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

Ageing of the brain is an important factor in overall ageing and mortality, and new insights have clarified the relationship between neuroregulation and ageing. First, neuronal loss in normal ageing is now known to be a minor change. Loss of synapses through dystrophic neuronal change is the hallmark of normal ageing. Second, similar dystrophic changes occur in the brain with chronic stress. In both instances, forebrain sites experience loss of synaptic input from brainstem regulatory nuclei. Third, functional ageing is attributed in part to lifetime stress, under the concept of 'allostatic load'. Being inseparable from the functions of appraising and responding to stress, the brain is an ultimate mediator of stress-related mortality, through hormonal changes that lead to proximate pathologies like hypertension, glucose intolerance, cardiovascular disease and immunological impairment. In chronic stress the brain shows clear allostatic compensations that lead to pathology. Two subtle and chronic mechanisms that may mediate brain pathology and accelerated ageing in chronic stress are proposed. These are abnormal glucocorticoid receptor (GR) occupancy over the 24 h cycle, and elevated body temperature. These factors lead to GR-mediated tissue changes and to acceleration of general cellular ageing mechanisms. Human depression is discussed as an exemplary demonstration of these principles.
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PMID:Ageing, stress and the brain. 1185 92

Abnormalities of glucocorticoid receptors were assumed to cause resistance or hypersensitivity to glucocorticoid, while only glucocorticoid resistance has been described clinically. Patients with familial cortisol resistance have continuously elevated serum cortisol without any clinical manifestations of Cushing's syndrome due to hyposensitivity to cortisol in all tissues including the hypothalamus and the pituitary. Clinical symptoms of the disease are characterized by hypertension with hypokalemia and hyporeninemia, virilism in women, isosexual precocity in a boy and mild general fatigue. As the cause of the disease, a defect in glucocorticoid receptor affinity or binding capacity due to mutations in the glucocorticoid receptor gene has been reported. Another cause of the disease is the presence of heat labile glucocorticoid receptor. In 5 of 6 families with cortisol resistance reported so far, mutations of the glucocorticoid receptor gene have been demonstrated.
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PMID:[Disorders caused by abnormalities of glucocorticoid receptors]. 1185 26

Increasing epidemiological evidence supports the notion that adverse events in fetal life permanently alter the structure and physiology of the adult offspring, a phenomenon dubbed 'fetal programming'. In particular, low weight or thinness at birth in humans is associated with an increased risk of cardiovascular and metabolic disorders as well as neuroendocrine dysfunction in adult life. Glucocorticoid administration during pregnancy is well-documented to both reduce offspring birth weight and alter the maturation of organs (hence their use to accelerate fetal lung maturation in premature labour). Here data are reviewed which show, in rodents and other models, that antenatal exposure to endogenous or exogenous glucocorticoids reduces offspring birth weight and produces permanent hypertension, hyperglycaemia, hyperinsulinaemia, altered behaviour and neuroendocrine responses throughout the lifespan. Processes underlying fetal programming include determination of the 'set point' of the hypothalamic-pituitary-adrenal (HPA) axis and of tissue glucocorticoid receptor (GR) expression. Similar HPA axis hyperreactivity occurs in lower birth weight humans and may be an early manifestation of the 'low birth weight' phenotype.
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PMID:Glucocorticoid programming of pituitary-adrenal function: mechanisms and physiological consequences. 1197 33

Epidemiological studies have led to the hypothesis that a major component of the risk of diseases such as hypertension, coronary heart disease and non-insulin-dependent diabetes (the 'metabolic syndrome') is established before birth. Although the underlying mechanisms of this 'programming' of disease have not yet been conclusively determined, a reduced fetal nutrient supply as a consequence of poor placental function or unbalanced maternal nutrition is strongly implicated. It has been proposed that one outcome of suboptimal nutrition is exposure of the fetus to excess glucocorticoids, which restrict fetal growth and programme permanent alterations in its cardiovascular, endocrine and metabolic systems. This review focuses on the effects of endogenous and exogenous glucocorticoid exposure in utero on postnatal hypothalamo-pituitary-adrenal (HPA) axis activity, both in humans and experimental animals. The physiological consequences and proposed underlying molecular and cellular mechanisms are discussed. Current data indicate that key targets for programming may include not only the HPA axis but also glucocorticoid receptor gene and 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) gene expression in a range of tissues.
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PMID:Prenatal programming of postnatal endocrine responses by glucocorticoids. 1236 63

