The Ca2+-sensing receptor (CaSR) mediates relaxation of isolated, phenylephrine-contracted mesenteric arteries, which express the receptor in the sensory network. We tested the hypothesis that high salt alters the expression of CaSR and its CYP enzymes downstream of the receptor in salt-sensitive hypertension. Dahl salt−sensitive (DS) and Dahl salt-resistant (DR) rats were placed on an 8% NaCl diet (HS) for 1, 2, and 4 weeks. Using tail cuff plethysmyography, blood pressures were measured before and after HS diet treatment. Our results show a significant increase in blood pressure in DS animals on HS diet (Control: 116 ± 4.8 mmHg; 1 week HS: 164.4 ± 8.7 mmHg; 2 weeks HS: 175.1 ± 7.2 mmHg; p < 0.05, ANOVA). Western blot analysis of proteins extracted from mesenteric arteries showed an increase in CaSR, CYP1A1, and CYP2J2 expression in DS rats on HS diet, but not in arteries from DR rats on the same diet. The data show that HS increased mean arterial blood pressure, as expected, and increased the expression of the mature form of the CaSR while decreasing expression of the immature form. Increased CYP isoform expression was observed as well, however, these changes did not reduce blood pressure. These new findings suggest an abnormality in CaSR activity in salt −sensitive hypertension, which may provide a molecular target for anti-hypertensive therapies.