Christopher R. W. Edwards

Localisation of 11β-hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid receptor

In vitro the mineralocorticoid receptor is non-specific and does not distinguish between aldosterone and cortisol. In vivo certain tissues with this receptor are aldosterone selective (eg, kidney and parotid) whereas others with the same receptor are not (eg, hippocampus and heart). Experiments in rats showed that 11 beta-hydroxysteroid dehydrogenase (which converts cortisol to cortisone in man and corticosterone to 11-dehydrocorticosterone in the rat) was much more highly concentrated in aldosterone-selective tissues than in non-selective tissues. The localisation in the selective tissues was such that the enzyme could act as a paracrine or possibly an autocrine mechanism protecting the receptor from exposure to corticosterone. Autoradiographic studies showed that protection is lost when the enzyme is inhibited; 3H-corticosterone and 3H-aldosterone were bound to similar sites. These findings seem to explain why sodium retention, hypokalaemia, and hypertension develop in subjects with congenital deficiency of 11 beta-OHSD and those in whom the enzyme has been inhibited by liquorice.

Glucocorticoid exposure in utero: new model for adult hypertension

Hypertension is strongly predicted by the combination of low birthweight and a large placenta. This association could be due to increased fetal exposure to maternal glucocorticoids. Fetal protection is normally effected by placental 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which converts physiological glucocorticoids to inactive products. We found that rat placental 11 beta-OHSD activity correlated positively with term fetal weight and negatively with placental weight. Offspring of rats treated during pregnancy with dexamethasone (which is not metabolised by 11 beta-OHSD) had lower birthweights and higher blood pressure when adult than did offspring of control rats. Increased fetal glucocorticoid exposure secondary to attenuated placental 11 beta-OHSD activity may link low birthweight and high placental weight with hypertension.

Placental 11β‐hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure

OBJECTIVE Placental 11β‐hydroxysteroid dehydrogenase (11β‐HSD), which converts active cortisol to inactive cortisone, has been proposed to be the mechanism guarding the fetus from the growth retarding effects of maternal glucocorticoids; however, other placental enzymes have also been implicated. Placental 11β‐HSD is unstable in vitro, and enzyme activity thus detected may not be relevant to the proposed barrier role. We have therefore examined placental glucocorticoid metabolism in dually perfused freshly isolated intact human placentas.

Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.

The first adult case of 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) deficiency is described. The impaired conversion of cortisol to cortisone (indicated by urinary cortisol and cortisone metabolites and failure to metabolize 11 alpha-[3H]cortisol to [3H]H2O), was associated with hypertension, hypokalemia, and suppression of the renin-angiotensin-aldosterone system. When established on a fixed Na+/K+ intake, dexamethasone, given orally, produced a natriuresis and potassium retention. Plasma renin activity became detectable. When hydrocortisone (10 mg daily s.c. for 4 d) was added, there was marked Na+ retention, a kaliuresis (urinary Na+/K+ falling from 1.2 to 0.15), with suppression of plasma renin activity and an increase in blood pressure. These changes were also seen with the subject on no treatment. Conversion of cortisone to cortisol was not affected. These results suggest that cortisol acts as a potent mineralocorticoid in 11 beta-OHSD deficiency. The major site for the oxidation of cortisol to cortisone is the kidney. In this patient congenital deficiency of 11 beta-OHSD results in high intrarenal cortisol levels which then act on renal type I mineralocorticoid receptors. This condition can be treated with dexamethasone, which suppresses cortisol secretion and binds to the type II glucocorticoid receptor. We suggest that 11 beta-OHSD exerts a critical paracrine role in determining the specificity of the type I receptor. In the normal state cortisol is converted by 11 beta-OHSD to cortisone which thus allows aldosterone to bind preferentially to the type I receptors in the kidney and gut. In this patient deficiency of 11 beta-OHSD results in high intrarenal cortisol concentrations that then bind to the type I receptor.

Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat

Hypertension is strongly predicted by a low birthweight:placental weight ratio. Two independent models have been described to explain this association; less than optimal maternal protein nutrition leading to fetal undernutrition, or glucocorticoid excess. Pregnant rats were fed diets containing 18 per cent casein (control) or 9 per cent casein, balanced for energy. On day 20 of gestation the pregnancies were terminated and placentae collected for determination of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) activity. Placental 11 beta HSD normally protects the fetus from the effects of maternal glucocorticoids. Activity was specifically attenuated by mild protein restriction (33 per cent in activity), whilst activities of glucocorticoid-insensitive control enzymes were unchanged and glucocorticoid-inducible glutamine synthetase activity was increased (27 per cent), relative to activity in placentae from control animals. The nutritional manipulation during pregnancy significantly increased systolic blood pressure (17 mmHg) in the resulting offspring in early adulthood. A possible common pathway whereby maternal environmental factors may influence fetal and placental growth and programme disease is inferred.

Inhibition of 11β-Hydroxysteroid Dehydrogenase in Pregnant Rats and the Programming of Blood Pressure in the Offspring

Recent epidemiological studies have linked low birth weight with the later occurrence of cardiovascular and metabolic disorders, particularly hypertension. We have proposed that fetal exposure to excess maternal glucocorticoids may underpin this association. Normally, the fetus is protected from maternal glucocorticoids by placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD). We have previously shown that treatment of pregnant rats with dexamethasone, a synthetic glucocorticoid that is poorly metabolized by the enzyme, reduces birth weight and produces elevated blood pressure in the adult offspring. Moreover, low activity of placental 11beta-HSD correlates with low birth weight in rats. Here, we show that maternal administration of carbenoxolone, a potent inhibitor of 11 beta-HSD, throughout pregnancy leads to reduced birth weight (mean 20 percent decrease) and elevated blood pressures (increase in mean arterial pressure, 9 mm Hg in males, 7 mm Hg in females) in the adult offspring of carbenoxolone-treated rats. This effect requires the presence of maternal adrenal products, as carbenoxolone given to adrenalectomized pregnant rats had no effect on birth weight or blood pressure. These data support the hypothesis that excess exposure of the fetoplacental unit to maternal glucocorticoids reduces birth weight and programs subsequent hypertension and indicate a key role for placental 11beta-HSD in controlling such exposure.

Hypertension in mice lacking 11β-hydroxysteroid dehydrogenase type 2

Deficiency of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in humans leads to the syndrome of apparent mineralocorticoid excess (SAME), in which cortisol illicitly occupies mineralocorticoid receptors, causing sodium retention, hypokalemia, and hypertension. However, the disorder is usually incompletely corrected by suppression of cortisol, suggesting additional and irreversible changes, perhaps in the kidney. To examine this further, we produced mice with targeted disruption of the 11beta-HSD2 gene. Homozygous mutant mice (11beta-HSD2(-/-)) appear normal at birth, but approximately 50% show motor weakness and die within 48 hours. Both male and female survivors are fertile but exhibit hypokalemia, hypotonic polyuria, and apparent mineralocorticoid activity of corticosterone. Young adult 11beta-HSD2(-/-) mice are markedly hypertensive, with a mean arterial blood pressure of 146 +/- 2 mmHg, compared with 121 +/- 2 mmHg in wild-type controls and 114 +/- 4 mmHg in heterozygotes. The epithelium of the distal tubule of the nephron shows striking hypertrophy and hyperplasia. These histological changes do not readily reverse with mineralocorticoid receptor antagonism in adulthood. Thus, 11beta-HSD2(-/-) mice demonstrate the major features of SAME, providing a unique rodent model to study the molecular mechanisms of kidney resetting leading to hypertension.

