The enzyme 11β-hydroxysteroid dehydrogenase type 2 (hsd11b2) confers mineralocorticoid specificity to the mineralocorticoid receptor (MR) by converting the potent agonist cortisol to inactive cortisone. Inactivating mutations in HSD11B2 cause Apparent Mineralocorticoid Excess (AME), resulting in severe hypertension and hypokalemia. AME is rare, but polymorphisms within the general population have been linked to Na⁺ sensitive hypertension (1, 2). We assessed the effect of a high Na⁺ diet on blood pressure (BP) and renal function in hsd11b2+/- mice, which have a 50% reduction in enzyme activity. Two protocols were used to measure BP and renal Na⁺ handling. In the first, male hsd11b2+/- (n=6) and hsd11b2+/+ (n=5) mice were housed in metabolic cages with daily Na⁺ excretion measured. Mice were fed control diet (0.25% Na⁺) for 3 days, followed by high Na⁺ diet (2.5% Na⁺) for 7 days. After this period, systolic BP (SBP) was recorded by tail plethysmography. In the second protocol, hsd11b2+/- and hsd11b2+/+ mice (both n=7) were maintained on a high Na+ diet before being anaesthetized (Inactin, 100mg/kg IP) and prepared for renal function experiments as described (3). After a control collection of urine, the ENaC antagonist amiloride (2mg/kg IV) was administered, and a second collection made. Arterial BP was measured throughout. Data are mean ± SE; statistical comparisons were made using either t-test or ANOVA, as appropriate. On control diet SBP was similar in hsd11b2+/- and hsd11b2+/+ groups (123±4mmHg vs 127±3mmHg), as was Na⁺ excretion (4.9±6.7 vs 6.3±1.4 µmol/24h/g). Rapid adaptation to the high Na⁺ diet in hsd11b+/+ mice contrasted with blunted natriuresis in hsd11b+/- mice (170.3±7.2 vs 81.7±10.2 µmol/24h/g within 24hrs). Indeed, hsd11b+/- mice did not match control levels of excretion during the study. As a result, after 7 days on high Na⁺ diet, SBP was significantly higher in hsd11b2+/- mice than controls (146±3 vs 127±2 mm Hg; P<0.05). Similar data were obtained in anaesthetized mice on high Na⁺ diet. BP was higher in hsd11b2+/- mice than controls (101±2 vs 90±2mmHg; P<0.01), and fractional Na⁺ excretion was lower (0.65±0.16 vs 1.54±0.19 %; P<0.01). Na⁺ loading prompted a down-regulation of ENaC in control mice so that amiloride did not increase Na⁺ excretion. In contrast, a robust amiloride-sensitive Na⁺ reabsorption was still observed in hsd11b2+/- mice (P<0.01). In summary, reduced 11β-HSD2 activity impairs the ability of the kidney to down-regulate ENaC-mediated Na⁺ reabsorption in response to Na+ loading, which has an adverse effect on BP. These data may be clinically significant: polymorphisms affecting the activity of 11β-HSD2 may contribute towards Na⁺ sensitive hypertension with in the general population.