Comparison between Isopropyl Unoprostone and Latanoprost by Prostaglandin E2Induction, Affinity to Prostaglandin Transporter, and Intraocular Metabolism

doi:10.1006/exer.2001.1104

Experimental Eye Research

Volume 74, Issue 1, January 2002, Pages 41-49

https://doi.org/10.1006/exer.2001.1104 Get rights and content

Abstract

The pharmacological differences between isopropyl unoprostone (referred to as unoprostone) and latanoprost, concerning their induction of endogenous prostaglandin E₂(PGE₂) and affinity to a human prostaglandin transporter (PGT), were investigated.

Freshly dissected bovine iris tissues were incubated with major intraocular metabolites of unoprostone, M1 and M2, acid of latanoprost, or PGF_{2 α}, and PGE₂induction was measured. Affinities of M1, M2, latanoprost, acid of latanoprost, and PGF_2αto PGT molecule were measured using PGT-cDNA transfected HeLa cells by an isotopic influx assay.³H-unoprostone was incubated with freshly prepared serum, aqueous humor, or frozen stored fetal bovine serum (FBS), and the radioactivity of supernatants was measured to investigate their metabolism of³H-unoprostone.

M2, acid of latanoprost, and PGF_{2 α}significantly increased a release of PGE₂compared with the control. 10 μM indomethacin completely inhibited PGE₂induction by acid of latanoprost and PGF_{2 α}, while 100 μM indomethacin was required to inhibit PGE₂induction completely by M1 and M2. Unoprostone, M1, M2, and latanoprost showed little affinity to PGT, while acid of latanoprost had an affinity to PGT. Freshly prepared serum and aqueous humor metabolized unoprostone, but frozen stored FBS did not. The release of endogenous PGE₂may play an important role of action by means of PG analogs, and differences in indomethacin-related inhibition of PGE₂release and in affinities to PGT may in part cause their different actions.

