Dopamine is a natriuretic hormone that acts by inhibiting tubular Na+JC+-ATPase activity by activation of the dopamine-1 receptor (the thick ascending limb [TAL] of Henle) or by a synergistic effect of dopamine-1 and dopamine-2 receptors (the proximal tubule). The dopamine-1 receptor is coupled to adenylate cyclase. In this article we show that prehypertensive Dahl salt-sensitive (DS) rats have a blunted natriuretic response to dopamine determined during euvolemk conditions compared with Dahl salt-resistant (DR) rats. Furthermore, we have examined the renal tubular effects of dopamine in DS and DR rats. Basal Na+, K+-ATPase activity was similar in DS and DR rats. In proximal tubule, dopamine (10−5M) inhibited Na+, K+-ATPase activity in DR but not in DS rats. The dopamine-2 agonist LY171555 (10−5M) together with dibutyryl cyclic AMP (10−6M) inhibited proximal tubule Na+, K+-ATPase activity in both DS and DR rats. LY171555 alone had no effect In TAL, the dopamine-1 agonist fenoldopam (10−5M) inhibited Na+,K+- ATPase activity in DR but not in DS rats. Dibutyryl cyclic AMP (10−5M) inhibited TAL Na+,K+-ATPase activity in both DS and DR rats. In cell suspensions from the cortex and the medulla, activation of the dopamine-1 receptor significantly increased cyclic AMP content in DR but not in DS rats. The results indicate that DS rats lack the capacity to inhibit tubular Na+,K+-ATPase activity because of a defective dopamine-1 receptor adenylate cyclase coupling. This defect may contribute to the impaired natriuretic capacity in DS rats.