UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The fetal environment is now recognized as a key determinant of the adult phenotype, being linked to development of diseases, including hypertension, as well as the timing of puberty. Such links may be related, in part, to the level of fetal exposure to maternal glucocorticoids in utero, which is normally regulated by placental expression of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD). The present study examined whether manipulation of fetal glucocorticoid exposure, either directly or indirectly via 11beta-HSD inhibition, influences the subsequent timing of puberty. Administration of dexamethasone acetate at low (LDEX, 0.25 microg/ml drinking water) or high doses (HDEX, 1 microg/ml) or carbenoxolone (CBX, 2 x 10 mg/day, sc; an inhibitor of 11beta-HSD) to pregnant rats from day 13 to term (day 23) reduced offspring birthweight (LDEX: 9%; HDEX: 27%; CBX: 8%) and resulted in a subsequent delay in the onset of puberty in females (control: 41.4 +/- 0.5; LDEX: 44.8 +/- 0.7; HDEX: 48.5 +/- 0.4; CBX: 43.6 +/- 0.5 days). Importantly, the effects of CBX were not observed in the absence of maternal adrenals, indicating that they were mediated by increased fetal exposure to endogenous maternal glucocorticoids. In contrast, maternal treatment with metyrapone (MET; an inhibitor of glucocorticoid synthesis; 500 microg/ml drinking water from day 13) increased birthweight by 5% and advanced puberty onset in male offspring (control: 48.8 +/- 1.0; MET: 45.7 +/- 0.8 days). Changes in the timing of puberty onset were not attributable to changes in either bodyweight at puberty or peripubertal plasma leptin concentrations. Peripubertal plasma LH was also unaffected in animals with delayed puberty but was elevated in male offspring of MET-treated mothers. Collectively, these results demonstrate that fetal glucocorticoid exposure is an important determinant of the timing of puberty onset in postnatal life, and that this effect is operable within the normal physiological range of glucocorticoid concentrations.
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PMID:Increased fetal glucocorticoid exposure delays puberty onset in postnatal life. 1087 42

We review various theories of the pathogenetic mechanisms of steroid-induced and essential hypertension. We investigated the possibility that a pathogenetic mechanism leading to glucocorticoid (GC)-induced hypertension or to mineralocorticoid (MC)-induced hypertension, or both, may be of critical importance in primary hypertension. We studied plasma levels of corticosterone (BK) and aldosterone (Aldo), and their concentrations in arterial and renal tissues of spontaneously hypertensive rats (SHR), a model of primary hypertension, and in the antecedent strain WKY rats as a normotensive control. Plasma levels of BK and Aldo were found to be normal and identical in SHRs and WKYs. Tissue (intracellular) levels of BK were more than double in SHRs than in WKYs. Subsequently we examined the activity of 11 beta-hydroxy steroid dehydrogenase (11-HSD) in both aortic and renal tissues of SHRs and WKYs. 11-HSD converts BK to the corresponding 11-keto compound, 11-dehydro-corticosterone (cpd.AK), which is inactive, in view of its inability to bind to the MC receptors (and also to the GC receptors). BK, the main glucocorticoid in the rat, as well as cortisol, have high affinity for the MC-receptor (MR). Normally BK or cortisol are present in 10(2)-10(3) times greater concentrations than Aldo in tissues possessing MR. The enzyme 11-HSD deactivates BK (or cortisol), thus protecting MC-receptors in the MC target tissues from being activated by GC. When we examined arterial and renal tissue activities of 11-HSD in SHRs, the activity of 11-HSD was only one-third that found in the WKY rats. This explained higher levels of BK in the tissues of SHR, and suggested that decreased activity of 11-HSD is a pathogenetic factor for hypertension in SHRs. Thus, in a model of primary hypertension such as SHR, decreased activity of 11-HSD in the target tissues of MC appears to lead to glucocorticoid-induced mineralocorticoid hypertension.
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PMID:[Mechanism of primary hypertension]. 1090 53