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SLCO2A1 protein expression was further confirmed in the retinal pigment epithelium and epithelial and endothelial cell layers of anterior segment tissues, such as the cornea, conjunctiva, iris, and ciliary body. Moreover, a PGF2α analog, latanoprost (acid form) is a substrate of SLCO2A1; hence, there may be an interaction between SLCO2A1 and latanoprost in the pathological eye (Kashiwagi et al., 2002). More recently, an association was reported between intronic SNPs of the PTGFR and SLCO2A1 genes and the response to latanoprost in Han Chinese patients with glaucoma, suggesting a role of SLCO2A1 in adjusting the regulation of intraocular pressure.
Solute carrier organic anion transporter family member 2A1 (SLCO2A1, also known as PGT, OATP2A1, PHOAR2, or SLC21A2) is a plasma membrane transporter consisting of 12 transmembrane domains. It is ubiquitously expressed in tissues, and mediates the membrane transport of prostaglandins (PGs, mainly PGE₂, PGF_2α, PGD₂) and thromboxanes (e.g., TxB₂). SLCO2A1-mediated transport is electrogenic and is facilitated by an outwardly directed gradient of lactate. PGs imported by SLCO2A1 are rapidly oxidized by cytoplasmic 15-hydroxyprostaglandin dehydrogenase (15-PGDH, encoded by HPGD). Accumulated evidence suggests that SLCO2A1 plays critical roles in many physiological processes in mammals, and it is considered a potential pharmacological target for diabetic foot ulcer treatment, antipyresis, and non-hormonal contraception. Furthermore, whole-exome analyses suggest that recessive inheritance of SLCO2A1 mutations is associated with two refractory diseases, primary hypertrophic osteoarthropathy (PHO) and chronic enteropathy associated with SLCO2A1 (CEAS). Intriguingly, SLCO2A1 is also a key component of the Maxi-Cl channel, which regulates fluxes of inorganic and organic anions, including ATP. Further study of the bimodal function of SLCO2A1 as a transporter and ion channel is expected to throw new light on the complex pathology of human diseases. Here, we review and summarize recent information on the molecular functions of SLCO2A1, and we discuss its pathophysiological significance.
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The eye fundus in higher mammals is supplied by two distinct vascular systems, namely the retinal and the uveal systems. Both systems are derived from the ophthalmic artery (OA), a branch of the internal carotid. The uveal system includes the anterior uvea, which comprises the iris and the ciliary body, and the choroid. The retina has a dual blood supply, the inner two-thirds being nourished by branches from the central retinal artery (CRA), whilst the outer third is nourished by the choroidal circulation. Quantitative information on blood velocity and flow in the normal human eye under physiological conditions has been obtained from the various ocular vascular systems using a number of different techniques. In the human eye, two vascular systems are present which differ anatomically and physiologically: the retinal vessels, which supply the neural region of the retina and the prelaminar portion of the ON and the uveal or ciliary blood vessels, which supply the rest of the eye. The rate of blood flow in the intraocular tissues is determined by the ocular perfusion pressure (OPP) and the vascular resistance (R). R depends upon the blood viscosity, length, and diameter of the blood vessels. The diameter of the resistance vessels is modulated by the interaction of multiple control mechanisms affecting the smooth muscle and vascular pericytes: myogenic, metabolic, neurogenic, humoral, and endothelium-derived factors. The determinants of ocular blood flow include systemic, local, neural, endothelial, endocrine, and paracrine factors.
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Prostaglandins (PGs) have been implicated in lowering intraocular pressure (IOP). A possible role of cyclooxygenase-2 (COX-2) in this process was emphasized by findings showing impaired COX-2 expression in the non-pigmented ciliary epithelium (NPE) of patients with primary open-angle glaucoma. The present study investigates the effect of the major COX-2 product, PGE₂, on the expression of its synthesizing enzyme in human NPE cells (ODM-2). PGE₂ led to an increase of COX-2 mRNA and protein expression, whereas the expression of COX-1 remained unchanged. Upregulation of COX-2 expression by PGE₂ was accompanied by time-dependent phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK, and was abrogated by inhibitors of both pathways. Moreover, PGE₂-induced COX-2 expression was suppressed by the intracellular calcium chelator, BAPTA/AM, and the protein kinase C inhibitor bisindolylmaleimide II, whereas the protein kinase A inhibitor H-89 was inactive in this respect. Induction of COX-2 expression was also elicited by butaprost (EP₂ receptor agonist) and 11-deoxy PGE₁ (EP₂/EP₄ receptor agonist), but not by EP₁/EP₃ receptor agonists (17-phenyl-ω-trinor PGE₂, sulprostone). Consistent with these findings, the EP₁/EP₂ receptor antagonist, AH-6809, and the selective EP₄ receptor antagonist, ONO-AE3-208, significantly reduced PGE₂-induced COX-2 expression. Collectively, our results demonstrate that PGE₂ at physiologically relevant concentrations induces COX-2 expression in human NPE cells via activation of EP₂- and EP₄ receptors and phosphorylation of p38 and p42/44 MAPKs. Positive feedback regulation of COX-2 may contribute to the production of outflow-facilitating PGs and consequently to regulation of IOP.
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Purpose. To identify and localize the expression of multispecific organic anion transporting polypeptides (Oatps/OATPs) in the ciliary body epithelium and to investigate their possible involvement in the transport of the antiglaucoma agent unoprostone.
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Citation Excerpt :
In addition to the smooth muscles of the iris, the anterior segment of the eye contains the ciliary muscle and trabecular meshwork which features smooth muscle-like properties (Wiederholt et al., 2000), both of which contribute actively to the regulation of aqueous humor outflow and thus IOP. Additional mechanisms that may contribute to the PG-mediated increase in aqueous humor outflow include relaxation of the smooth muscles of the anterior segment, thus we (Yousufzai et al., 1996) and others (Bergh et al., 2002; Kashiwagi et al., 2002) have previously reported release of PGE2, a cAMP-elevating agent, from iridial and ciliary muscle preparations of different mammalian species after stimulation with exogenous PGF2α or latanoprost. Contraction of smooth muscle depends on cellular Ca2+ influx, which activates the myosin light chain kinase (MLCK) to activate the myosin-actin interactions that underlie contraction.
A potential role for myosin light chain kinase (MLCK) in regulating intraocular pressure and outflow function has recently been reported in living monkey eye and rabbit eye. There is little information about the effects of the ocular hypotensive agents, prostaglandin F_2α (PGF_2α) and latanoprost on this signaling pathway in ocular tissues. The aim of this study was to determine the agonist activity of PGF_2α, latanoprost and carbachol (CCh) on the MLCK pathway in isolated bovine iris sphincter and furthermore to investigate the existence of the FP receptor in this tissue. In the present studies on the MLCK pathway four signal transduction mechanism assays were employed, phosphoinositide (PI) turnover, p42/p44 MAP kinase phosphorylation and activation, MLC phosphorylation and contraction. In the studies on the existence of the FP receptor in the bovine iris sphincter, the pharmacology and expression of the FP receptor protein, using a polyclonal anti-FP-receptor antibody and Western blot analysis, were determined. The data obtained on the MLCK pathway showed that the three agonists stimulated the biochemical and pharmacological responses in a concentration and time-dependent manner and that the order of potency and efficacy is PGF_2α>latanoprost>CCh. The EC₅₀ values in the PI turnover, MAP kinase phosphorylation, MLC phosphorylation and contraction assays were for PGF_2α: 9, 42, 200 and 140 nm, respectively, for latanoprost: 13, 59, 250 and 828 nm, respectively, and for CCh: 22, 200, 630 and 910 nm, respectively. Wortmannin, a selective inhibitor of MLCK, dose-dependently inhibited MLC phosphorylation and contraction induced by PGF_2α, demonstrating a close relationship between activation of the MLCK pathway and contraction. The pharmacological studies showed that in the concentration range of 1 nm to 10 μm, the FP-receptor agonists caused concentration-response curves with the following order of potencies: 17-phenyl trinor PGF_2α (bimatoprost acid)>PGF_2α>cloprostenol>latanoprost>latanoprost acid>bimatoprost amide≫fluprostenol. Immunoblot analysis of the FP receptor demonstrated expression of the prostaglandin FP receptor protein in this smooth muscle. These results clearly indicate that the MLCK signaling pathway is involved in the FP-receptor function of the bovine iris sphincter and furthermore demonstrate that functional FP receptors exist and are expressed in this tissue.

