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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Surv Ophthalmol. Author manuscript; available in PMC Nov 1, 2009.
Published in final edited form as:
PMCID: PMC2727743
NIHMSID: NIHMS82317

Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction

Abstract

A decade has passed since the first topical prostaglandin analog was prescribed to reduce intraocular pressure (IOP) for the treatment of glaucoma. Now four prostaglandin analogs are available for clinical use around the world and more are in development. The three most efficacious of these drugs are latanoprost, travoprost, and bimatoprost, and their effects on IOP and aqueous humor dynamics are similar. A consistent finding is a substantial increase in uveoscleral outflow and a less consistent finding is an increase in trabecular outflow facility. Aqueous flow appears to be slightly stimulated as well. Prostaglandin receptors and their associated mRNAs have been located in the trabecular meshwork, ciliary muscle, and sclera providing evidence that endogenous prostaglandins have a functional role in aqueous humor drainage. Earlier evidence found that topical PG analogs release endogenous prostaglandins. One well-studied mechanism for the enhancement of outflow by prostaglandins is the regulation of matrix metalloproteinases and remodeling of extracellular matrix. Other proposed mechanisms include widening of the connective tissue-filled spaces and changes in the shape of cells. All of these mechanisms alter the permeability of tissues of the outflow pathways leading to changes in outflow resistance and/or outflow rates. This review summarizes recent (since 2000) animal and clinical studies of the effects of topical prostaglandin analogs on aqueous humor dynamics and recent cellular and molecular studies designed to clarify the outflow effects.

Keywords: aqueous humor, intraocular pressure, matrix metalloproteinases, prostaglandin, trabecular outflow, uveoscleral outflow

Introduction

All of the clinically available drugs for the treatment of elevated intraocular pressure (IOP) have direct effects on one or more parameters of aqueous humor dynamics. IOP usually is reduced by slowing the production rate of aqueous humor, by decreasing the resistance to flow through the trabecular meshwork, by increasing drainage through the uveoscleral outflow pathway, or by a combination of these mechanisms. Currently, the most effective outflow drugs approved for clinical use are prostaglandin (PG) F analogs. These drugs reduce IOP by stimulation of aqueous humor drainage primarily through the uveoscleral outflow pathway but significant effects on trabecular outflow facility also have been reported.67, 85 Three PGF2 α analogs (bimatoprost, latanoprost, and travoprost) are approved for glaucoma therapy in the USA, one additional analog (unoprostone) is prescribed in Japan and a new analog (tafluprost) is in clinical trials in Japan. Travoprost and latanoprost are ester prodrugs of PGF2 α. Bimatoprost is the amide prodrug of 17-phenyl-PGF2 α 86 and has been classified by some as a prostamide, 86 although this classification has been somewhat controversial.7, 37, 56, 57, 58, 86, 87 Unoprostone is an analog of a pulmonary metabolite of PGF2 α and sometimes labeled a docosanoid. 26 Tafluprost is a difluoroprostaglandin derivative of PGF2 α. 62 Agonists of DP, EP, and TP receptors have been or are being investigated in animal models for their IOP efficacy and potential as new glaucoma therapeutic drugs. None of these agonists has yet to be approved for clinical use.

This review summarizes recent (since 2000) animal and clinical English-language studies of the effects of topical PG agonists on aqueous humor dynamics and recent cellular and molecular studies designed to clarify the outflow effects.

Aqueous Humor Dynamics (Table 1)

Table 1
Studies of aqueous humor dynamics in humans and nonhuman primates treated with prostaglandin analogs published from 2000 to 2008

Latanoprost, travoprost, and bimatoprost produce similar increases in uveoscleral outflow of several-fold. Increases in trabecular outflow facility also have been reported but this finding has not been found consistently (Table 1). Unoprostone, the least efficacious of the four compounds, appears to have little effect on uveoscleral outflow in humans. Rather it works mainly by increasing trabecular outflow facility. 69 The new fluoroprostaglandin F, tafluprost, increases uveoscleral outflow and aqueous flow in monkeys 62 but has yet to be studied in humans. Earlier studies13, 90 have reported that the topical PG analogs release endogenous prostaglandins that may contribute to the observed ocular hypotensive effects. Tafluprost in mice reportedly works in part through FP receptor-mediated prostaglandin production acting through the prostanoid EP3 receptor. 49 Studies published between 2000 and 2008 of FP, DP, and EP receptor agonists and their effects on aqueous humor dynamics in humans and nonhuman primates are summarized in Table 1. Studies predating 2000 are found in an earlier review. 67

