Objectives: Glitazones are efficient insulin sensitizers that blunt the effects of angiotensin II (Ang II) in the rat. Sodium chloride is another important modulator of the systemic and renal effects of Ang II. Whether glitazones interfere with the interaction between sodium and the response to Ang II is not known. Therefore, we investigated the effects of pioglitazone on the relation between sodium and the systemic and renal effects of Ang II in rats. Methods: Pioglitazone, or vehicle were administered for 4 weeks to 8 week old obese Zucker rats. Animals were fed a normal sodium (NS) or a high sodium (HS) diet. Intravenous glucose tolerance tests, systemic and renal hemodynamic responses to Ang II and the renal Ang II binding and expression of AT₁ receptors were measured. Results: Food intake and body weight increased whereas BP, heart rate, filtration fraction and insulin levels decreased significantly with pioglitazone in obese rats on both diets. Pioglitazone blunted the systemic response to Ang II and abolished the increased responsiveness to Ang II induced by a HS diet. Pioglitazone modified the renal hemodynamic response to changes in salt intake while maintaining a lower filtration fraction with angiotensin II perfusion. These effects were associated with a decrease in the number and expression of the Ang II AT1 receptor in the kidney. Conclusions: These data demonstrate that the PPAR- agonist pioglitazone modifies the physiological relationship between sodium chloride and the response to Ang II in insulin resistant rats.