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

Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension
Inhibition of 11beta-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 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isozymes (11beta-HSD1 activating cortisol from cortisone, 11beta-HSD2 inactivating cortisol to cortisone). AIM: To analyse expression of 11beta-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 11beta-HSD1 in normal human anterior segments was evaluated by in situ hybridization (ISH). RT-PCR for 11beta-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 11beta-HSD) on IOP. RESULTS: ISH defined expression of 11beta-HSD1 in the ciliary epithelium, while RT-PCR analysis of ciliary body tissue confirmed expression of 11beta-HSD1, with additional GR and MR, but not 11beta-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 11beta-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 11beta-HSD1 in the ciliary epithelium. Selective and topical inhibitors of 11beta-HSD1 could provide a novel treatment for patients with glaucoma
patients, sodium, protein, glucocorticoid, methods, female, drug therapy, glaucoma, double-blind method, male, carbenoxolone, physiopathology, receptors, enzyme inhibitors, role, hypertension, 11-beta-hydroxysteroid dehydrogenase type 2, infection, water, prospective studies, non-u.s.gov't, pharmacology, therapeutic use, in situ hybridization, aged, radioimmunoassay, drainage, intraocular pressure, cortisone, antagonists & inhibitors, immunity, analysis, ocular hypertension, cortisol, pressure, drug effects, epithelium, research support, design, mineralocorticoid, trabecular meshwork, hydrocortisone, chemistry, human, enzymology, hydroxysteroid dehydrogenases, humans, aqueous humor
1460-2725
481-490
Rauz, S.
f18c0179-964b-4f95-b886-d36c0f095b15
Cheung, C.M.G.
372c62f6-2b8a-475b-a182-1d43cc3feaa9
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.G.
372c62f6-2b8a-475b-a182-1d43cc3feaa9
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.G., Wood, P.J., Coca-Prados, M., Walker, E.A., Murray, P.I. and Stewart, P.M. (2003) Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension. QJM: An International Journal of Medicine, 96 (7), 481-490. (doi:10.1093/qjmed/hcg085).

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 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isozymes (11beta-HSD1 activating cortisol from cortisone, 11beta-HSD2 inactivating cortisol to cortisone). AIM: To analyse expression of 11beta-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 11beta-HSD1 in normal human anterior segments was evaluated by in situ hybridization (ISH). RT-PCR for 11beta-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 11beta-HSD) on IOP. RESULTS: ISH defined expression of 11beta-HSD1 in the ciliary epithelium, while RT-PCR analysis of ciliary body tissue confirmed expression of 11beta-HSD1, with additional GR and MR, but not 11beta-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 11beta-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 11beta-HSD1 in the ciliary epithelium. Selective and topical inhibitors of 11beta-HSD1 could provide a novel treatment for patients with glaucoma

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More information

Published date: July 2003
Keywords: patients, sodium, protein, glucocorticoid, methods, female, drug therapy, glaucoma, double-blind method, male, carbenoxolone, physiopathology, receptors, enzyme inhibitors, role, hypertension, 11-beta-hydroxysteroid dehydrogenase type 2, infection, water, prospective studies, non-u.s.gov't, pharmacology, therapeutic use, in situ hybridization, aged, radioimmunoassay, drainage, intraocular pressure, cortisone, antagonists & inhibitors, immunity, analysis, ocular hypertension, cortisol, pressure, drug effects, epithelium, research support, design, mineralocorticoid, trabecular meshwork, hydrocortisone, chemistry, human, enzymology, hydroxysteroid dehydrogenases, humans, aqueous humor

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Local EPrints ID: 60147
URI: http://eprints.soton.ac.uk/id/eprint/60147
ISSN: 1460-2725
PURE UUID: abf3f74c-e6da-4072-a756-ad4b8707d5a5

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Date deposited: 08 Sep 2008
Last modified: 15 Mar 2024 11:19

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Contributors

Author: S. Rauz
Author: C.M.G. 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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