TRABECULAR OUTFLOW FACILITY

Trabecular outflow facility is not always increased following topical treatment with PG analogs but evidence is building that the effect is real and not unique to any one drug of this class. Latanoprost, travoprost, bimatoprost, and unoprostone all have been found to significantly increase trabecular outflow facility in at least one clinical study (Table 1).

Compared to humans, the trabecular meshwork of monkeys seems to be less affected by PG analogs. Trabecular outflow facility was unchanged following multiple topical treatments of monkeys with PGF-isopropyl ester, 22 tafluprost, 62 and travoprost, 71 the DP receptor agonist AL-6598, 72 and EP receptor agonists butaprost 44 and 8-iso PGE2 23 (Table 1). Exceptions do exist. One drop of 17-phenyl trinor 8-iso PGE2 and the selective EP4 receptor agonist, 3,7-dithia PGE1 increased outflow facility sufficiently in normotensive monkey eyes to account for most, if not all of the IOP reduction 88 (Table 1). An older study found an increase in outflow facility at 4 hours after one topical drop of PGF. 35

One potential reason for the apparent differences in trabecular outflow facility effect among the various PG agonists is the method of measurement. Two noninvasive methods, tonography and fluorophotometry, and two invasive methods, two-level constant pressure perfusion, and isotope accumulation, are used to make the assessment. All methods measure trabecular outflow facility, but confounding factors are known to exist, including ocular rigidity (a measure of eye stiffness), pseudofacility (the facility of flow of aqueous humor from the posterior to anterior chamber resulting from the probe-induced increase in IOP), and uveoscleral outflow facility. The name of the measured variable trabecular outflow facility is not entirely accurate because of the inclusion of these other factors in the various measurements. All of the measurement techniques assume that uveoscleral outflow facility is very small and affected little by the measurement itself. This assumption is based on monkey studies8, 68 reporting that uveoscleral outflow is relatively pressure-independent. However, if an experimental manipulation were to increase uveoscleral outflow facility, this could be interpreted erroneously, as an increase in trabecular outflow facility. It is thought by some that PGs increase uveoscleral outflow facility but this has yet to be proven experimentally. These methods may not detect changes in trabecular outflow facility if the changes are overshadowed by strong effects on uveoscleral outflow and/or uveoscleral outflow facility.

The length of time of treatment could be another factor contributing to the differing effects of PGs on trabecular outflow facility. The immediate IOP effects that occur from a single dose of a PG analog may be mediated by cellular mechanisms different from those that occur after repeated applications or continuous exposure.9, 83, 91 Therefore, findings from multiple doses of each PG should be compared before concluding that one PG analog acts through mechanisms different from all others.

Mice are being used with increasing frequency to evaluate aqueous humor dynamics because of their potential for genetic manipulation in addition to their ocular similarities to humans. These animals exhibit increases in outflow facility 2 hours after one 4-µl drop of latanoprost. 18 Several limitations to using this animal model should be mentioned. The size of the eye makes accurate measurement difficult. Inflow and outflow are very slow (many-fold slower than in humans), 1 and changes in flow can be near the limit of detection. Additionally, the anesthesia needed for most measurements quickly and profoundly affects IOP. 31 IOPs vary among strains of mice, 30 and aqueous humor outflow rates may vary among strains as well. Further research is needed to characterize differences in aqueous humor dynamics among the murine strains.