Childhood obesity is accompanied by a variety of cardiovascular risk factors (hypertension, insulin resistance, dyslipidaemia) which tend to aggregate (syndrome X). 11beta-hydroxysteroid dehydrogenase (11beta-HSD) is supposed to play a role in the pathogenesis of hypertension and the development of syndrome X. There are two isoforms of 11beta-HSD. 11beta-HSD-2 is responsible for the inactivation of cortisol to inactive cortisone. In the case of impaired enzyme activity the ratio of urinary tetrahydrocortisol (THF)+ its isomer allotetrahydrocortisol (5alpha-THF)/tetrahydrocortisone (THE) is elevated. 11beta-HSD-1 is an oxo-reductase, which type catalyses the conversion of cortisone to cortisol. The aim of the present study was to investigate if there was any alteration in the urinary cortisol metabolites reflecting 11beta-HSD activity in hypertensive obese children (no.=15) as compared to normotensive obese (no.=11) and normotensive non-obese children (no.=15). We found an increased excretion of cortisol metabolites in hypertensive obese children compared to obese and normal - weight children having normal blood pressure. The ratio of THF+5alpha(THF/THE had a significant correlation with systolic blood pressure. On the basis of our study the ratio of THF+5alpha-THF/ THE reflecting on altered enzyme activity seems to be an independent factor influencing especially systolic blood pressure in hypertensive obese children.
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PMID:Urinary cortisol to cortisone metabolites in hypertensive obese children. 1100 67

Apparent mineralocorticoid excess (AME) syndrome is a rare inherited disorder caused by 11beta-hydroxysteroid dehydrogenase (11-HSD 2) isozyme deficiency in the kidney. This enzyme is responsible for oxidizing cortisol to its inactive metabolite cortisone. An elevated tetrahydrocortisol (THF) and allotetrahydrocortisol (aTHF) to tetrahydrocortisone (THE) ratio in the urine is pathognomonic of AME syndrome. Clinical features include hypertension, hypokalemia, alkalosis, reduced plasma renin activity (PRA), low aldosterone levels, and occasionally nephrocalcinosis. Here we describe a 13-year-old boy who presented with severe hypertension, hypokalemia, low PRA and aldosterone levels, and elevated THF plus aTHF/THE ratio in the urine consistent with a diagnosis of AME syndrome. On ultrasound examination, he had severe nephrocalcinosis, and bilateral renal cysts. Renal cysts have not been previously reported in AME syndrome. The development of nephrocalcinosis and renal cysts may be associated with chronic long-standing hypokalemia. An early diagnosis and treatment of AME syndrome could help to prevent these sequelae, and to preserve renal function.
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PMID:Nephrocalcinosis and renal cysts associated with apparent mineralocorticoid excess syndrome. 1109 13

The association between excess glucocorticoids and hypertension has been much discussed but poorly understood. From both clinical observations and laboratory studies, it is clear that glucocorticoids exert their effects at many different sites responsible for blood pressure regulation. Isoforms of the enzyme 11ss-hydroxysteroid dehydrogenase (11ss-HSD), located in steroid-responsive tissues, metabolize endogenously produced glucocorticoids. These enzymes limit steroid access to mineralocorticoid and/or glucocorticoid receptors. In the kidney, synthetic and endogenous glucocorticoids are capable of enhancing transepithelial sodium transport in the presence of 11ss-HSD inhibition. Proximal tubule reabsorption of sodium can be indirectly augmented after chronic exposure to glucocorticoids. In this segment, steroids have a permissive effect, increasing the expression of both Na(+), K(+) adenosine triphosphatase along the basolateral membrane and Na(+)-H(+) exchanger along the apical membrane of epithelial cells. Although glucocorticoids themselves produce no increase in sodium reabsorption in this segment, angiotensin II-stimulated sodium transport is significantly greater in proximal tubular cells pretreated with glucocorticoids. The increased transport in distal renal segments is more direct and stems in part from glucocorticoid cross-over binding to mineralocorticoid receptors. In vascular tissue, synthetic and endogenous glucocorticoids, after inhibition of the dehydrogenase reaction, magnify the response to circulating vasoconstrictors. The effects of glucocorticoids in vascular tissue is indirect, upregulating the expression of receptors to many vasoconstrictors and downregulating the effects of potential vasodilators. Thus, glucocorticoids have the potential to alter both circulating volume and vascular resistance.
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PMID:Insights Into Glucocorticoid-Associated Hypertension. 1113 61

