title: Everything we always wanted to know about furosemide but were afraid to ask.
abstract: Furosemide is a widely used, potent natriuretic drug, which inhibits the Na(+)-K(+)-2Cl(-) cotransporter (NKCC)-2 in the ascending limb of the loop of Henle applied to reduce extracellular fluid volume expansion in heart and kidney disease. Undesirable consequences of furosemide, such as worsening of kidney function and unpredictable effects on sodium balance, led to this critical evaluation of how inhibition of NKCC affects renal and cardiovascular physiology. This evaluation reveals important knowledge gaps, involving furosemide as a drug, the function of NKCC2 (and NKCC1), and renal and systemic indirect effects of NKCC inhibition. Regarding renal effects, renal blood flow and glomerular filtration rate could become compromised by activation of tubuloglomerular feedback or by renin release, particularly if renal function is already compromised. Modulation of the intrarenal renin angiotensin system, however, is ill-defined. Regarding systemic effects, vasodilation followed by nonspecific NKCC inhibition and changes in venous compliance are not well understood. Repetitive administration of furosemide induces short-term (braking phenomenon, acute diuretic resistance) and long-term (chronic diuretic resistance) adaptations, of which the mechanisms are not well known. Modulation of NKCC2 expression and activity in kidney and heart failure is ill-defined. Lastly, furosemide's effects on cutaneous sodium stores and on uric acid levels could be beneficial or detrimental. Concluding, a considerable knowledge gap is identified regarding a potent drug with a relatively specific renal target, NKCC2, and renal and systemic actions. Resolving these questions would increase the understanding of NKCCs and their actions and improve rational use of furosemide in pathophysiology of fluid volume expansion.
authors.affiliation: Department of Medicine, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada;
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Medicine/Nephrology, Utrecht University, Vorden, The Netherlands;
authors.forename: Evert
authors.initials: E
authors.lastname: Dorhout Mees
authors.affiliation: Dianet Dialysis Centers, Utrecht, The Netherlands; and.
authors.forename: Pieter
authors.initials: P
authors.lastname: Vos
authors.affiliation: Department of Medicine, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada; Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Shereen
authors.initials: S
authors.lastname: Hamza
authors.affiliation: Department of Medicine, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada; Department of Physiology, University of Alberta, Edmonton, Alberta, Canada branko.braam@ualberta.ca.
authors.forename: Branko
authors.initials: B
authors.lastname: Braam
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D004351:Drug Resistance; D005665:Furosemide / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006801:Humans; D009318:Natriuresis / Q000187:drug effects*; D051436:Renal Insufficiency, Chronic; D065608:Renal Reabsorption / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects; D064466:Solute Carrier Family 12, Member 1 / Q000037:antagonists & inhibitors*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D058787:GABA-A Receptor Antagonists; D064466:Solute Carrier Family 12, Member 1; D005665:Furosemide
keywords: chronic kidney disease; extracellular fluid volume; heart failure; natriuresis; renal function