UVEOSCLERAL OUTFLOW

Increases in uveoscleral outflow have been reported with topical treatment of bimatoprost and latanoprost in ocular normotensive and hypertensive subjects (Table 1).11, 16, 20, 73 Travoprost increased uveoscleral outflow in monkeys 71 and marginally increased it in ocular hypertensive patients as well. 70 Unoprostone, the weakest of the four prescribed PG analogs, is the only one that did not affect uveoscleral outflow in humans despite 5 days of twice-daily dosing. 69

Multiple topical drops of agonists for FP receptors (tafluprost 62), DP receptors (AL-6598 72), and EP2 receptors (butaprost 44 and 8-iso PGE2 78) increased uveoscleral outflow in monkeys (Table 1). In contrast, one drop of the EP4 agonist, 3,7-dithia PGE1, had no effect on uveoscleral outflow in monkeys 88. A multiple dose study is needed to clarify whether the effect persists with repeat dosing.

AQUEOUS FLOW

Most studies investigating aqueous flow have found that PG analogs produce a small (10–15%) increase that may or may not be statistically significant and is not clinically important. A significant increase in aqueous flow was found at night in young healthy Japanese volunteers treated with latanoprost, 41 and during the day and at night in healthy predominantly Caucasian volunteers treated with bimatoprost. 11 Additionally aqueous flow increased during the day in monkeys treated with a DP agonist. 72 This effect does not contribute to any reduction in IOP but an increase in aqueous flow could be considered a healthy side-effect of topical PG analogs because aqueous humor carries essential nutrients and removes waste products, crucial for keeping the avascular tissues of the anterior segment healthy.

EPISCLERAL VENOUS PRESSURE

Three studies have reported no change in episcleral venous pressure in patients with ocular hypertension treated for one week with latanoprost, travoprost, or unoprostone (Table 1). The measurements, (made with a commercially available episcleral venomanometer, EyeTech, Morton Grove, IL), are difficult to make with accuracy and consistency. Nevertheless, because no study found any trend to suggest a change, it seems reasonable to conclude that the PG effect on episcleral venous pressure is minimal.

Cellular and Molecular Studies (Table 2)

Table 2
Molecular and cellular studies of the effects of prostaglandin-related compounds on the aqueous humor outflow pathways

TRABECULAR MESHWORK

Organ-cultured anterior segments and trabecular meshwork cell cultures provide strong evidence that PG analogs can alter the resistance in trabecular outflow. PGs have direct effects on matrix metalloproteinases (MMPs), neutral proteases that initiate degradation of the extracellular matrix and play a major role in regulating resistance to flow through tissues. MMPs are expressed by human trabecular meshwork 2 and directly control outflow resistance in human organ-cultured anterior segments. 9 The activity of MMPs is regulated by tissue inhibitors of metalloproteinases (TIMPs). 10 Currently four TIMPS (TIMP-1, -2, -3, -4) have been identified in mammals and each TIMP targets specific MMPs. 42 In one study, 47 cultures of human trabecular meshwork cells treated with latanoprost acid for 24 hours had increased expression of MMPs -1, -3, -17 and -24 and TIMPs -2,-3, and -4. A study 6 of human organ-cultured anterior segments infused with latanoprost acid found increased outflow facility at 24 hours after administration when compared to control anterior segments (67% versus 6%) but no changes in the amount of MMPs or scleral hydraulic conductivity. 6 Histological examination found regions of focal detachment and loss of Schlemm’s canal endothelial cells and extracellular matrix in some areas of the trabecular meshwork. 6 The focal cell loss was reasoned to be due to cytoskeletal and focal adhesion changes, 6 since PGs in aortic smooth muscle cells cause disassembly of actin stress fibers and inhibition of phosphorylation of paxillin and other focal adhesion proteins. 12

Bimatoprost increases outflow facility by 40% in human organ-cultured anterior segments within 48 hours of treatment. This effect was blocked by preincubation with AGN 211334, thought to be a prostamide-selective antagonist, 76 or , alternatively, an inhibitor of bimatoprost hydrolysis. 7 Similarly, pig organ-cultured anterior segments perfused at a constant pressure of 15 mmHg, showed increased outflow by up to 62% at 8 hours after topical administration of bimatoprost and by 30% at 5 hours after intracameral administration of PGF. 74 Human trabecular meshwork monolayer cultures 6 treated with bimatoprost had a 78% increase in hydraulic conductivity which also was blocked by AGN211334. 76

