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

We have studied a man suspected of having primary cortisol resistance on the basis of high 24-h mean plasma cortisol levels (27.4 micrograms/dl) and no stigmata of Cushing's syndrome. His son had slightly elevated 24-h mean plasma cortisol levels (9.9 micrograms/dl; normal 7.52 micrograms/dl). Both had high plasma protein unbound cortisol and increased urinary free cortisol. Plasma ACTH concentration was high, and both were resistant to adrenal suppression by dexamethasone. The father appeared to have mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis. This was found to be due to markedly elevated plasma levels of deoxycorticosterone and corticosterone. The son, who was normotensive, had mildly increased plasma corticosterone and normal deoxycorticosterone levels. To study the apparent end-organ resistance to cortisol, we examined the glucocorticoid receptor in the white cells and fibroblasts of these patients. In both tissues, using both whole cell and cytosol assays, the glucocorticoid receptor was found to have reduced affinity for dexamethasone. In the cytoxol assays, a reduced receptor number was found as well. We conclude that cortisol resistance is a rare familial syndrome owing to an abnormal glucocorticoid receptor with a decreased affinity for cortisol.
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PMID:Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease. 628 33

Acute subcutaneous (s.c.) administration of aldosterone increases ex vivo 22Na efflux from rat tail artery smooth muscle, which appears to be due to a specific action on mineralocorticoid receptors. Indeed, this effect is blocked by the antimineralocorticoid compounds RU 28318 [17 beta-hydroxy-3-oxo,7 alpha-propyl(17 alpha)-pregn 4-ene, 21 potassium carboxylate] and spironolactone. The specific glucocorticoid receptor agonist RU 26988 [11 beta,17 beta-dihydroxy-17-(1-propynyl) androesta-1,4,6 trien-3-one] does not modify 22Na efflux. We show here that aldosterone has, at physiological concentrations, a mineralocorticoid specific stimulating effect on passive and sodium pump dependent transmembrane movements of sodium from the rat tail artery smooth muscle. Aldosterone exerts two types of action on sodium transport: 1) a delayed stimulation of ouabain-dependent 22Na efflux and ouabain-independent 22Na efflux, which are completely blocked by actinomycin D; and 2) a very rapid increase of passive 22Na efflux, which is insensitive to actinomycin D and therefore does not seem to depend on transcription of genomic information.
Hypertension
PMID:Direct action of aldosterone on transmembrane 22Na efflux from arterial smooth muscle. Rapid and delayed effects. 632 52

Primary cortisol resistance in man is a familial disease. It is characterized by increased plasma cortisol concentrations, high urinary free cortisol excretion, a normal circadian pattern of cortisol secretion, resistance to adrenal suppression by dexamethasone and absence of clinical stigmata of Cushing's syndrome. In its severe form, hypertension and hypokalemic alkalosis are present, owing to increased secretion of the sodium-retaining corticoids, corticosterone and deoxycorticosterone. In subjects with a less severe resistance to cortisol, there are no clinical abnormalities and the disease is revealed only by detailed examination of several parameters of cortisol metabolism. In the whole-cell assay (peripheral mononuclear leukocytes or fibroblasts) the glucocorticoid receptor shows a low affinity for dexamethasone. The receptor may be unsaturable as suggested by decreased receptor concentrations in broken-cell systems. Thus, generalized target-tissue resistance to cortisol, including the pituitary gland and the hypothalamus, is accompanied by a decreased negative feedback of the cortisol-ACTH feedback system resulting in increased ACTH secretion. This causes higher plasma cortisol to compensate for the end-organ resistance and also increases the production of adrenal mineralocorticoids, as by-products. Thus hypertension and hypokalemic alkalosis depends on the degree of the resistance. Cortisol resistance in many New World primate species is characterized by greatly increased plasma cortisol concentrations, decreased cortisol binding globulin capacity and affinity, high levels of plasma and urinary free cortisol, marked resistance of ACTH suppression by dexamethasone, and no physiologic evidence of glucocorticoid hormone excess. Target tissues have normal concentrations of glucocorticoid receptors with decreased affinity for dexamethasone. The New World primates, unlike man, have compensated for this cortisol resistance with intra-adrenal adaptations over the 50 million years of their evolutionary development. These primates also have abnormalities of other steroid hormone-receptor systems such as progesterone, estrogen, androgen and mineralocorticoid. In contrast, the human syndrome appears to be a recent mutation with pathophysiologic consequences.
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PMID:Primary cortisol resistance: a familial syndrome and an animal model. 688 85