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^f1: Address correspondence to: Kenji Kashiwagi, Department of Ophthalmology, Yamanashi Medical University, 1110 Shimokato, Tamaho, Yamanashi 409-3898, Japan. E-mail: [email protected]

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Regular ArticleComparison between Isopropyl Unoprostone and Latanoprost by Prostaglandin E2Induction, Affinity to Prostaglandin Transporter, and Intraocular Metabolism

Abstract

Ophthalmology

Am. J. Ophthalmol.

Prostaglandins Leukot Essent Fatty

Prostaglandins

Surv. Ophthalmol.

Ophthalmology

Surv. Ophthalmol.

J. Biol. Chem.

Am. J. Ophthalmol.

Jpn. J. Pharmacol.

Am. J. Ophthalmol.

J.Pharm. Sci.

Surv. Ophthalmol.

Ophthalmology

Exp. Eye Res.

Surv. Ophthalmol.

FEBS Lett.

J. Biol. Chem.

Jpn. J. Ophthalmol.

Ophthalmology

Exp. Eye Res.

The potential of prostaglandin derivatives in glaucoma therapy

Curr. Opin. Ophthal.

Clinical evaluation of UF-201 ophthalmic solution in glaucoma patients refractory to maximum tolerable therapy

Nippon Ganka Gakkai Zassi (Acta Soci Ophthalmol. Jpn.)

Regular Article
Comparison between Isopropyl Unoprostone and Latanoprost by Prostaglandin E₂Induction, Affinity to Prostaglandin Transporter, and Intraocular Metabolism