Background: Functional differences between the clipped and unclipped kidneys in a 2-kidney-1-clip (2K-1C) hypertension model have been reported. However, the molecular basis of these changes is poorly understood. Objectives: Expression of NHE-1 and NHE-3 isoforms and sodium pump activity (PNP), and their modulation by blood pressure (BP), PGE<sub>2</sub> and TXB<sub>2</sub> were examined in the kidneys of 2K-1C rats treated with cilazapril for short- (4 and 24 h) and long-term (7 days) periods. Methods: 2K-1C rats were divided into two groups. Group 1 (short-term) animals were treated with a single dose of cilazapril for 4 or 24 h. Group 2 (long-term) animals received a daily dose of cilazapril for 7 days. 2K-1C animals receiving water served as clipped controls, and sham-operated animals were normal controls. Western blot analysis was used to estimate the protein levels and ELISA for PGE<sub>2</sub> and TXB<sub>2</sub>. Results: Levels of NHE-1 and NHE-3 protein in the unclipped kidneys of both treatment groups were increased, whereas levels of α-actin, PNP activity and crude microsomes remained unchanged. These changes were significantly reduced by long-term, and not by short-term treatment with cilazapril. In group 1 clipped kidneys, NHE-3 and α-actin proteins were increased, and crude microsomes and PNP activity were decreased. In group 2 clipped kidneys, both NHE-1 and 3 isoforms were induced, whereas PNP activity was decreased. Cilazapril did not reverse the changes in the clipped kidneys in both groups, but reduced the crude microsomes. Group 2 unclipped kidneys showed hypertrophy, which remained unaffected by cilazapril treatment. Induced levels of BP, PGE<sub>2</sub> and TXB<sub>2</sub> in both groups were reduced significantly except for the 24-hour post-cilazapril treatment. Conclusions: These findings demonstrate a differential expression of NHE-1 and NHE-3 isoforms which is dependent on the rise in BP, PGE<sub>2</sub> or TXB<sub>2</sub> in the long-term treatment group, but not in the short-term treatment group. Thus, the changes in NHE isoforms and sodium pump activity, together, contribute to functional differences that exist in the 2K-1C kidneys.