In recent decades, there has been an increasing interest in the role of endogenous glucocorticoids such as cortisol in the pathogenesis of metabolic syndrome. Studies in humans have suggested a positive association between obesity, hypertension, and insulin resistance, with alleles at the glucocorticoid receptor (GR) gene. For instance, the BclI polymorphism within the intron upstream of GR exon 2 has been associated with cardiovascular risk factors such as visceral obesity, hypertension, insulin resistance, and elevated cortisol concentrations. However, the location of the BclI polymorphism is not known, and the variant has so far not been compared with the wild-type receptor for its ability to be activated by glucocorticoids. Although several other mutations in the GR gene have been postulated as being relevant to the progression to type 2 diabetes and cardiovascular diseases, conflicting results makes it difficult to determine exactly what effect these GR variations have on metabolic syndrome incidence and progression. Further studies focusing on the most compelling GR mutations might offer a better understanding of metabolic syndrome pathogenesis and progression, aiding in the development of more effective treatments for this condition.
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PMID:The glucocorticoid receptor gene and its association to metabolic syndrome. 1237 90

Cushing's syndrome results from prolonged exposure to excessive circulating glucocorticosteroids, and is associated with significant morbidity and mortality. While the treatment of choice in most patients is surgical, the metabolic consequences of the syndrome, including increased tissue fragility, poor wound healing, hypertension, and diabetes mellitus, increase the risks of such surgery. The hypercortisolemia and its sequelae can be efficiently reversed using medical therapy, either as a temporary measure prior to definitive treatment, or longer term in more difficult cases. Drug treatment has been targeted at the hypothalamic/pituitary level, the adrenal glands, and also at the glucocorticoid receptor level. In this review we discuss the pharmacotherapeutic agents that have been used in Cushing's syndrome, and their efficacy, the monitoring of treatment, and potential therapies that may prove useful in the future in this complex endocrinological disorder.
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PMID:The medical management of Cushing's syndrome. 1238 47

Overweight is associated with the N363S variant in the glucocorticoid receptor (encoded by nuclear receptor subfamily 3, group C, member 1 gene: NR3C1). The present study examined whether the N363S polymorphism might also be associated with coronary artery disease (CAD). This involved 556 patients with CAD, of which 437 were analyzed, and 302 control subjects, all being of Anglo-Celtic descent residing in Sydney. An extensive range of phenotypic parameters was collected from the patients, and leukocyte DNA from all subjects was genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis for the A1218G (N363S) variant. Frequency of the S363 allele was 0.04 in healthy normal-weight control subjects but was 0.15 in patients with CAD (P=2.0x10(-5)) and was also elevated in subjects with CAD who were not overweight (0.14) (P=2.6x10(-5)), supporting a primary association with CAD. Frequency of S363 allele carriers in subjects with CAD who had angina was particularly high: unstable angina (0.45), stable angina (0.29), and no angina (0.26) (P for trend=0.016). Elevated cholesterol (P=0.027), triglycerides (P=0.005), and total cholesterol/HDL ratio (P=0.011), after Bonferroni, tracked with the S363 allele, consistent with accentuation of mechanisms that predispose to atheroma formation in coronary vessels. The data suggest a role for glucocorticoid receptor variation in the underlying cause of CAD.
Hypertension 2003 Mar
PMID:Association of coronary artery disease with glucocorticoid receptor N363S variant. 1282 2

