Recent reports indicate that alpha 1-Sodium,Potassium-ATPase from Dahl salt-sensitive (DS) rats contains a glutamine for leucine substitution associated with increased Sodium-Potassium coupling at unchanged maximal velocity. Genetic analyses suggest that alpha-1-Sodium,Potassium-ATPase is a potential hypertension gene. Therefore, we investigated whether renal Sodium+metabolism could constitute a pathophysiological link between the molecular/functional change in Sodium,Potassium-ATPase and hypertension. We simulated the consequences of increased Sodium-Potassium coupling on overall Sodium-bicarbonate reabsorption in a proximal tubular transport model that incorporates apical Sodium-Hydrogen exchanger and basolateral Sodium-bicarbonate cotransporter, Potassium+channel, and Sodium,Potassium-ATPase. As expected, increases in the levels of the former three transport pathways yielded higher Sodium+reabsorption. In contrast, increases in the maximal velocity of the Sodium,Potassium-ATPase with a normal 3:2 (Sodium-Potassium) coupling ratio did not increase Sodium+reabsorption when apical Sodium-Hydrogen exchange activity was limiting overall absorption. However, an increase in the Sodium-Potassium coupling from 3:2 to 3:1, reported for the mutant alpha 1-Sodium,Potassium-ATPase in DS rats, was associated with greater Sodium+reabsorption. This increase is a consequence of lower cytosolic pH and secondary stimulation of the Sodium-Hydrogen exchanger at its allosteric Hydrogen+site. Decreased pH results from activation of Sodium-bicarbonate co-transport by Sodium,Potassium-ATPase-dependent membrane hyperpolarization due to greater charge movement in 3:1 Sodium-Potassium coupling. Thus, an increase in the Sodium-Potassium coupling ratio results in an altered set point for cellular Sodium+metabolism, with higher Sodium reabsorption at unchanged Sodium,Potassium-ATPase levels. The simulations thereby lend support for a unifying explanation for the salt sensitivity of DS rats, which has been proposed to stem from a mutation in the alpha 1-Sodium,Potassium-ATPase. (Hypertension. 1996;27:219-227.)