We examined the effect of a high-salt (HS) diet on the regulation of renal cortical Na+-K+-adenosinetriphosphatase (Na+-K+-ATPase) in young Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The activity of Na+-K+-ATPase, determined in permeabilized proximal tubule segments, was similar in DS and DR rats on normal salt (NS) diet. HS diet resulted in a twofold increase in proximal tubule Na+-K+-ATPase activity in DS rats but not in DR rats. The mRNA abundance, which was also similar in DS and DR rats on NS diet, increased after 2 days on HS diet in both innervated and denervated kidneys from DS rats but had no effect in DR rats. The activity of Na+-K+-ATPase and the content of alpha1- and beta-protein in cortical homogenate were similar in DS and DR rats on both NS and HS diets. Treatment with benserazide, an inhibitor of dopa decarboxylase, upregulated proximal tubule Na+-K+-ATPase activity and increased Na+-K+-ATPase mRNA in DR rats on HS diet. Taken together, these data indicate that there is a primary defect in the dynamic hormonal regulation of Na+-K+-ATPase activity in intact tubular cells, which might stimulate Na+-K+-ATPase transcription.