Aldosterone increases cation transport and contractility of vascular smooth muscle, but the specific transporter involved and how it is linked to smooth muscle tone is unknown. Because the Na-K-2Cl cotransporter (NKCC1) contributes to vascular smooth muscle contraction and is regulated by vasoactive compounds, we sought to determine whether this transporter is a target of aldosterone in rat aorta. Treatment of adrenalectomized rats with aldosterone for 7 days resulted in a 63% increase in NKCC1 activity as measured by bumetanide-sensitive efflux of 86Rb+. Treatment of normal aortas in culture with aldosterone for 3 and 7 days resulted in 29% and 47% increases in NKCC1 activity, respectively. Aldosterone had no acute effect on 86Rb+ efflux. Stimulation of NKCC1 was blocked by spironolactone, a mineralocorticoid receptor antagonist, but not by RU38486, a glucocorticoid receptor antagonist. Aldosterone did not augment the stimulation of NKCC1 by phenylephrine and did not increase NKCC1 mRNA as determined by real-time polymerase chain reaction. We conclude that aldosterone regulates the Na-K-2Cl cotransporter in vascular smooth muscle through classic mineralocorticoid receptors but not through changes in the abundance of NKCC1 mRNA. This could account for the increase in Na+, K+, and Cl- fluxes previously observed in vascular smooth muscle from mineralocorticoid-treated animals and may contribute to increased vascular tone.
Hypertension 2003 May
PMID:Aldosterone regulates the Na-K-2Cl cotransporter in vascular smooth muscle. 1266 85

Epidemiological and experimental studies have demonstrated that maternal undernutrition during pregnancy is associated with abnormal placental growth. In sheep, maternal nutrient restriction over the period of rapid placental growth (30-80 days) restricts placentome growth. Then following adequate nutrition up to term (147 days), placental mass is greater in association with a higher total abundance of the predominant placental glucose transporter-1. The resulting lambs are larger at birth, have heavier kidneys with an increased expression of the glucocorticoid-responsive type 1 angiotensin II receptor. Near to term, these fetuses possess more adipose tissue, the endocrine sensitivity of which is markedly enhanced. For example, the abundance of mRNA for 11beta-hydroxysteroid dehydrogenase type 1, which catalyses the conversion of cortisone to bio-active cortisol is increased. This is associated with a higher abundance of both leptin and glucocorticoid receptor mRNA. At 6 months of age, the juvenile offspring of nutrient restricted ewes have lower resting blood pressure that was positively correlated with plasma cortisol concentration, suggesting their blood pressure could be more strongly driven by circulating cortisol. These offspring also exhibited a greater pressor response to vasoconstrictor challenges, but showed no difference in vasodilatory response. At this age, the kidney weight was similar between groups, but the abundance of cytochrome c in kidney mitochondria was enhanced in lambs born to nutrient restricted ewes that could indicate increased mitochondrial activity. Reduced maternal nutrition during the period of rapid placental growth may therefore contribute to hypertension in later life through physiological and vascular adaptations during fetal life.
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PMID:Maternal nutrient restriction during placental growth, programming of fetal adiposity and juvenile blood pressure control. 1271 69

Two isoforms of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 acts predominantly as an oxo-reductase in vivo using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 is a NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tIssues, both enzymes serve to control the availability of cortisol to bind to corticosteroid receptors. 11beta-HSD2 protects the mineralocorticoid receptor from cortisol excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of 'apparent mineralocorticoid excess', in which 'Cushing's disease of the kidney' results in cortisol-mediated mineralocorticoid excess. Inhibition of 11beta-HSD2 explains the mineralocorticoid excess state seen following liquorice ingestion and more subtle defects in enzyme expression might be involved in the pathogenesis of 'essential' hypertension. 11beta-HSD1 by generating cortisol in an autocrine fashion facilitates glucocorticoid receptor-mediated action in key peripheral tIssues including liver, adipose tissue, bone and the eye. 'Cushing's disease of the omentum' has been proposed as an underlying mechanism in the pathogenesis of central obesity and raises the exciting possibility of selective 11beta-HSD1 inhibition as a novel therapy for patients with the metabolic syndrome. 'Pre-receptor' metabolism of cortisol via 11beta-HSD isozymes is an important facet of corticosteroid hormone action. Aberrant expression of these isozymes is involved in the pathogenesis of diverse human diseases including hypertension, insulin resistance and obesity. Modulation of enzyme activity may offer a future therapeutic approach to treating these diseases whilst circumventing the endocrine consequences of glucocorticoid excess or deficiency.
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PMID:Tissue-specific Cushing's syndrome, 11beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action. 1294 16


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