Is Worsening Renal Function an Ominous Prognostic Sign in Patients with Acute Heart Failure? The Role of Congestion and Its Interaction with Renal Function

Background— Worsening renal function (WRF), traditionally defined as an increase in serum creatinine levels ≥0.3 mg/dL, is a frequent finding in patients with acute heart failure (AHF) and has been associated with poorer outcomes in some but not all studies. We hypothesized that these discrepancies may be caused by the interaction between WRF and congestion in AHF patients. Methods and Results— We measured serum creatinine levels on a daily basis during the hospitalization and assessed the persistence of signs of congestion at discharge in 599 consecutive patients admitted at our institute for AHF. They had a postdischarge mortality and mortality or AHF readmission rates of 13% and 43%, respectively, after 1 year. Patients were subdivided into 4 groups according to the development or not of WRF and the persistence of ≥1 sign of congestion at discharge. Patients with WRF and no congestion had similar outcomes compared with those with no WRF and no congestion, whereas the risk of death or of death or AHF readmission was increased in the patients with persistent congestion alone and in those with both WRF and congestion (hazard ratio, 5.35; 95% confidence interval, 3.0–9.55 at univariable analysis; hazard ratio, 2.44; 95% confidence interval, 1.24–4.18 at multivariable analysis for mortality; hazard ratio, 2.14; 95% confidence interval, 1.39–3.3 at univariable analysis; and hazard ratio, 1.39; 95% confidence interval, 0.88–2.2 at multivariable analysis for mortality and rehospitalizations). Conclusions— WRF alone, when detected using serial serum creatinine measurements, is not an independent determinant of outcomes in patients with AHF. It has an additive prognostic value when it occurs in patients with persistent signs of congestion.Background— Worsening renal function (WRF), traditionally defined as an increase in serum creatinine levels ≥0.3 mg/dL, is a frequent finding in patients with acute heart failure (AHF) and has been associated with poorer outcomes in some but not all studies. We hypothesized that these discrepancies may be caused by the interaction between WRF and congestion in AHF patients. Methods and Results— We measured serum creatinine levels on a daily basis during the hospitalization and assessed the persistence of signs of congestion at discharge in 599 consecutive patients admitted at our institute for AHF. They had a postdischarge mortality and mortality or AHF readmission rates of 13% and 43%, respectively, after 1 year. Patients were subdivided into 4 groups according to the development or not of WRF and the persistence of ≥1 sign of congestion at discharge. Patients with WRF and no congestion had similar outcomes compared with those with no WRF and no congestion, whereas the risk of death or of death or AHF readmission was increased in the patients with persistent congestion alone and in those with both WRF and congestion (hazard ratio, 5.35; 95% confidence interval, 3.0–9.55 at univariable analysis; hazard ratio, 2.44; 95% confidence interval, 1.24–4.18 at multivariable analysis for mortality; hazard ratio, 2.14; 95% confidence interval, 1.39–3.3 at univariable analysis; and hazard ratio, 1.39; 95% confidence interval, 0.88–2.2 at multivariable analysis for mortality and rehospitalizations). Conclusions— WRF alone, when detected using serial serum creatinine measurements, is not an independent determinant of outcomes in patients with AHF. It has an additive prognostic value when it occurs in patients with persistent signs of congestion.

Deficient inactivation of cortisol by 11β‐hydroxysteroid dehydrogenase in essential hypertension

OBJECTIVE 11 β‐Hydroxysteroid dehydrogenase protects renal mineralocorticoid receptors from Cortisol by converting Cortisol to inactive cortisone. 11 β‐Dehydrogenase deficiency, either congenital or after inhibition by liquorice and carbenoxolone, results in cortisol‐dependent mineralocorticoid excess and hypertension. We tested the hypothesis that the same mechanism occurs in some patients with essential hypertension.

Mineralocorticoid excess and inhibition of 11 β‐hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome

OBJECTIVE 11 β‐Hydroxysteroid dehydrogenase protects renal mineralocorticoid receptors from Cortisol by converting Cortisol to inactive cortisone. We hypothesize that 11 β‐dehydrogenase is inhibited by ACTH, providing a mechanism whereby Cortisol induces hypokalemic alkalosis in ectopic ACTH syndrome.