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).


OBJECTIVE
To analyse expression of 11beta-HSD in the human eye and investigate its putative role in AH formation.


METHODS
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).


CONCLUSIONS
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.
Rauz
S
S
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham, Birmingham, UK.
Cheung
C M G
CM
Wood
P J
PJ
Coca-Prados
M
M
Walker
E A
EA
Murray
P I
PI
Stewart
P M
PM
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000368:Aged; D001082:Aqueous Humor / Q000737:chemistry / Q000201:enzymology; D002229:Carbenoxolone / Q000494:pharmacology*; D003348:Cortisone / Q000032:analysis; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009798:Ocular Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D011446:Prospective Studies; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D002229:Carbenoxolone; D003348:Cortisone; D006854:Hydrocortisone