The role of endogenous inhibitors of vascular Na,K-ATPase (NKA) activity in salt-induced hypertension was evaluated by examining the inhibition of 86Rb+ uptake in aortae of Sprague-Dawley (SD) rats by plasma derived from Dahl sensitive (DS) and resistant (DR) rats given high (8%) and low (0.4%) NaCl diet for four weeks. With 4 weeks of high salt diet DS rats demonstrated marked increase in systolic blood pressure. When compared to DR and DS rats on low salt diet, plasma from DR and DS rats on high salt diet had a stimulatory (not inhibitory) effect on NKA as measured by 86Rb+ uptake of SD rat aortae. As compared to DR rats plasma from DS rats on similar salt intakes had a stimulatory effect on NKA of SD rats. Aortae from the 4 groups of Dahl rats were also assayed for NKA activity. Total, ouabain-sensitive and ouabain-insensitive NKA activities were higher in DS rats as compared to DR rats on similar salt diet. Both DS and DR rats on high salt diet had higher NKA activity than on low salt diet. There was no evidence for a decrease in vascular sodium pump activity accompanying hypertension. Furthermore, high salt diet did not increase plasma Na,K-ATPase inhibitory activity in DS rats when hypertensive. These results suggest that NKA inhibition plays a minor role if any in hypertension of DS rats, in contrast to what has been hitherto believed.