The glucocorticoid metabolising enzymes, 11beta-hydroxysteroid dehydrogenases (11beta-HSD), play a critical role in determining the availability of glucocorticoids to activate their receptors and hence modulate target gene transcription. There are two isozymes, 11beta-HSD-1 and -2, which act in opposing directions. 11beta-HSD-2 acts as a dehydrogenase, converting active corticosterone (cortisol in humans) to its inactive 11-keto derivative (11-dehydrocorticosterone in rodents and cortisone in humans), whereas 11beta-HSD-1 acts as a reductase, regenerating active glucocorticoids in a tissue-specific manner. Owing to the lack of specific inhibitors of these enzymes, it has been difficult to confirm the roles and determine the importance of these enzymes in vivo. Hence, to address this, we produced transgenic mice with null-mutations in the genes encoding the 11beta-HSD-1 or 11beta-HSD-2 enzymes. 11beta-HSD-2 -/- mice show signs of hypertension, hypotonic polyuria, hypokalemia and hypochloremia. These symptoms arise from illicit activation of mineralocorticoid receptors by glucocorticoids, in the absence of the protective action of 11beta-HSD-2. The phenotype is directly comparable to the Syndrome of Apparent Mineralocorticoid Excess, seen in humans with mutations in the 11beta-HSD-2 gene. Mice lacking 11beta-HSD-1, however, show a more subtle phenotype with reduced activation of glucocorticoid-induced processes. They were unable to convert 11-dehydrocorticosterone to corticosterone in vivo, confirming 11beta-HSD-1 as the sole 11-reductase in the mouse. They have elevated circulating levels of plasma corticosterone levels and adrenal hyperplasia, but they also have attenuated glucocorticoid-induced activation of gluconeogenic enzymes in response to fasting, and lower glucose levels in response to obesity or stress. Overall, these transgenic models have proved very useful for elucidating the roles of 11beta-HSDs in vivo and will be a unique resource for investigating the importance of each enzyme in the diverse actions of glucocorticoids.
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PMID:Phenotypic analysis of mice bearing targeted deletions of 11beta-hydroxysteroid dehydrogenases 1 and 2 genes. 1116 6

11beta-Hydroxysteroid dehydrogenases (11beta-HSD) are microsomal enzymes that catalyze the conversion of active glucocorticoids (GC) to their inactive 11-dehydro products and vice versa. Two isoenzymes of 11beta-HSD have been characterized and cloned in human tissues. The tissue-specific metabolism of GC by these enzymes is important for mineralocorticoid (MC) and GC receptor occupancy and seems to play a crucial role in the pathogenesis of diseases such as apparent MC excess syndrome, and may play roles in hypertension, obesity and impaired hepatic glucose homeostasis. This article reviews the literature and examines the role and importance of 11beta-HSD in humans.
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PMID:Clinical implications of glucocorticoid metabolism by 11beta-hydroxysteroid dehydrogenases in target tissues. 1118 44

11beta-Hydroxysteroid dehydrogenases (11beta-HSD) interconvert cortisol, the physiological glucocorticoid, and its inactive metabolite cortisone in humans. There are two isoforms. The type 1 isoform (11beta-HSD1) catalyzes both 11beta-dehydrogenation (cortisol to cortisone) and the reverse oxoreduction (cortisone to cortisol), but the type 2 isoform (11beta-HSD2) catalyzes only 11beta-dehydrogenation. The diminished dehydrogenase activity has been demonstrated in resistance vessels of genetically hypertensive rats. However, the isoform(s) that plays a significant role in conferring the dehydrogenase activity on vasculature has not been determined. We investigated 11beta-HSD activities in human vascular smooth muscle cells by manipulating 11beta-HSD expressions with antisense oligonucleotides. The results showed that 11beta-HSD2 dominates functioning in the dehydrogenase mode in these cells. This indicates that impairment of 11beta-HSD2 activity in vascular wall may be related to the pathogenesis of hypertension.
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PMID:11beta-hydroxysteroid dehydrogenase activity in human aortic smooth muscle cells. 1121 28