PGE1 increases outflow facility by 26% in human organ-cultured anterior segments. 19 This effect probably occurs by an adenylyl cyclase-dependent pathway activated primarily by the predominant EP2 receptors in the trabecular meshwork. 32 Stimulation of EP2 receptors in trabecular meshwork is coupled to the activation of high-conductance Ca+2-activated K+ channels (BK) which may contribute to the relaxant activity of EP2 agonists in isolated trabecular meshwork strips. 61 However, outflow facility was not stimulated and cAMP production was not altered after short exposure periods with PGF or placebo in human organ-cultured anterior segments. 19

Prostaglandin receptors have been identified in human trabecular meshwork tissue but a prostamide receptor has not yet been cloned. The genes for all prostanoid receptors are expressed in human trabecular meshwork. Gene expression for the EP2 receptor is most abundant, followed by FP, TP, IP and EP4, with DP and EP3 at the lowest levels. 32 Immunofluorescent labeling of FP and EP pαostanoid receptor subtypes in normal human trabecular meshwork tissue showed positive staining for EP1 on trabecular cells of the outer portion of the meshwork and cells lining Schlemm’s canal. EP2 was localized to the outer wall and periphery of Schlemm’s canal. EP3 and EP4 labeling was present on trabecular cells along the entire meshwork. Moderate expression of FP receptor protein was present in the outer portion of the trabecular meshwork and endothelial cells of Schlemm’s canal, collector channels and aqueous veins. 55

Human trabecular meshwork cells in culture express many of the same PG receptors as are found in intact tissue. Cultured trabecular meshwork cells can produce PGE2 and low levels of PGF.83, 84 Additionally, FP receptors have been identified in human trabecular meshwork cells as determined by the presence of mRNA, protein, and a functional response (increased inositol phosphate accumulation and intracellular calcium release) to PGF 5 and numerous synthetic FP-selective PG agonists. 58 PGE2 elicits its biological effects via four G-protein-coupled receptor subtypes which stimulate phosphoinositide turnover with elevation in intracellular-free calcium (EP1 and some EP3), activation of adenylyl cyclase and elevation of intracellular cAMP (EP2 and EP4) or inhibition of adenylyl cyclase (EP3).17, 43 Prolonged treatment of human trabecular meshwork cells with latanoprost or PGF ethanolamide causes an increase in expression of genes for insulin-like growth factor-1 (IGF-1) and fibroleukin that could act to increase outflow facility. IGF-1 is reported to increase the level of MMPs, stromelysin and gelatinase in trabecular meshwork cells. The protease activity of fibroleukin may be active against a component in the extracellular matrix. 91

Unoprostone free acid (UF-021) shows low affinity for all prostanoid receptors and weak functional responses via FP receptor activation. 57 Several molecular events have been associated with unoprostone exposure. A reduction in the activity of L-type Ca2+ channels via a signal transduction pathway was mediated by tyrosine kinases. 65 Activation of BK channels by unoprostone free acid inhibited trabecular meshwork contraction leading to an increase in outflow. 66

Endothelin-1 is involved in regulating the contractility of the trabecular meshwork. FP receptor agonists can block endothelin-1 induced contractility of the trabecular meshwork. Evidence indicates this inhibition is mediated by the FP receptor. 64

UVEOSCLERAL TISSUES

Immunohistochemistry studies of EP and FP receptor localization in the uveoscleral tissue in normal human donor eyes indicate the presence of EP-1, -2, -3, -4 and FP receptors in the ciliary body and sclera. FP receptors are most abundant in the circular portion of the ciliary muscle. 55

Several mechanisms have been proposed to explain the PG-induced increase in uveoscleral outflow: remodeling of the extracellular matrix of the ciliary muscle,45, 53, 80 and sclera33, 82 (Molik et al, unpublished data, abstract 406 presented at the 2006 ARVO annual meeting) causing changes in the permeability of these tissues, widening of the connective tissue-filled spaces among the ciliary muscle bundles,39, 63 which may be caused in part by relaxation of the ciliary muscle,51, 75 and changes in the shape of ciliary muscle cells as a result of alterations in actin and vinculin localization within the cells. 60

