Furosemide and 11β-hydroxysteroid dehydrogenase activity, in man

Summary

Mineralocorticoid receptors possess the same affinity for aldosterone and for cortisol and preferential binding of aldosterone is modulated by the 11β-hydroxysteroid dehydrogenase (11β-OHSD) enzyme, which converts cortisol to its inactive metabolite cortisone. Several endogenous or exogenous compounds able to inhibit the enzyme have been described and, as a consequence, produce the syndrome of apparent mineralocorticoid excess (AME) characterized by hypertension, hypokalemia, volume repletion and suppression of the renin-angiotensin-aldosterone system. High doses of furosemide, a diuretic that works in the luminal surface of the thick ascending limb of Henle's loop, have been reported to inhibit 11β-OHSD activity to the same extent as licorice in vivo and in vitro, in rat.

The aim of our study was to verify the effect of the drug on 11β-OHSD activity in man at the doses currently used in clinical practice. We tested the activity of 11β-OHSD following both acute and protracted administration of furosemide. In the acute study, the drug was administered at low (40 mg i.v. in bolo) and high doses (infusion of 10 mg/kg bw i.v for six hours); the protracted furosemide administration consisted in 50 mg/day for 20 days, by mouth. The ratios between the cortisol metabolites tetrahydrocortisol plus allo-tetrahydrocortisol to tetra-hydrocortisone and urinary free cortisol to urinary free cortisone were used to measure the activity of 11β-OHSD. Urinary cortisol, cortisone and their metabolites were tested by a gas-chromatographic/mass spectrometric method.

Neither acute nor prolonged administration of furosemide did affect the activity of 11β-OHSD although the drug was able to modify plasma aldosterone and PRA secretion and to determine hypokalemia. Our results suggest that furosemide does not play a significant role in 11β-OHSD modulation in humans, at least at the dosage used in clinical practice.

Key words:

Furosemide - 11β-hydroxysteroid dehydrogenase - Cortisol - Cortisone - Hypertension

