Mannitol might inhibit paracellular reabsorption of water and sodium chloride in the proximal tubules by reducing the osmotic driving force. We examined this hypothesis in anesthetized dogs. Bicarbonate reabsorption was kept constant by sodium bicarbonate infusion, and transcellular sodium chloride reabsorption was inhibited by ethacrynic acid. The glomerular filtration rate (GFR) was varied by altering renal perfusion pressure. Mannitol infusion reduced sodium chloride reabsorption from 62 +/- 5% to 33 +/- 5% of the filtered load. The calculated increase in reabsorbate osmolality, averaging 82 +/- 6 mOsm/kg H2O, was due to sodium bicarbonate and equalled the increase in plasma osmolality. Mannitol concentration averaged 81 +/- 7 mM in plasma and 101 +/- 12 mM in urine. A linear relationship between reabsorption and GFR (glomerulo-tubular balance) was maintained over the same range of GFR before and after mannitol infusion. Mannitol infusion reduced sodium chloride reabsorption from 2.6 to 1.4 moles for each mole of sodium bicarbonate reabsorbed. During mannitol infusion, acetazolamide inhibited sodium bicarbonate reabsorption as in control experiments, but reduced sodium chloride reabsorption less. We conclude that reduced water reabsorption increases sodium bicarbonate concentration in the paracellular fluid as much as mannitol concentration is raised in the plasma and glomerular filtrate. Along the proximal tubules, net osmotic force is progressively reduced as mannitol concentration rises, accounting for reduced water and sodium chloride reabsorption.