Ciliary muscle relaxation has been suggested as responsible for the initial reduction in IOP from topical PGs. This does not appear to be the case for all PGs and their agonists. PGE1 and PGE2 relaxed isolated monkey ciliary muscle strips precontracted with carbachol 89 but 3,7-dithia PGE1 88, PGF and latanoprost did not. 89

Remodeling of the extracellular matrix within the ciliary muscle and sclera is the most thoroughly understood effect of PG treatment. Dissolution of collagen types I and III within the connective tissue-filled spaces between the outer longitudinally oriented muscle bundles39, 63 results from PG-stimulated induction of enzymes MMP1, 2, and 3 in the ciliary muscle and surrounding sclera. 25 Long-term (1 year) unilateral treatment of monkey eyes with topical bimatoprost, latanoprost, sulprostone (EP3/EP1 agonist) or AH13205 and butaprost (EP2 agonists) found that in all cases the tissue spaces of the ciliary muscle were enlarged and organized into elongated tube-like spaces, covered by endothelial-like cells often in contact with the basement membrane, and contained myelinated nerve fiber bundles.44, 52 These fluid pathways resembled a kind of lymphatic system described in the choroid. 34 Changes in the trabecular meshwork also were present. MMP expression in human ciliary body tissue and ciliary muscle cells was determined after latanoprost acid treatment for 24 hours. The mRNA of MMP-1,-2, -3, -11, -12, -14, -15, -16, -17, -19, and -24 as well as TIMP-1 to -4 were found in ciliary body tissue and ciliary muscle cells. Latanoprost increased MMP-3,-9, -17, and TIMP-3 and down-regulated MMP-1, -2, -12, -14, -15, and -16 and TIMP-4. 46 Latanoprost acid induced a concentration-dependent increase in MMP-1, -3, and -9 gene transcription 81 and a concentration - and time-dependent increase in TIMP-1 but not TIMP-2 mRNA and protein. 4

Loss of cyclooxygenase (COX)-2 expression in the ciliary body of humans has been associated with glaucoma. 40 This association has led to studies investigating the connection between PGs, COX-2 expression and MMPs. Indeed, the IOP-lowering action of latanoprost appears to be associated with induction of COX-2 and subsequent MMP-1 expression in human nonpigmented epithelial cells. 27 MMP-1 released into the aqueous humor would be expected to flow into the ciliary muscle and through the trabecular meshwork and Schlemm’s canal to potentially increase outflow via multiple routes.

Studies to elucidate additional cellular mechanisms associated with PG-induced MMP secretion are ongoing. PGF- and latanoprost-induced secretion and activation of MMP-2 in ciliary muscle cells were shown to occur via protein kinase C and extracellular signal regulated protein kinase 1/2-dependent pathways. 28 Mitogen-activated protein kinase activity was stimulated in human ciliary muscle cells with travoprost acid>PGF2α> latanoprost acid> bimatoprost > latanoprost = bimatoprost acid. The FP antagonist AL-8810 completely inhibited the mitogen-activated protein kinase activity induced by bimatoprost and bimatoprost acid, indicating that both agonists were activating the FP receptor. 57

Inhibition of the latanoprost-induced reduction of IOP in rats by thalidomide suggested that the IOP-lowering response is mediated, in part, through tumor necrosis factor-α-dependent signaling pathways. Treatment of human ciliary muscle cells with tumor necrosis factor-α increased the secretion of MMP-1, and -2 (Husain et al., unpublished data, abstract 219 presented at the 2006 ARVO annual meeting).

