Abstract
11β-Hydroxsteroid dehydrogenase 2 (11β-OHSD2) protects the nonselective renal mineralocorticoid receptor from the endogenous glucocorticoid cortisol. Thus, drugs inhibiting 11β-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 11β-OHSD2. Furosemide was the only inhibitor. Its inhibition constant (Ki) was 30 μmol when extracts from COS-1 cells transfected with human 11β-OHSD2 were used as an enzyme source. The type of inhibition was competitive. To establish whether furosemide inhibits 11β-OHSD2 and 11β-OHSD1 in the renal target tissue, isolated tubular segments from rats were analyzed. Furosemide decreased the oxidative activity of 11β-OHSD2 in intact distal tubules and 11β-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 5α-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 11β-OHSD. Thus, furosemide inhibits the 11β-OHSD2 enzyme in the target tissue and might by that mechanism enhance the mineralocorticoid effect of 11β-hydroxyglucocorticoids.
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