et al.

    International Union of Pharmacology classification of prostanoid receptorsproperties, distribution, and structure of the receptors and their subtypes

    Pharmacol Rev

    (1994)
  • K Crawford et al.

    The DP-receptor agonist SQ27986 raises but does not lower intraocular pressure in ocular normotensive monkeys

    J Glaucoma

    (1992)
  • K Crawford et al.

    Pilocarpine antagonizes prostaglandin F2 alpha-induced ocular hypotension in monkeys. Evidence for enhancement of Uveoscleral outflow by prostaglandin F2 alpha

    Arch Ophthalmol

    (1987)
  • K Crawford et al.

    Effects of topical PGF2 alpha on aqueous humor dynamics in cynomolgus monkeys

    Curr Eye Res

    (1987)
  • K.S Crawford et al.

    Dose-related effects of prostaglandin F2-isopropyl ester on intraocular pressure, refraction and pupil diameter in monkeys

    Invest Ophthalmol Vis Sci

    (1991)
  • H Fujino et al.

    Differential regulation of prostaglandin F

    (2000)
  • R.C Funck et al.

    Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease

    Adv Exp Med Biol

    (1997)
  • Z.S Galis et al.

    Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion

    Circ Res

    (1994)
  • D.D Gaton et al.

    Increased matrix metalloproteinases 1, 2, and 3 in the monkey uveoscleral outflow pathway after topical prostaglandin F(2 alpha)- isopropyl ester treatment

    Arch Ophthalmol

    (2001)
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    Supported in part by NIH grants EY05590 (RNW) and EY02698 (PLK) and unrestricted grants from Research to Prevent Blindness, Inc., New York, NY (University of California San Diego, University of Nebraska, University of Wisconsin). Johan Stjernschantz, M.D, Ph.D. critically reviewed the manuscript. The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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