Enhanced vascular responsiveness to angiotensin II at the AT1 receptor has been considered one of the major contributing factors to vascular hypertrophy and high blood pressure. The transcription of the rat angiotensin II type 1A receptor gene is stimulated by glucocorticoids. To clarify the molecular mechanism for glucocorticoid action in rat vascular smooth muscle cells, we investigated the effects of dexamethasone on the promoter activity of the angiotensin II type 1A receptor by using promoter/luciferase reporter gene constructs and heterologous context constructs (containing the thymidine kinase promoter) in transfected vascular smooth muscle cells (< 12 passages). There are three putative glucocorticoid responsive elements (GREs) in the promoter. However, only one GRE was found to respond to dexamethasone (1 mumol/L) and was located at positions -756 to -770 bp upstream from the transcription initiation site. When compared with the consensus sequence of GRE, 9 of 12 bases were identical. RU38486, a glucocorticoid antagonist, completely blocked the induction by dexamethasone, suggesting that the GRE was functional through a specific glucocorticoid receptor. The response to dexamethasone was lost in vascular smooth muscle cells at higher passage numbers (> 8 passages) but was restored when the cells were transfected with a glucocorticoid-receptor expression construct. This finding provided additional support that the response to dexamethasone was mediated by the glucocorticoid receptor. The gel mobility supershift assay showed that the GRE binds in vitro-translated rat glucocorticoid receptors in a specific manner. Compared with the angiotensin II type 1A receptor promoter, no effect by dexamethasone was observed in vascular smooth muscle cells transfected with the angiotensin II type 1B receptor promoter/luciferase reporter gene constructs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of a cis-acting glucocorticoid responsive element in the rat angiotensin II type 1A promoter. 761 11

Glucocorticoid resistance results from incomplete but apparently generalized inability of glucocorticoids to exert their effects on their target tissues. The condition is associated with compensatory elevation of circulating ACTH and cortisol, with the former causing excess secretion of both adrenal androgens and adrenal steroid biosynthesis intermediates with salt-retaining activity. The manifestations of glucocorticoid resistance vary from asymptomatic to different degrees of hypertension and/or hypokalemic alkalosis and/or hyperandrogenism, caused by elevation cortisol and other salt-retaining steroids, and of adrenal androgens, respectively. In women, hyperandrogenism can result in acne, hirsutism, male type baldness, menstrual irregularities, oligoanovulation, and infertility; in men, it may lead to infertility; and in children to precocious puberty. Different molecular defects, such as point mutations or microdeletions of the highly conserved glucocorticoid receptor gene, alter the functional characteristics or concentrations of the intracellular receptor and cause glucocorticoid resistance. The extreme variability in the clinical manifestations of glucocorticoid resistance and its mimicry of many common diseases can be explained by different degrees of glucocorticoid resistance, differing sensitivity of target tissues to mineralocorticoids and/or androgens or both, and perhaps different biochemical defects of the glucocorticoid receptor. Mineralocorticoid resistance results from the inability of aldosterone to exert its effect on target tissues. The syndrome is associated with salt loss, hypotension, and hyperkalemic acidosis. We have cloned and sequenced the cDNA of five unrelated patients with this syndrome and have not found any mutations of pathophysiological significance that would explain the resistance of these patients to aldosterone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Syndromes of glucocorticoid and mineralocorticoid resistance. 779 8

A certain number of HIV-infected patients (about 17% in our series) manifest symptoms of cortisol resistance--weakness, weight loss, hypertension, chronic fatigue and intense mucocutaneous melanosis--symptoms which are also typical of Addison's disease. The diagnosis of cortisol resistance is determined through the increased plasma and urinary cortisol values and limited increases in ACTH values. Compared with patients with primary glucocorticoid resistance, AIDS patients have no symptoms of mineral-corticoid or androgen excess, only of glucocorticoid deficiency at target tissues. Mononuclear leukocytes from these patients show receptor changes which consist of an increased receptor number and decreased receptor affinity for glucocorticoids. They also show defective glucocorticoid-induced inhibition of [3H]thymidine incorporation. Glucocorticoid-resistant AIDS patients have a characteristic persistent increase in interferon-alpha production. The inverse correlation between plasma values of interferon-alpha and the receptor affinity for glucocorticoids clearly suggests that interferon production is regulated by the glucocorticoid receptor: the smaller the glucocorticoid effect on lymphocyte cells is, the greater interferon production is. Owing to the antiviral effect of interferon-alpha, it is possible that glucocorticoid-resistant AIDS patients have greater defences against viral infection than other AIDS patients. As interferon-alpha is melanogenetic, its increased production may also explain the intense skin pigmentation found in patients with the glucocorticoid-resistance syndrome.
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PMID:The syndrome of acquired glucocorticoid resistance in HIV infection. 781 Dec 21

