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Inhibition of 11ß-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension

Inhibition of 11ß-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension
Inhibition of 11ß-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension
Background: Intraocular pressure (IOP) is maintained by a balance between aqueous humour (AH) production (dependent on sodium transport across a ciliary epithelial bi-layer) and drainage (predominantly through the trabecular meshwork). In peripheral epithelial tissues, sodium and water transport is regulated by corticosteroids and the 11ß-hydroxysteroid dehydrogenase (11ß-HSD) isozymes (11ß-HSD1 activating cortisol from cortisone, 11ß-HSD2 inactivating cortisol to cortisone).
Aim: To analyse expression of 11ß-HSD in the human eye and investigate its putative role in AH formation.
Design: Multipart prospective study, including a randomized controlled clinical trial.
Methods: The expression of 11ß-HSD1 in normal human anterior segments was evaluated by in situ hybridization (ISH). RT-PCR for 11ß-HSDs, glucocorticoid and mineralocorticoid receptors (GR, MR) was performed on human ciliary body tissue. AH cortisol and cortisone concentrations were measured by radioimmunoassay on specimens taken from patients with primary open-angle glaucoma (POAG) and age-matched controls. Randomized, placebo-controlled studies of healthy volunteers and patients with ocular hypertension (OHT, raised IOP but no optic neuropathy) assessed the effect of oral carbenoxolone (CBX, an inhibitor of 11ß-HSD) on IOP.
Results: ISH defined expression of 11ß-HSD1 in the ciliary epithelium, while RT-PCR analysis of ciliary body tissue confirmed expression of 11ß-HSD1, with additional GR and MR, but not 11ß-HSD2 expression. In both POAG patients and controls, AH concentrations of cortisol exceeded those of cortisone. The CBX-treated healthy volunteers who demonstrated the largest change in urinary cortisol metabolites, indicative of 11ß-HSD1 inhibition, had the greatest fall in IOP. Patients with OHT showed an overall reduction of IOP by 10% following CBX administration, compared to baseline (p<0.0001).
Discussion: CBX lowers IOP in patients with ocular hypertension. Our data suggest that this is mediated through inhibition of 11ß-HSD1 in the ciliary epithelium. Selective and topical inhibitors of 11ß-HSD1 could provide a novel treatment for patients with glaucoma.
1460-2725
481-490
Rauz, S.
f18c0179-964b-4f95-b886-d36c0f095b15
Cheung, C.M.
31a4e6d3-4ce7-453b-bc8d-a02f8e6fb321
Wood, P.J.
f0dfe718-fa0f-43b1-9b2d-4bdc9c41320a
Coca-Prados, M.
7968b308-5aca-40bb-a659-7e60923e5495
Walker, E.A.
eac8e5fe-b23e-4512-9b98-b7ab20602201
Murray, P.I.
b34dfd53-89be-4457-a3e5-2e24d928d62a
Stewart, P.M.
5ba66e34-c467-4089-956f-cf3103b277b9
Rauz, S.
f18c0179-964b-4f95-b886-d36c0f095b15
Cheung, C.M.
31a4e6d3-4ce7-453b-bc8d-a02f8e6fb321
Wood, P.J.
f0dfe718-fa0f-43b1-9b2d-4bdc9c41320a
Coca-Prados, M.
7968b308-5aca-40bb-a659-7e60923e5495
Walker, E.A.
eac8e5fe-b23e-4512-9b98-b7ab20602201
Murray, P.I.
b34dfd53-89be-4457-a3e5-2e24d928d62a
Stewart, P.M.
5ba66e34-c467-4089-956f-cf3103b277b9

Rauz, S., Cheung, C.M., Wood, P.J., Coca-Prados, M., Walker, E.A., Murray, P.I. and Stewart, P.M. (2003) Inhibition of 11ß-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension. QJM: An International Journal of Medicine, 96 (7), 481-490.

Record type: Article

Abstract

Background: Intraocular pressure (IOP) is maintained by a balance between aqueous humour (AH) production (dependent on sodium transport across a ciliary epithelial bi-layer) and drainage (predominantly through the trabecular meshwork). In peripheral epithelial tissues, sodium and water transport is regulated by corticosteroids and the 11ß-hydroxysteroid dehydrogenase (11ß-HSD) isozymes (11ß-HSD1 activating cortisol from cortisone, 11ß-HSD2 inactivating cortisol to cortisone).
Aim: To analyse expression of 11ß-HSD in the human eye and investigate its putative role in AH formation.
Design: Multipart prospective study, including a randomized controlled clinical trial.
Methods: The expression of 11ß-HSD1 in normal human anterior segments was evaluated by in situ hybridization (ISH). RT-PCR for 11ß-HSDs, glucocorticoid and mineralocorticoid receptors (GR, MR) was performed on human ciliary body tissue. AH cortisol and cortisone concentrations were measured by radioimmunoassay on specimens taken from patients with primary open-angle glaucoma (POAG) and age-matched controls. Randomized, placebo-controlled studies of healthy volunteers and patients with ocular hypertension (OHT, raised IOP but no optic neuropathy) assessed the effect of oral carbenoxolone (CBX, an inhibitor of 11ß-HSD) on IOP.
Results: ISH defined expression of 11ß-HSD1 in the ciliary epithelium, while RT-PCR analysis of ciliary body tissue confirmed expression of 11ß-HSD1, with additional GR and MR, but not 11ß-HSD2 expression. In both POAG patients and controls, AH concentrations of cortisol exceeded those of cortisone. The CBX-treated healthy volunteers who demonstrated the largest change in urinary cortisol metabolites, indicative of 11ß-HSD1 inhibition, had the greatest fall in IOP. Patients with OHT showed an overall reduction of IOP by 10% following CBX administration, compared to baseline (p<0.0001).
Discussion: CBX lowers IOP in patients with ocular hypertension. Our data suggest that this is mediated through inhibition of 11ß-HSD1 in the ciliary epithelium. Selective and topical inhibitors of 11ß-HSD1 could provide a novel treatment for patients with glaucoma.

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Published date: 2003

Identifiers

Local EPrints ID: 24909
URI: http://eprints.soton.ac.uk/id/eprint/24909
ISSN: 1460-2725
PURE UUID: ca93eeff-716c-46ba-b14e-81d9c5a0c9f1

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Date deposited: 05 Apr 2006
Last modified: 22 Jul 2022 20:29

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Contributors

Author: S. Rauz
Author: C.M. Cheung
Author: P.J. Wood
Author: M. Coca-Prados
Author: E.A. Walker
Author: P.I. Murray
Author: P.M. Stewart

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