segment,a drug that specifically blocked proximal tubular absorption of NaCl would be a particularly powerful diuretic.No such drug is currently available Sodium bicarbonate reabsorption by the PCT is initiated by the action of a Na/H exchanger(NHE3)located in the luminal membrane of the proximal tubule epithelial cell (Figure 2).This transport system allows Na"to enter the cell from the tubular lumen in exchange for a proton (H)from inside the cell.As in all portions of the nephron,Na/K*ATPase in the basolateral membrane pumps the reabsorbed Na*into the interstitium so as to maintain a low intracellular Na'concentration.The H secreted into the lumen combines with bicarbonate(HCO3)to form H2CO3(carbonic acid),which is rapidly dehydrated to CO2 and H2O by carbonic anhydrase.Carbon dioxide produced by dehydration of H2CO3 enters the proximal tubule cell by simple diffusion where it is then rehydrated back to H2CO3,facilitated by intracellular carbonic anhydrase.After dissociation of H2CO3,the H is available for transport by the Na/H exchanger,and the HCO3 is transported out of the cell by a basolateral membrane transporter(Figure 2).Bicarbonate reabsorption by the proximal tubule is thus dependent on carbonic anhydrase.This enzyme can be inhibited by acetazolamide and related agents. In the late proximal tubule,as HCO3 and organic solutes have been largely removed from the tubular fluid,the residual luminal fluid contains predominantly NaCl.Under these conditions,Na reabsorption continues,but the H secreted by the Na/H exchanger can no longer bind to HCO3.Free H causes luminal pH to fall,activating a still poorly defined Cl/base exchanger(Figure 2).The net effect of parallel Na/H exchange and Cl/base exchange is NaCl reabsorption.As yet,there are no diuretic agents that are known to act on this conjoint process. Because water is reabsorbed in direct proportion to salt reabsorption in the proximal tubule,luminal fluid osmolality remains nearly constant along its length and an impermeant solute like inulin rises in concentration as water is reabsorbed.If large amounts of an impermeant solute such as mannitol (an osmotic diuretic,see below) are present in the tubular fluid,water reabsorption causes the concentration of the solute and osmolality of tubular fluid to rise,eventually preventing further water reabsorption. Organic acid secretory systems are located in the middle third of the straight part of the proximal tubule(S2 segment).These systems secrete a variety of organic acids (uric acid,nonsteroidal anti-inflammatory drugs [NSAIDs],diuretics,antibiotics,etc) into the luminal fluid from the blood.These systems thus help deliver diuretics to the luminal side of the tubule,where most of them act.Organic base secretory systems (creatinine,choline,etc)are also present,in the early (S1)and middle(S2)segments of the proximal tubule. 33 segment, a drug that specifically blocked proximal tubular absorption of NaCl would be a particularly powerful diuretic. No such drug is currently available. Sodium bicarbonate reabsorption by the PCT is initiated by the action of a Na+ /H+ exchanger (NHE3) located in the luminal membrane of the proximal tubule epithelial cell (Figure 2). This transport system allows Na+ to enter the cell from the tubular lumen in exchange for a proton (H+ ) from inside the cell. As in all portions of the nephron, Na+ /K+ ATPase in the basolateral membrane pumps the reabsorbed Na+ into the interstitium so as to maintain a low intracellular Na+ concentration. The H+ secreted into the lumen combines with bicarbonate (HCO3 - ) to form H2CO3 (carbonic acid), which is rapidly dehydrated to CO2 and H2O by carbonic anhydrase. Carbon dioxide produced by dehydration of H2CO3 enters the proximal tubule cell by simple diffusion where it is then rehydrated back to H2CO3, facilitated by intracellular carbonic anhydrase. After dissociation of H2CO3, the H+ is available for transport by the Na+ /H+ exchanger, and the HCO3 - is transported out of the cell by a basolateral membrane transporter (Figure 2). Bicarbonate reabsorption by the proximal tubule is thus dependent on carbonic anhydrase. This enzyme can be inhibited by acetazolamide and related agents. In the late proximal tubule, as HCO3 - and organic solutes have been largely removed from the tubular fluid, the residual luminal fluid contains predominantly NaCl. Under these conditions, Na+ reabsorption continues, but the H+ secreted by the Na+ /H+ exchanger can no longer bind to HCO3 - . Free H+ causes luminal pH to fall, activating a still poorly defined Cl- /base exchanger (Figure 2). The net effect of parallel Na+ /H+ exchange and Cl- /base exchange is NaCl reabsorption. As yet, there are no diuretic agents that are known to act on this conjoint process. Because water is reabsorbed in direct proportion to salt reabsorption in the proximal tubule, luminal fluid osmolality remains nearly constant along its length and an impermeant solute like inulin rises in concentration as water is reabsorbed. If large amounts of an impermeant solute such as mannitol (an osmotic diuretic, see below) are present in the tubular fluid, water reabsorption causes the concentration of the solute and osmolality of tubular fluid to rise, eventually preventing further water reabsorption. Organic acid secretory systems are located in the middle third of the straight part of the proximal tubule (S2 segment). These systems secrete a variety of organic acids (uric acid, nonsteroidal anti-inflammatory drugs [NSAIDs], diuretics, antibiotics, etc) into the luminal fluid from the blood. These systems thus help deliver diuretics to the luminal side of the tubule, where most of them act. Organic base secretory systems (creatinine, choline, etc) are also present, in the early (S1) and middle (S2) segments of the proximal tubule