It has been assumed that low birth weight and high placenta weight were key factors for predicting hypertension in human adulthood. A deficiency in placental 11 beta-HSD-II enzyme activity was supposed to be the underlying cause. To possibly establish 11 beta-HSD-II as a leading factor, we determined 11 beta-HSD-II activities in 133 healthy pregnancies, 21 proteinuric pregnancies complicated by pregnancy-induced hypertension (PIH), 26 non proteinuric PIH pregnancies and 15 pregnancies complicated by fetal growth restriction (32nd-41st gestational week). We could not identify differences in 11 beta-HSD-II activity between pregnancies with the rare combination of small babies with big placentas and others (p = 0.59; Kruskal-Wallis test). And although there was no correlation between 11 beta-HSD-II activity and birth weight, in the control gestational age correlated with 11 beta-HSD-II activity (r = 0.22; p < 0.05; Spearman). 11 beta-HSD-II activity in the proteinuric PIH group was significantly higher than in the controls (11.7 pmol/min/mg prot.; range 10-13.2 vs. 7.9; range 7.0-9.1; p < 0.05). The lowest, but not significant, enzyme activities were in the IUGR group (5.8 pmol/min/mg prot.; range 4.0-9.2). In this group, analysis of variance detected a correlation between enzyme activity and placental weight. In conclusion, we could not confirm that placental 11 beta-HSD-II deficiencies act as an indicator for the risk of adult hypertension in small fetuses with large placentas. However, in growth restriction 11 beta-HSD-II activity might play a role. To clarify the influence in this group, further research is needed. Increased 11 beta-HSD-II activities with gestational age in the control may serve to sustain fetal adrenal steroid genesis and to prepare the fetus for autonomic life.
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PMID:11 beta-hydroxysteroid dehydrogenase (11 beta-HSD-II) activity in human placenta: its relationship to placental weight and birth weight and its possible role in hypertension. 1123 13

11beta-hydroxysteroid dehydrogenase (11beta-HSD), an enzyme regulating mineralocorticoid like action of glucocorticoid, oxidizes active cortisol to inactive cortisone. Impaired activity of this enzyme is associated with apparent mineralocorticoid excess (AME) syndrome and is characterized by hypertension and hypokalemia. Recent investigations suggest the presence of hypertensive subjects with low activity of 11beta-HSD. The blood concentration ratio of cortisone/cortisol reflects the overall conversion of cortisol to cortisone and may be an index to assess the systemic activity of 11beta-HSD. We evaluated the peripheral blood concentration ratio of cortisone/cortisol as a possible marker to identify subjects with hypertension thought to represent impaired 11beta-HSD activity. We compared this ratio in healthy subjects and patients with diabetes mellitus (DM) or chronic renal failure (CRF). Peripheral blood samples were collected from 69 healthy subjects, 44 DM, and 36 CRF patients in the morning (9:00 to 11:00 AM). Twenty-six DM patients (59%) and 32 CRF patients (89%) met the criteria for having hypertension. Serum cortisol and cortisone concentrations were determined by high performance liquid chromatography (HPLC). All values for serum cortisone and cortisol levels were within the normal range. Serum cortisone/cortisol ratio in the healthy subjects was distributed with a range of 0.113 to 0.494 (median, 0.243). Compared with healthy subjects, DM and CRF patients had significantly low (P <.01) serum cortisone/cortisol levels (median, 0.188 [range, 0.092 to 0.313] in DM and 0.088 [range, 0.031 to 0.140] in CRF). Bimodal distribution of cortisone/cortisol, found in DM patients with hypertension, represented high- and low-ratio groups around the border of the ratio 0.2. Kidney function, DM duration, and complications varied between the high- and low-ratio groups. The low ratio group (<0.2), whose 11beta-HSD activity was considered low, had an increase in blood urea nitrogen (BUN) levels and experienced nephropathy, neuropathy, retinopathy, and prolonged DM duration when compared with the group with a ratio greater than 0.2. The data suggest that the serum cortisone/cortisol ratio reflects the change in 11beta-HSD activity and is dependent kidney function. This is a possible marker to evaluate glucocorticoid excess hypertension observed in DM and CRF patients.
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PMID:Assessing systemic 11beta-hydroxysteroid dehydrogenase with serum cortisone/cortisol ratios in healthy subjects and patients with diabetes mellitus and chronic renal failure. 1143 85

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