The model of sodium and chloride transport proposed for the colon is based on studies performed in the distal segment and tacitly assumes that ion transport is similar throughout the colon. In rat distal colon, neutral sodium-chloride absorption accounts for the major fraction of overall sodium absorption and aldosterone stimulates electrogenic, amiloride-sensitive sodium absorption. Since we have demonstrated qualitative differences in potassium transport in proximal and distal segments of rat colon, unidirectional 22Na and 'Cl fluxes were performed under shortcircuit conditions across isolated proximal colon of control and sodium-depleted rats with secondary hyperaldosteronism. In the control group, net sodium absorption (JN:) (7.4±0.5 Ateq/h * cm2) was greater than I,, (1.4±0.1 lueq/h cm2), and JPt was 0 in Ringer solution. Residual flux (J) was -5.2±0.5 teq/h cm2 consistent with hydrogen ion secretion suggesting that neutral sodium absorption may represent sodium-hydrogen exchange. 1 mM mucosal amiloride, which inhibits sodium-hydrogen exchange in other epithelia, produced comparable decreases in J" and JR (4.1±0.6 and 3.2±0.6 ;&eq/h * cm2, respectively) without a parallel fall in I,<. Sodium depletion stimulated JN, JA, and I., by 7.0±1.4, 6.3±1.9, and 0.8±0.2 ;eq/h cm2, respectively, and 1 mM amiloride markedly inhibited JN' and J by 6.0±1.1 and 4.0±1.6 ,ueq/h * cm2, respectively, with only a minimal reduction in I4.. Conclusions: the predominant neutral sodium-absorptive mechanism in proximal colon is sodium-hydrogen exchange. Sodium depletion stimulates electroneutral chloride-dependent sodium absorption (most likely as a result of increasing sodium-hydrogen and chloride-bicarbonate exchanges), not electrogenic chloride-independent sodium transport. The model of ion transport in the proximal colon is distinct from that of the distal colon.