Familial glucocorticoid resistance (FGR) is a rare hereditary disorder characterized by hypercortisolism and the absence of stigmata of Cushing's syndrome. The inability of glucocorticoids to exert their effects on target tissues is compensated for by increases in circulating corticotropin (ACTH) and cortisol, the former causing excess secretion of both adrenal androgens and adrenal steroid-biosynthesis intermediates with salt-retaining activity. There is considerable variability in the clinical presentations of FGR ranging from asymptomatic, to isolated chronic fatigue and to hypertension with or without hypokalemic alkalosis or to hyperandrogenism, or both. In women, hyperandrogenism can result in acne, hirsutism, menstrual irregularities, oligoanovulation, and infertility; in men it may lead to infertility and in children to precocious puberty. The reported molecular defects in FGR, such as point mutations and a microdeletion of the glucocorticoid receptor (GR) gene, cause partial resistance by, respectively, compromising the function of the GR or decreasing its intracellular concentration in glucocorticoid target tissues. Complete glucocorticoid resistance is believed to be incompatible with life in humans. Hence, the glucocorticoid resistance cases reported have been partial and of variable degree. The extreme variability in the clinical manifestations of the disorder can, additionally, be explained by differing sensitivity of target tissues to mineralocorticoids or androgens or both, and perhaps by different biochemical defects of the glucocorticoid receptor, causing selective resistance of certain glucocorticoid responses in specific tissues. Isolated tissue-resistance from a somatic mutation of the GR in a corticotropinoma from a patient with Nelson's syndrome was also found, suggesting that this may be a mechanism of tumorigenesis. There is additional evidence that defects of GR function can appear surreptitiously in a variety of clinical conditions, suggesting that glucocorticoid resistance in humans may be involved in the pathogenesis and/or clinical picture of a plethora of disease states, of which FGR is the archetype.
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PMID:Glucocorticosteroid resistance in humans. Elucidation of the molecular mechanisms and implications for pathophysiology. 782 90

Familial glucocorticoid resistance results from the partial inability of glucocorticoids to exert their effects on their target tissues throughout the organism. The condition is associated with compensatory elevations of circulating ACTH and cortisol, with the former causing excess abnormal secretion of steroids with mineralocorticoid and androgen activity. The manifestations of glucocorticoid resistance vary from asymptomatic to chronic fatigue, to varying degrees of hypertension and/or hypokalaemic alkalosis and hyperandrogenism. The latter can be manifest in women as acne, hirsutism, menstrual irregularity, oligoanovulation and infertility, in men as infertility, and in children as precocious puberty. Different molecular defects of the highly conserved glucocorticoid receptor gene, altering its concentration and functional characteristics, appear to cause the syndrome of familial glucocorticoid resistance. Depending on the molecular defect, this syndrome is transmitted by an autosomal dominant or recessive trait. There are recent suggestions that non-generalized forms of glucocorticoid resistance may exist, resulting in autoimmune-inflammatory phenomena or psychiatric manifestations.
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PMID:Hormone-nuclear receptor interactions in health and disease. Glucocorticoid resistance. 798 Aug 39

Inhibitors of steroid synthesis such as o,p'-DDD, aminoglutethimide, metyrapone, trilostane and ketoconazole are usually used for treatment of Cushing's syndrome in order to reduce the steroid production in the patients showing several complications, including severe hypertension and diabetes mellitus, and also an incomplete remission after the surgical treatment. o,p'-DDD and metyrapone are recommended to use for treatment of adrenocortical cancer and rapid reduction of cortisol levels, respectively. Aminoglutethimide and trilostane do not always have any side effects, although ketoconazole which is commonly used for treatment of Cushing's disease shows severe hepatic damage. RU 486 is effective for inhibiting the activity of glucocorticoid receptor, and will be used for treatment of Cushing's syndrome in near future.
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PMID:[Clinical usefulness of pharmacological treatment of Cushing's syndrome]. 816 84

Uninephrectomized rats drinking 1% sodium chloride were given aldosterone (Aldo, 0.75 microgram/h, subcutaneous [s.c.] infusion), deoxycorticosterone (DOC, 20 mg/wk, s.c.), corticosterone (B, 2 mg/d, s.c.), or the antiglucocorticoid-antiprogestin RU486 (2 mg/d, s.c.) for 8 wk, and hemodynamic and tissue responses were compared with a non-steroid-treated control group. Aldo and DOC markedly increased systolic BP and caused considerable (40-50%) cardiac hypertrophy; B and RU486 caused neither hypertension nor cardiac hypertrophy. Measurements of ventricular cross-sectional areas showed hypertrophy due to an increase in mass of the left ventricle only. Cardiac hydroxyproline concentration was increased considerably by Aldo and DOC, to a lesser degree by RU486, and not by B. Aldo markedly elevated left ventricular interstitial collagen (2.5-fold vs control, P < 0.01 vs all groups); other steroid treatments also increased interstitial collagen over control (DOC x 1.8-, RU486 x 1.6-, B x 1.3-fold), with identical responses for right and left ventricles (r = 0.94). A different pattern of perivascular fibrosis was noted; DOC elevated perivascular collagen (2.1-fold vs control, P < 0.01 vs all other groups); RU486 raised levels 1.4-fold vs control, but neither Aldo nor B significantly affected perivascular collagen. These data are consistent with interstitial cardiac fibrosis reflecting type I (mineralocorticoid) receptor occupancy by administered Aldo or DOC, or by elevated endogenous B after type II (glucocorticoid) receptor blockade after RU486 administration; perivascular fibrosis may reflect a composite response after type I receptor agonist/type II glucocorticoid receptor antagonist occupancy.
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PMID:Mineralocorticoids, hypertension, and cardiac fibrosis. 820 Sep 95


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