The Na+/Ca2+ exchanger regulates intracellular calcium ([Ca2+]i. and attenuation of Na +/Ca2+ exchange by oxidative stress might lead to dysregulation of [Ca2+]i. We have shown that the Na +/Ca2+ exchanger differs functionally and at the amino acid level between salt-sensitive and salt-resistant rats. Therefore, the purpose of these studies was to determine how oxidative stress affects the activities of the 2 Na+/Ca2+ exchangers that we cloned from mesangial cells of salt-resistant (RNCX) and salt-sensitive (SNCX) Dahl/Rapp rats. The effects of oxidative stress on exchanger activity were examined in cells expressing RNCX or SNCX by assessing 45Ca 2+ uptake (reverse mode) and [Ca2+]i elevation (forward mode) in the presence and absence of H2O2 and peroxynitrite. Our results showed that 45Ca2+ uptake in SNCX cells was attenuated at 500 and 750 μmol/L H2O2 (63±12% and 25±7%, respectively; n = 16) and at 50 and 100 μmol/L peroxynitrite (47±9% and 22±29%, respectively; n = 16). In RNCX cells, 45Ca2+ uptake was attenuated at only 750 and 100 μmol/L H2O2 and peroxynitrite (61±9% and 63±6%, respectively; n = 16). In addition, the elevation in [Ca 2+]i was greater in SNCX cells than in RNCX cells in response to 750 μmol/L H2O2 (58±5.5 vs 17±4.1 nmol/L; n = 13) and 100 μmol/L peroxynitrite (33±5 vs 11±6 nmol/L; n = 19). The enhanced impairment of SNCX activity by oxidative stress might contribute to the dysregulation of [Ca2+] i that is found in this model of salt-sensitive hypertension.