Furosemide inhibits 11 beta-hydroxysteroid dehydrogenase in vitro and in vivo

11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) protects the non-selective renal mineralocorticoid receptor from the endogeneous glucocorticoid cortisol. Thus, drugs inhibiting 11 beta-OHSD might enhance urinary loss of potassium. In an attempt to find drugs inhibiting 11 beta-OHSD, 23 commonly used agents known to interfere with the potassium metabolism have been screened for inhibitory effect on 11 beta-OHSD. Furosemide appeared as the only inhibitor. Its inhibition constant (Ki) was 19.5 microM when kidney and 21.3 microM when liver microsomes were used as a source of 11 beta-OHSD. The type of inhibition was competitive. For confirmation that furosemide specifically inhibits 11 beta-OHSD, the complementary DNA (cDNA) of 11 beta-OHSD was transfected into COS-1 cells devoid of spontaneous expression of 11 beta-OHSD. In these cells, oxidation of corticosterone (Ki = 17.4 microM) and reduction of dehydrocorticosterone (Ki = 12.5 microM) was inhibited by furosemide. To establish whether this inhibition also occurs in vivo, the 11 beta-hydroxysteroid prednisolone was administered with and without furosemide to rats. The concentration ratio of prednisolone to its 11-ketometabolite prednisone increased in kidney and liver tissue after furosemide administration, indicating inhibition of 11 beta-OHSD. These data suggest that furosemide modulates in vivo the access of 11 beta-OH glucocorticoids to their target organs.