Furosemide inhibits 11beta-hydroxysteroid dehydrogenase type 2

Area of Science:

• Biochemistry
• Pharmacology
• Nephrology

Background:

• 11Beta-hydroxsteroid dehydrogenase 2 (11beta-OHSD2) is crucial for protecting the mineralocorticoid receptor from cortisol in the kidneys.
• Diuretics can affect renal potassium handling, necessitating an investigation into their interaction with 11beta-OHSD2.

Purpose of the Study:

• To investigate the impact of 13 common diuretics on 11beta-OHSD2 activity.
• To determine if furosemide inhibits 11beta-OHSD2 and 11beta-OHSD1 in renal tissues.
• To assess the in vivo effects of furosemide on 11beta-OHSD activity in rats.

Main Methods:

• Enzyme inhibition assays using COS-1 cell extracts expressing human 11beta-OHSD2.
• Analysis of 11beta-OHSD2 and 11beta-OHSD1 activity in isolated rat renal tubular segments.
• In vivo study in rats measuring urinary corticosterone metabolite ratios after furosemide administration.

Main Results:

• Furosemide was identified as the sole inhibitor of 11beta-OHSD2 among the 13 diuretics tested, with a competitive inhibition constant (Ki) of 30 micromol.
• Furosemide demonstrated inhibition of 11beta-OHSD2 in distal tubules and 11beta-OHSD1 in proximal convoluted tubules of rat kidneys.
• In vivo administration of furosemide to rats led to an increased ratio of specific corticosterone metabolites in urine, confirming 11beta-OHSD inhibition.

Conclusions:

• Furosemide inhibits 11beta-OHSD2 activity within the renal target tissue.
• This inhibition by furosemide may potentiate the mineralocorticoid effects of 11beta-hydroxyglucocorticoids.
• The findings suggest a potential mechanism for furosemide's influence on renal potassium handling.