What is the mechanism of action of loop diuretics such as furosemide?

• A. Inhibit Na+-Cl− cotransporter in the distal tubule
• B. Inhibit aldosterone receptor
• C. Inhibit Na+-K+-2Cl− cotransporter in the thick ascending limb
• D. Inhibit carbonic anhydrase in the proximal tubule

Answer: (C)

Loop diuretics block the Na+-K+-2Cl− cotransporter (NKCC2) in the thick ascending limb of the loop of Henle. This transporter normally reabsorbs sodium, potassium, and chloride from the filtrate; inhibiting it causes those ions to remain in the tubule, and water follows, producing a strong diuretic effect. Additionally, blocking NKCC2 reduces the lumen-positive potential that drives paracellular reabsorption of calcium and magnesium, so calcium and magnesium are excreted more in the urine. This action is distinct from thiazide diuretics, which target the Na+-Cl− cotransporter in the distal tubule, aldosterone receptor antagonists, and carbonic anhydrase inhibitors in the proximal tubule.