Proximal bicarbonate reabsorption and acetazolamide
Acetazolamide blocks carbonic anhydrase, an enzyme that interconverts carbon dioxide and carbonic acid, so the proximal convoluted tubule, which reclaims about 85% of filtered bicarbonate, reclaims less.
Remember
Acetazolamide inhibits carbonic anhydrase, so the proximal tubule reclaims less bicarbonate, which is lost in the urine, and a metabolic acidosis (in which the plasma bicarbonate falls) can develop.
The proximal convoluted tubule reclaims bicarbonate indirectly, because filtered bicarbonate cannot simply be carried across the cell membrane. First, NHE3, the sodium-hydrogen exchanger, swaps sodium from the lumen for a hydrogen ion from the cell.
Second, that hydrogen ion combines with filtered bicarbonate in the lumen to make carbonic acid, which carbonic anhydrase on the luminal surface splits into carbon dioxide and water. Third, carbon dioxide enters the cell, where carbonic anhydrase inside the cell rebuilds bicarbonate. Fourth, the new bicarbonate leaves across the basolateral membrane (the side facing the blood) through NBCe1, a sodium-bicarbonate cotransporter that moves sodium and bicarbonate out together.
Each cycle reabsorbs one sodium and one bicarbonate, and about 85% of the filtered bicarbonate is reclaimed in this segment.
Acetazolamide inhibits carbonic anhydrase, so the chain is interrupted at both ends: less carbonic acid is converted to carbon dioxide and less new bicarbonate is made. Bicarbonate that is not reclaimed stays in the tubular fluid and is lost in the urine. Plasma bicarbonate then falls, and a metabolic acidosis can follow.
Key facts
- Bicarbonate reclaimed
- About 85% of the filtered bicarbonate is reclaimed in the proximal convoluted tubule.
- First step
- NHE3 secretes hydrogen ions into the lumen in exchange for sodium.
- Enzyme
- Carbonic anhydrase is needed in the lumen and inside the cell.
- Exit route
- NBCe1 on the basolateral membrane carries newly made bicarbonate, together with sodium, into the blood.
- Per cycle
- The net result is reabsorption of one sodium and one bicarbonate.
- Drug effect
- Acetazolamide inhibits carbonic anhydrase, so less bicarbonate is reabsorbed and bicarbonate is lost in the urine.
Exam traps
- Acetazolamide does not stimulate the sodium-hydrogen exchanger, and more exchanger activity would increase hydrogen secretion and bicarbonate reclamation, which would work against acidosis.
- Bicarbonate is not mainly reabsorbed by simple leakage between the cells, because its reabsorption depends on sodium-hydrogen exchange and on carbonic anhydrase.
- NHE3 does not carry bicarbonate into the blood: it secretes hydrogen ions into the lumen, which starts the indirect reclamation of bicarbonate.
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