Salt sensitivity of blood pressure is an independent risk factor for cardiovascular morbidity. Mechanistically, abnormal
mineralocorticoid action and subclinical renal impairment may blunt the natriuretic response to high
sodium intake, causing blood pressure to rise. 11β-Hydroxysteroid
dehydrogenase type 2 (11βHSD2) controls
ligand access to the
mineralocorticoid receptor, and ablation of the
enzyme causes severe
hypertension. Polymorphisms in HSD11B2 are associated with
salt sensitivity of blood pressure in normotensives. In this study, we used mice heterozygote for a null mutation in Hsd11b2 (Hsd11b2(+/-)) to define the mechanisms linking reduced
enzyme activity to
salt sensitivity of blood pressure. A high-
sodium diet caused a rapid and sustained increase in blood pressure in Hsd11b2(+/-) mice but not in wild-type littermates. During the adaptation to high-
sodium diet, heterozygotes displayed impaired
sodium excretion, a transient positive
sodium balance, and
hypokalemia. After 21 days of high-
sodium feeding, Hsd11b2(+/-) mice had an increased heart weight.
Mineralocorticoid receptor antagonism partially prevented the increase in heart weight but not the increase in blood pressure.
Glucocorticoid receptor antagonism prevented the rise in blood pressure. In Hsd11b2(+/-) mice, high-
sodium feeding caused suppression of
aldosterone and a moderate but sustained increase in
corticosterone. This study demonstrates an inverse relationship among 11βHSD2 activity, heart weight, and blood pressure in a clinically important context. Reduced activity causes
salt sensitivity of blood pressure, but this does not reflect illicit activation of
mineralocorticoid receptors by
glucocorticoids. Instead, we have identified a novel interaction among 11βHSD2, dietary
salt, and circulating
glucocorticoids.