PGF can stimulate the formation of endogenous PGs by stimulation of phospholipase A2 and release of arachidonic acid for PG synthesis. 90 Human ciliary muscle cells exposed to PGF ethanolamide or latanoprost for 9 days show a downregulation of the FP receptor. In the same study, downregulation of the aquaporin-1 and versican genes are proposed to increase flow through the ciliary muscle and decrease IOP. 91

PG-induced changes in the sclera also are important in the regulation of uveoscleral outflow and may be used to enhance transscleral delivery of peptides and other high-molecular-weight substances to the posterior segment of the eye. Five days of topical treatment with PGF-isopropyl ester increased MMP-1, -2, and -3 in the sclera of monkeys. 79 Immunocytochemistry studies and mRNA analysis of human sclera and cultured human scleral fibroblasts showed the presence of EP1, EP2 and FP receptor subtypes but not EP3 and EP4 subtypes. 3 Human scleral permeability to dextrans was measured in an Ussing chamber following exposure to PGF and latanoprost acid for 1–3 days. Scleral permeability increased in a dose- and time-dependent manner. This was accompanied by an increase in MMP concentration in the media with the greatest increases in MMP-2 and -3 compared to MMP-1. 33 PGF and latanoprost acid also induced increases in mRNA for MMPs and TIMPs in human scleral organ cultures. 82 X-ray diffraction analysis of human scleral explants showed that incubation in PGF-containing media caused the collagen helix to undergo gelatinization similar to what was found after incubation with MMP-enriched media (Molik et al, unpublished data, abstract 406 presented at the 2006 ARVO annual meeting).

GENETIC STUDIES

Mice deficient in various PG receptors have been used to determine the role of prostanoid receptor subtypes in mediating the IOP-lowering response to clinical PG analogs. Studies in FP receptor-deficient mice have shown that the FP receptor is essential for the early IOP-lowering response to topical latanoprost, travoprost, bimatoprost, and unoprostone. 48 The involvement of the FP receptor in the IOP reduction with long-term dosing is unknown. Upregulation of MMP-2, -3, -9 and FP mRNA in the sclera following 7 days of topical treatment with latanoprost also was dependent on an intact FP receptor gene (Crowston et al, unpublished data, abstract 1551 presented at the 2007 ARVO annual meeting). EP receptor-deficient mice have been studied in similar ways. When EP1, EP2, and EP3 receptor-deficient mice and their wild-type background strain were treated topically with latanoprost, travoprost, bimatoprost, or unoprostone, it was found that EP3 receptors were involved in the IOP- lowering response to latanoprost, travoprost, and bimatoprost at 3 hours after drug administration but EP1 and EP2 receptors are not. 50

PHARMACOLOGIC DIFFERENCES AMONG THE PROSTAGLANDINS

Natural prostaglandins (PGF, PGE2, PGD2, PGI2) have the highest affinity for their respective receptors (FP, EP, DP, IP) but are relatively nonselective for these and other PG receptors (TP) and their subtypes (DP1, DP2, EP1–4) in receptor-binding studies. 57 Prostamides are also naturally occurring neutral lipids which have very little activity at prostaglandin receptors but, thus far, only pharmacologic evidences exists for a prostamide receptor. 87 The therapeutic derivatives of PGF, either amide or ester prodrugs, are powerful ocular hypotensive drugs and either mediate their effects primarily via FP receptor activation or potentially via some yet unidentified receptor activation. 57

It has been reported that the prostamide bimatoprost stimulates neither FP nor EP2 receptors and its effects on aqueous humor outflow, although similar to latanoprost and travoprost, are accomplished via a receptor distinct from these pure FP receptor agonists. However, bimatoprost acid (17-phenyl PGF), which is found in the aqueous humor of humans after topical application of bimatoprost,(Dahlin et al, ARVO 2004 abstract 2096)14, 15 exhibits a relatively high affinity for three different PG receptors (i.e., FP [Ki=83nM], EP1 [Ki=95nM], EP3 [Ki-387nM]). Bimatoprost acid also exhibits functional activity (phosphoinositide turnover) at the EP1 (EC50=2.7nM) and FP (EC50=2.8–3.8nM) receptors in most cell types. 57 Bimatoprost acid is a potent, non-selective PGF analog.

