How do loop diuretics produce diuresis?

• A. Inhibiting Na+/H+ exchanger in the proximal tubule.
• B. Blocking aquaporins in the collecting duct.
• C. Inhibiting Na-K-2Cl cotransport in the thick ascending limb.
• D. Inhibiting carbonic anhydrase in the proximal tubule.

Answer: (C)

Loop diuretics produce diuresis by blocking the Na-K-2Cl cotransporter (NKCC2) in the thick ascending limb of the loop of Henle. This transporter normally reabsorbs a large amount of Na+, K+, and Cl- from the tubular lumen while the limb is impermeable to water. When NKCC2 is inhibited, NaCl reabsorption in this segment drops dramatically, so more salt remains in the tubule and water follows osmotically, generating a large increase in urine output.

Blocking NKCC2 also disrupts the generation of the medullary osmotic gradient that normally helps concentrate urine, which further reduces water reabsorption downstream in the collecting duct. Additionally, because the lumen becomes less positive, there is increased excretion of calcium and magnesium. This is why loop diuretics are potent diuretics and can cause hypokalemia and metabolic alkalosis as side effects.