The majority (two-thirds) of filtered Na+ is reabsorbed by proximal tubules. A number of transport mechanisms, including Na+-H+ exchange, Na+-phosphate co-transport, Na+-glucose, Na+-lactate, and Na+-amino acid cotransport, participate in Na+ reabsorption. Na+-H+ exchange is the primary mechanism of Na+ transport in the proximal tubules (Fig. 21.2). Na+ and HCO3~ enter the proximal tubule after being filtered at the glomerulus. Na+ diffusion from the lumen into the cell is coupled to the extrusion of a hydrogen ion into the lumen. In the lumen, the H+ combines with HCO3~ to form carbonic acid (H2CO3), which in the presence of the zinc metalloenzyme carbonic anhydrase is rapidly converted to H2O and CO2. The CO2 generated in this reaction readily diffuses into proximal tubule cells, and the process reverses.That is, the CO2 that was generated combines with intracellular water and in the presence of cytoplasmic carbonic anhydrase forms carbonic acid. The carbonic acid in turn is dehydrated to HCO3~ and H+. The HCO3~ is transported across the basolateral membranes into the blood, while the H+ becomes available for another cycle of Na+-H+ exchange. The net result of this process is the reabsorption of Na+ and HCO3. Carbonic anhydrase plays a pivotal role both in the cytoplasm and in the lumen in mediating Na+-H+ exchange and thus in some 40% of total proximal Na+ and H2O absorption. If this enzyme is inhibited, Na+ absorption is slowed because of the accumulation of H2CO 3 in the lumen and the lack of H+ within the cell that can be exchanged for Na+. Similarly, HCO3~ reabsorption is reduced with a concomitant increase of HCO3~ excretion.
Several additional noteworthy features of proximal Na+ transport are relevant to diuretic action. First, since several transport proteins mediate proximal Na+ reabsorption, no single diuretic would be expected to inhibit all these processes. Consequently, inhibition of any one mechanism leaves the others unaffected and able to
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