Unlike PGF or the EP2 agonist butaprost, bimatoprost did not upregulate orphan nuclear receptor (Nur77) or connective tissue growth factor (CTNF) expression in human ciliary muscle cells or trabecular meshwork. In addition, the FP antagonist, AL-8810 blocked the PGF-induced Nur77 mRNA expression in human ciliary muscle cells and trabecular meshwork indicating PGF -induced Nur77 mRNA expression is via the activation of FP receptors.36, 37 Bimatoprost induced the upregulation of Cyr61 (cysteine-rich angiogenic protein 61) gene expression in cat iris and human ciliary muscle cells. Cry61 is involved in regulating extracellular matrix-associated signaling proteins and may be a unique mechanism by which bimatoprost exerts its pharmacological action to lower IOP independent of Nur77 or CTNF. 37 The importance of the induction or lack of induction of these various genes for IOP reduction remains to be determined. The production of transgenic mice lacking these genes and their IOP responses to PGF, bimatoprost, and butaprost is needed.

Bimatoprost appears to reduce the IOP of patients who are unresponsive to latanoprost, 24 suggesting that the prostamide bimatoprost and the FP receptor agonist latanoprost stimulate different receptor populations. This is consistent with studies on isolated iridial cells where bimatoprost stimulated an entirely different cell population to those sensitive to PGF and bimatoprost acid (17-phenyl PGF). 59 An equally plausible explanation is that some eyes may be deficient in corneal esterase and thus are not able to adequately convert the prodrug latanoprost into its free acid active form. 21 Also splice variants of the FP receptor may exist that have not yet been discovered. Single nucleotide polymorphisms in the promoter and intron 1 regions of the FP receptor gene are correlated with the variability in the IOP-lowering response to latanoprost in normal human eyes. 54

Summary

Clinical and animal studies of aqueous humor dynamics have reported that PG analogs effectively reduce IOP by enhancing aqueous humor outflow. The relative effects of PG analogs on each of the two outflow pathways may vary, but it appears that they reduce IOP predominantly by increasing uveoscleral outflow and to a lesser extent trabecular outflow facility. Morphological studies have identified PG receptors and described significant cellular changes in PG-treated tissues of both outflow pathways. Biochemical studies have reported many complex cellular events in PG-treated outflow tissues, including activation of multiple signaling pathways, and increased expression of some factors and downregulation of others. Genetic studies of knockout mice treated with PGs have found that a reduction in IOP requires intact FP and EP3 receptors.

Many questions remain unanswered but progress continues to be made. Prostamide antagonists have been described76, 87 but this has raised new questions. 7 A prostamide receptor needs to be cloned and its biosynthesis enzyme identified to conclude that a unique prostamide-sensitive receptor exists. Further work is required to confirm that bimatoprost acts through this receptor. Multiple-dosing studies of each PG should be compared before concluding that one PG analog acts through mechanisms different from all others. Live animal and clinical studies are needed to support claims made by in vitro experiments. Receptor subtype selectivity of topical PGs should be identified. The importance of induction or lack of induction of various genes for IOP reduction needs to be clarified. One day, the current research may lead to future new drugs that exceed the utility of the PGFanalogs.

Method of Literature Search

These studies, dating between 2000 and 2008 were found from a series of literature searches of PubMed and from the reference lists of these articles. The searches included the following terms in various combinations: anterior segment organ culture, aqueous flow, aqueous humor dynamics, bimatoprost, ciliary muscle, DP receptor, EP receptor, fluorophotometry, FP receptor, latanoprost, matrix metalloproteinase, monkey, ocular, outflow facility, prostaglandins, prostamide, prostanoid, tafluprost, tonography, travoprost, unoprostone, uveoscleral outflow. Original research articles, review articles and meeting abstracts are included in this review.

Acknowledgment

The supplement in which this article is published was funded by Pfizer. The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. The article was supported in part by unrestricted grants from Research to Prevent Blindness, Inc., New York, NY (CT, PK), NIH/NEI EY002698 (PK); NEI P30 EY016665 (Core Grant for Vision Research) (PK); unrestricted departmental and Physician-Scientist awards (PK); Ocular Physiology Research and Education Foundation (PK); Walter Helmerich Chair from the Retina Research Foundation (PK).

Footnotes

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