Oxygen consumed by the kidney (Q_O2) is primarily obligated to sodium reabsorption (T_Na). The relationship of Q_O2 to T_Na (Q_O2/T_Na) may be altered by hormones and autacoids. To examine whether Q_O2/T_Na depends on the mechanism of sodium reabsorption we first evaluated the effects on Q_O2 and Q_O2/T_Na of benzolamide (BNZ), a proximal diuretic that works by inhibiting membrane carbonic anhydrase. During BNZ infusion in anesthetized rats, Q_O2 increased by 50% in spite of a 25% decline in T_Na. However, BNZ failed to increase Q_O2/T_Na when given along with the adenosine A1 receptor blocker, DPCPX, which inhibits basolateral Na-bicarbonate co-transport (NBC1), or EIPA, which inhibits sodium-hydrogen exchange (NHE). Incubating freshly harvested rat proximal tubules with BNZ also caused Q_O2 to increase by 62%, an effect that was prevented by blocking the apical NHE3 with S3226. Blocking NBC1 or NHE3 in the proximal tubule will have opposite effects on cell pH, but both maneuvers should reduce active chloride transport. Conclusions: Inhibiting membrane carbonic anhydrase in the proximal tubule increases Q_O2 and reduces the energy efficiency of sodium reabsorption by the kidney This is not purely due to shifting the burden of reabsorption to a more expensive site downstream from the proximal tubule. Instead, increased cost is incurred within the proximal tubule, probably due to a shift to active chloride transport.