We developed a model of volume contraction in rabbits by using a furosemide/low-salt diet to follow changes, if any, in proximal tubule Na⁺/H⁺ exchanger 3 (NHE3) mRNA and brush-border protein. The rabbits' plasma renin, aldosterone, and urine sodium content confirmed the volume-contracted state. RNase protection assays demonstrated increases in treated-animal NHE3 mRNA as a percentage of control with 172 ± 23, 154 ± 15, 153 ± 14, and 141 ± 7 (SE) % (P < 0.05) at 1, 5, 10, and 31 days, respectively. Western analysis of brush-border membrane with NHE3 antibody revealed increased immunoreactivity in treated animals as a percentage of control with 120 ± 30, 190 ± 59, 307 ± 72, and 427 ± 41% (P < 0.05) at 1, 5, 10, and 31 days, respectively. There was no significant difference in serum potassium, bicarbonate, and cortisol in control vs. experimental animals. These data suggest that there is chronic upregulation of NHE3 in the volume-contracted state.