To evaluate the role of chloride in the pathogenesis of salt-dependent deoxycorticosterone (DOC) hypertension, we studied young Wistar rats chronically loaded with sodium bicarbonate (NaHCO3) or sodium chloride (NaCl) which were administered either in the diet or in the drinking fluid. Selective sodium loading (without chloride) increased blood pressure (BP) in DOC-treated animals only if NaHCO3 was provided in the diet. In contrast, no significant blood pressure changes were induced by DOC treatment in rats drinking NaHCO3 solution. Hypernatremia and high plasma osmolality occurred only in rats drinking NaCl or NaHCO3 solutions. Compared to great volume expansion in NaCl-loaded DOC-treated rats, the degree of extracellular fluid volume expansion (namely of its interstitial fraction) was substantially lower in both NaHCO3-loaded groups in which significant hypokalemia was observed. NaHCO3-drinking rats without significant blood pressure response to DOC treatment represented the only experimental group in which blood volume was not expanded. In conclusion, our data confirm previous observations that NaHCO3 loading is less potent in eliciting DOC hypertension than NaCl loading, but blood pressure rise in rats fed NaHCO3 diet clearly demonstrated that selective sodium loading could potentiate the development of DOC hypertension if NaHCO3 is offered within the appropriate dietary regimen. The reasons for the failure of NaHCO3-drinking rats to elevate blood pressure in response to chronic mineralocorticoid treatment are not obvious. However, the absence of a significant plasma volume expansion together with hypernatremia and increased plasma osmolality suggest a considerable degree of dehydration in these animals which fail to increase their fluid consumption compared to water drinking rats.