Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension?
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11-beta-Hydroxysteroid Dehydrogenases↗
Biomedical subjects
R Benediktsson
Publications and source records attributed to R Benediktsson.
Congenital and acquired syndromes of apparent mineralocorticoid excess.
The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) interconverts cortisol and cortisone. Congenital deficiency of the renal isoform of the enzyme results in hypertension, hypokalemia and suppression of the renin-angiotensin-aldosterone system--the apparent mineralocorticoid excess syndrome (AME). In these patients cortisol acts as a potent mineralocorticoid. Suppression of plasma cortisol with dexamethasone results in natriuresis, potassium retention and reduction in blood pressure. Ingestion of excess liquorice or taking carbenoxolone produces an acquired form of AME. The active component of liquorice is glycyrrhetinic acid (GE) and carbenoxolone is the hemisuccinate derivative. Both GE and carbenoxolone are potent inhibitors of 11 beta-OHSD. In vitro studies have shown that 11 beta-OHSD is present in aldosterone-selective tissues and acts as an autocrine mechanism which prevents cortisol from gaining access to the non-specific mineralocorticoid receptor (MR). Congenital or acquired absence of this enzyme allows cortisol to bind to MR resulting in AME. 11 beta-OHSD also appears to be important in controlling cortisol access to glucocorticoid receptors. Variable placental 11 beta-OHSD may alter foetal exposure to maternal cortisol and affect growth as indicated by the correlation between foetal weight and placental 11 beta-OHSD. Thus the tissue-specific distribution, ontogeny and modulation of this enzyme allows it to dictate glucocorticoid effects in addition to its key role in ensuring the specificity of the MR.
11-beta-Hydroxysteroid Dehydrogenases↗
11 beta-Hydroxysteroid dehydrogenase in the rat ovary: high expression in the oocyte.
The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the conversion of physiological glucocorticoids to inactive products, thus modifying the access of glucocorticoids to glucocorticoid and mineralocorticoid receptors. Glucocorticoids may affect ovarian function both indirectly and via binding to ovarian receptors. We have demonstrated 11 beta-HSD bioactivity and mRNA expression in rat ovary in vitro. The enzyme was localized to oocytes and luteal bodies immunohistochemically using two antibodies raised against purified rat liver 11 beta-HSD. These data are supported by in-situ hybridization studies, which also localized 11 beta-HSD mRNA expression to oocytes and luteal bodies. The results suggest that 11 beta-HSD may modulate the effects of glucocorticoid on ovarian function.
11-beta-Hydroxysteroid Dehydrogenases↗
Liquorice.
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11-beta-Hydroxysteroid Dehydrogenases↗
Natural history of chronic left ventricular aneurysm; a population based cohort study.
In order to evaluate the morbidity and mortality of chronic left ventricular aneurysm a population based cohort study was carried out. All cardiac catheterizations performed in Iceland during the years 1983-1985 were examined (n = 1261). Sixty seven patients with left ventricular aneurysm defined as: (1) normal diastolic contour with segmental dyskinesis (n = 6), (2) abnormal diastolic contour with (a) akinetic (n = 36) or (b) dyskinetic (n = 25) segments in systole, were included. Sixty seven patients with normal diastolic contour and akinetic segments in systole served as controls. The groups had similar mean age, sex ratio, number of diseased vessels and left ventricular end diastolic pressure. Mean ejection fraction was significantly lower in the aneurysm group (46 vs 56%, p = 0.00005). Collaterals were detected significantly more often in controls (88 vs 72%, p = 0.03). At follow up in 1989, 19 in the aneurysm group had died as compared to 12 in the control group. Life table analysis revealed significant differences between survival curves. The relative risk ratio was 2.18 with 95% confidence interval of 1.00-4.74 (p less than 0.05). However, when the amount of myocardial damage was taken into account the differences in survival were no longer statistically significant (relative risk ratio 1.77 with 95% confidence interval of 0.79-3.99). We conclude that the reduced survival probability of patients with chronic left ventricular aneurysm in comparison to controls with akinetic scars is accounted for by the more extensive myocardial damage and not by the presence of aneurysm per se.
Adult↗
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.
Animals↗
Lack of effect of nicotine or ethanol on the activity of 11beta-hydroxysteroid dehydrogenase type 2.
Low birth weight in combination with a large placenta predicts human hypertension. The pathophysiological link remains unclear, but glucocorticoid excess impairs fetal growth and leads to offspring hypertension. A key controller of fetal glucocorticoid exposure and local tissue availability is 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). The activity of placental 11beta-HSD2 correlates with fetal growth in animals and humans. Ethanol abuse and smoking are known to retard fetal growth which may relate to altered glucocorticoid action or dynamics. This study has examined whether nicotine or ethanol modulate glucocorticoid action in the placenta or fetus by inhibiting 11beta-HSD2, using clonal cell cultures, freshly isolated dually perfused intact human placentas and placentas from in vivo treated rats. No significant effect on the activity of 11beta-HSD2 by pathophysiologically relevant nicotine or ethanol concentrations was observed. The mechanism of action of nicotine and ethanol relevant to reduced fetal growth requires further study.
11-beta-Hydroxysteroid Dehydrogenases↗