References

• 1 Albiston A L, Obeyesekere V R, Smith R E, Krozowski Z S. Cloning and tissue distribution of the human 11β-hydroxysteroid dehydrogenase type 2 enzyme.  Steroids. 59 100-104 1994; 
• 2 Agarwal A K, Mune T, Monder C, White P C. Nad-dependent isoform of 11β-hydroxysteroid dehydrogenase.  J of Biol Chem. 269, 42 25 959-25 962 1994; 
• 3 Bernardi M, D'Intino P E, Trevisani F, Cantelli-Forti G, Raggi M A, Turchetto E, Gasbarrini G. Effect of prolonged ingestion of graded doses of licorice by healthy volunteers.  Life Science. 55 863-872 1994; 
• 4 Best R, Walker B R. Additional value of measurement of urinary cortisone and unconjucated cortisol metabolites in assessment of 11β-hydroxysteroid dehydrogenase in vivo.  Clin Endocrinol (Oxf) 47 ((2)) 231-236 1997; 
• 5 Brater D C. Determinants of the overall response to furosemide: Pharmacokinetics and pharmadynamics.  Federation Proceedings. 42 1711-1713 1983; 
• 6 Edwards C RW, Stewart P M, Burt D, Brett L, McIntyre M A, Sutanto W S, de Kloet E R, Monder C. Localization of 11β-hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid receptor.  Lancet. 2 986-989 1995; 
• 7 Escher G, Meyer K V, Vishwanath B S, Frey B M, Frey F J. Furosemide inhibits 11β-hydroxysteroid dehydrogenase in vitro and in vivo.  Endocrinology. 136 1759-1765 1995; 
• 8 Fuster G, Escher G, Vogt B, Ackermann D, Dick B, Frey B M, Frey F J. Furosemide inhibits 11β-hydroxysteroid dehydrogenase type 2.  Endocrinology. 139 3849-3854 1998; 
• 9 Hammarlund-Udenaes M, Benet L Z. Furosemide pharmacokinetics and pharmacodynamics in health and disease. An update..  J Phamacokinetics and Biopharmaceutics. 17 1-43 1988; 
• 10 Krozowski Z, Funder J W. Renal mineralocorticoid receptores and hippocampal corticosteroid-binding sites have identical intrinsic steroid specificity.  Proc Natl Acad Sci USA. 80 6056-6060 1983; 
• 11 Monder C, White P C. 11β-Hydroxysteroid dehydrogenase.  Vitam Horm. 47 187-271 1993; 
• 12 Mune T, White P C. Apparent mineralocorticoid excess. Genotype is correlated with biochemical phenotype.  Hypertension. 27 1193-1199 1996; 
• 13 Palermo M, Delitala G, Sorba G B, Cossu M, Satta R, Tedde R, Pala A, Shackleton C HL. Does kidney transplantation normalise cortisol metabolism in apparent mineralocorticoid excess syndrome?.  J Endocrinol Invest. 23 457-462 2000; 
• 14 Palermo M, Gomez-Sanchez C E, Roitman E, Shackleton C HL. Quantitation of cortisol and related 3-oxo-4-ene steroids in urine using gaschromatography/mass spectrometry with stable isotope-labeled internal standards.  Steroids. 61 583-589 1996; 
• 15 Palermo M, Shackleton C HL, Mantero F, Stewart P M. Urinary free cortisone and the assessment of 11β-hydroxysteroid dehydrogenase activity in man.  Clin Endocrinol. 45 605-611 1996; 
• 16 Ricketts M L, Stewart P M. Regulation of 11β-hydroxysteroid dehydrogenase type 2 by diuretics and the renin-angiotensin-aldosterone axis.  Clin Science. 96 669-675 1999; 
• 17 Seckl J R. 11β-hydroxysteroid dehydrogenase isoforms and their implications for blood pressure regulation.  Eur J Clin Invest. 23 589-601 1993; 
• 18 Shackleton C HL. Mass spectrometry in the diagnosis of steroid-related disorders and in hypertension research.  J Steroid Biochem Molec Biol. 45 127-140 1993; 
• 19 Shimojo M, Stewart P M. Apparent mineralocorticoid excess syndrome.  J Endocrinol Invest. 18 518-532 1995; 
• 20 Song D, Lorenzo B, Reidenberg M M. Inhibition of 11β-hydroxysteroid dehydrogenase by gossypol and bioflavonoids..  J Lab Clin Med. 120 792-797 1992; 
• 21 Stewart P M, Murry B A, Mason J I. Human kidney 11β-hydroxysteroid dehydrogenase is a high affinity nicotinamide adenine dinucleotide - dependent enzyme and differs from the cloned type 1 isoform.  J Clin Endocrinol Metab. 78 480-484 1994; 
• 22 Stewart P M, Mason J I. Cortisol to cortisone: glucocorticoid to mineralocorticoid.  Steroids. 60 143-146 1995; 
• 23 Tannin G M, Agarwal A K, Monder C, New M I, White P C. The human gene for 11β-hydroxysteroid dehydrogenase. Structure, tissue distribution and chromosomal localization.  J Biol Chem. 266 16 653-16 658 1996; 
• 24 Walker B R, Agarwal A K, Stewart P M, Padfield P L, Edwards C RW. Endogenous inhibitors of 11β-hydroxysteroid dehydrogenase in hypertension.  J Clin Endocrinol Metab. 80 529-533 1995; 
• 25 Withworth J A, Stewart P M, Burt D, Atherden S M, Edwards C RW. Kidney is the major site of cortisone production in man..  Clin Endocrinol. 113 255-261 1989; 
• 26 Zhang Y D, Lorenzo B, Reidenberg M M. Inhibition of 11β-hydroxysteroid dehydrogenase obtained from guinea pig kidney by furosemide, naringenin and some other compounds.  J Ster Biochem Mol Biol. 49 81-85 1994;