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Furosemide Inhibits 11ß-Hydroxysteroid Dehydrogenase Type 2¹

Division of Nephrology and Hypertension, Department of Medicine, University Hospital of Berne, Inselspital, 3010 Berne, Switzerland

Address all correspondence and requests for reprints to: Felix J. Frey, M.D., Division of Nephrology, Freiburgstrasse 3, Inselspital, 3010 Berne, Switzerland. E-mail: felix.frey{at}insel.ch

11ß-Hydroxsteroid dehydrogenase 2 (11ß-OHSD2) protects the nonselective renal mineralocorticoid receptor from the endogenous glucocorticoid cortisol. Thus, drugs inhibiting 11ß-OHSD2 might enhance urinary loss of potassium. As diuretics influence the renal handling of potassium, we analyzed the impact of 13 commonly used diuretics on 11ß-OHSD2.

Furosemide was the only inhibitor. Its inhibition constant (K_i) was 30 µmol when extracts from COS-1 cells transfected with human 11ß-OHSD2 were used as an enzyme source. The type of inhibition was competitive. To establish whether furosemide inhibits 11ß-OHSD2 and 11ß-OHSD1 in the renal target tissue, isolated tubular segments from rats were analyzed. Furosemide decreased the oxidative activity of 11ß-OHSD2 in intact distal tubules and 11ß-OHSD1 in proximal convoluted tubules. For the assessment of furosemide on the excretion of corticosterone metabolites in vivo, rats were given furosemide ip, and the ratio of tetrahydrocorticosterone plus 5-tetrahydrocorticosterone to 11-dehydrotetrahydrocorticosterone was determined in urine. This ratio increased after the administration of furosemide in all animals, indicating inhibition of the oxidative activity of 11ß-OHSD. Thus, furosemide inhibits the 11ß-OHSD2 enzyme in the target tissue and might by that mechanism enhance the mineralocorticoid effect of 11ß-hydroxyglucocorticoids.

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