Dopamine-induced inhibition of Na⁺-K⁺-ATPase has been suggested to play a role in the regulation of Na⁺ absorption at the intestinal level and these effects were mediated by dopamine D₁-like receptors. The aim of this work was to evaluate the effect of the activation of the D₁-like receptors on the activity of the Na⁺/H⁺ exchanger (NHE) in the rat intestinal epithelial cell line IEC-6. The presence of D₁ receptors was confirmed by immunoblotting. The dopamine D₁-like receptor agonist SKF 38393 produced a concentration-dependent inhibition of NHE activity and stimulation of adenylyl cyclase (AC), this being antagonized by the D₁ selective antagonist SKF 83566. Effects of SKF 38393 on NHE and AC activities were maximal at 5 min of exposure to the agonist and rapidly diminished with no effect at 25 min. Exposure of cells for 25 min to dibutyryl-cAMP (0.5 mM) or to the AC activator forskolin (3 µM) effectively inhibited NHE activity. Pretreatment of cells with heparin (1 µM), a non-selective G protein coupled-receptor kinase (GRK) inhibitor, prevented the loss of effects on NHE activity after 25 min exposure to SKF 38393. The presence of GRK 4, GRK 6A and GRK 6B was confirmed by immunoblotting. Overnight treatment with the anti-GRK 4-6 antibody complexed with Lipofectin was also effective in preventing loss of the effects of SKF 38393 on NHE and AC activities. It is concluded that dopamine D₁ receptors in IEC-6 rapidly desensitize to D₁-like agonist stimulation and GRK 4 and 6 appear to be involved in agonist-mediated responsiveness and desensitization.