The natriuretic effect NO is decreased in the Dahl Salt-Sensitive (SS) rat. This is in part due to decreased NO-induced inhibition of thick ascending limb (TAL) NaCl reabsorption. However, the mechanism responsible for this defect in SS rats is unclear. In normal rats, NO inhibits TAL NaCl reabsorption via cGMP. cGMP stimulates phosphodiesterase 2 (PDE2) which degrades cAMP and in turn decreases apical surface levels of the Na-K-2Cl cotransporter NKCC2. We hypothesized that the blunted effect of NO in TALs from SS rats is in part due to a decreased response to cGMP and reduced PDE2 expression. To test our hypothesis, we isolated TALs from adult SS and Dahl Salt-Resistant (SR) rats fed a normal salt diet and measured the effect of cGMP on apical NKCC2 levels by surface biotinylation and Western blot. Incubation of TALs (20 min) with the membrane permeable cGMP analogue db-cGMP (250 μM) decreased surface NKCC2 in SR rats by 22 ± 6% (p<0.05), while 500 μM decreased it to a maximum of 40 ± 6% (p<0.01). In SS TALs, the effect db-cGMP was blunted (p<0.05 vs SR) and only tended to decrease surface NKCC2 (-10± 9%) at 500 μM. Consistent with a decreased response to cGMP, the expression of PDE2 was 20 ± 5% lower in TALs from SS rats (p<0.05). Finally, we tested whether the effect of the PDE2 selective agonist DM-cBIMP was decreased in SS rats. Incubation of SR TALs with DM-cBIMP decreased surface NKCC2 expression in a dose-dependent manner with a maximum inhibition of 41 ± 6% at 250 μM. In SS TALs, the response was significantly blunted with a maximal inhibition of 20 ± 6% at 250 μM (p<0.05 vs. SR). We concluded that the decreased response to cGMP in TALs from SS rats is in part due to decreased PDE2 activation and expression. This mechanism is likely responsible for the blunted inhibitory effect of NO in TAL NaCl reabsorption in SS rats and may be involved in the development of salt-sensitive hypertension.