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

The renin angiotensin system plays a major role in the control of blood pressure and electrolyte balance. It consists of a cascade of proteolytic cleavages leading to the biologically active angiotensin II (AII). Renin acts on angiotensinogen to yield angiotensin I (AI). AI is a prohormone and must be cleaved to the octapeptide AII by the action of the angiotensin I converting enzyme. Application of recombinant DNA technology has made possible the cloning of the renin gene and its cDNA which has provided newer insights into the regulation of renin gene expression, biosynthesis, and secretion. The information gained from such molecular biology techniques may contribute importantly to the efforts in the development of an effective renin inhibitor for the treatment of hypertension. The mouse and rat renin gene contains nine exons separated by eight intervening sequences, in contrast the human renin gene contains ten exons separated by nine introns. However, the renin gene of the three species spans 12 kb approximately. In its 5' flanking region, major control elements are present which include promotors and enhancers as well as regulatory elements such as estrogen and glucocorticoid receptor sites, and cAMP induction sequences. The combined action of these elements will result in tissue specific expression and regulation of the gene. In addition to the control at the gene expression level, renin is also regulated at the post-translational and secretory levels. The translational product of renin mRNA is preprorenin, which is cotranslationally cleaved to prorenin, an inactive precursor of renin. The majority of the new synthesized human prorenin is constitutively secreted. However, prorenin is also processed intracellularly and converted to the mature single chain active renin which is stored in secretory granules. Active renin is released by a regulated mechanism which can be stimulated by cAMP and other secretagogues. Studies are under way to examine the responses of renin gene expression, biosynthesis and secretion to various physiological conditions and to determine if there are alterations in the structure and expression of the renin gene that may be involved in the development of clinical and experimental hypertension.
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PMID:[Renin: structure and expression regulation of the gene, biosynthesis, and cellular pathways of secretion]. 821 Jul 68

Glucocorticoid resistance results from the partial, albeit apparently generalized, inability of glucocorticoids to exert their effects on target tissues. The condition is associated with compensatory increases in circulating pituitary corticotropin 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 chronic fatigue (perhaps a result of glucocorticoid deficiency in the central nervous system) to various degrees of hypertension with or without hypokalemic alkalosis or hyperandrogenism, or both, caused by increased cortisol and other salt-retaining steroids and adrenal androgens, respectively. 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. Different molecular defects, such as point mutations or a microdeletion of the highly conserved glucocorticoid receptor gene, alter the functional characteristics or concentrations of the intracellular receptor and appear to cause glucocorticoid resistance. The extreme variability in the clinical manifestations of glucocorticoid resistance and its mimicry of many common diseases can be explained by the overall degree of glucocorticoid resistance, differing sensitivity of target tissues to mineralocorticoids or androgens or both, and perhaps different biochemical defects of the glucocorticoid receptor, with selective resistance of certain glucocorticoid responses in specific tissues. The various different symptoms of classic glucocorticoid resistance and the theoretical potential of this condition to appear surreptitiously emphasize the importance of the glucocorticoid receptor in the pathogenesis of human disease.
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PMID:Syndromes of glucocorticoid resistance. 818 39

Apparent mineralocorticoid excess (AME) is a rare form of low renin hypertension caused by deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), the enzyme responsible for conversion of cortisol to the bio-inactive metabolite, cortisone. This results in prolonged cortisol half-life, activation of type I (mineralocorticoid) receptors by cortisol, sodium and fluid retention, and consequent childhood-onset hypertension. The cortisol secretion rate is low, perhaps due to cortisol's binding to type II (glucocorticoid) receptors and suppressing corticotropin secretion. Patients with AME thus lack stigmata of Cushing's syndrome. To evaluate any potential contribution of the type II (glucocorticoid) receptor to the development of hypertension in AME patients, we administered RU486, a steroid analogue that acts as a pure type II receptor blocker. Selective glucocorticoid receptor blockade did not decrease blood pressure in our patient; instead, a significant increase in average blood pressure was observed (125.1 +/- 1.7 pre-RU486 v 144.7 +/- 1.2 during RU486 treatment, P = .0001). We conclude that the type II receptor does not contribute to the development of hypertension in patients with AME.
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PMID:Investigation of the mechanism of hypertension in apparent mineralocorticoid excess. 839 54

Over the past year, the focus in corticosteroid hypertension has been on the cloning of the enzyme 11 beta-hydroxysteroid dehydrogenase, and the demonstration of a variety of mutations or deletions in the sequence coding for this enzyme in the syndrome of apparent mineralocorticoid excess. This syndrome is the third single-gene cause of human hypertension to be characterized, with glucocorticoid remediable aldosteronism (1992) and Liddle's syndrome (1994). The three conditions are characterized by inappropriate control of aldosterone secretion (glucocorticoid remediable aldosteronism), sodium retention (Liddle's syndrome) or aldosterone action (apparent mineralocorticoid excess), and underline a potential role of an aldosterone: salt imbalance in mineralocorticoid hypertension. No comparable mechanisms of hypertension following glucocorticoid receptor occupancy have been documented to date.
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PMID:Corticosteroid hypertension. 856 48

Glucocorticoids raise blood pressure but were thought not to play a pathophysiological role in essential hypertension when it was demonstrated that cortisol secretion rates and circulating concentrations are normal in this disease. However, recent observations suggest that increased tissue sensitivity to cortisol, mediated by either abnormal glucocorticoid receptors or impaired inactivation of cortisol by 11 beta-dehydrogenase, may allow cortisol to raise blood pressure despite normal circulating concentrations. We studied 11 patients with essential hypertension and 11 matched normotensive control subjects. Dermal vasoconstriction after topical application of both cortisol (16 +/- 4 versus 32 +/- 5 U, control subjects versus hypertensive patients; P < .02) and beclomethasone dipropionate (75 +/- 10 versus 100 +/- 7 U; P < .05) was increased in the hypertensive patients. Hypothalamic-pituitary glucocorticoid receptor sensitivity was normal, as judged by basal cortisol secretion rates and suppression of plasma cortisol during sequential overnight dexamethasone suppression tests. 11 beta-Dehydrogenase activity was impaired in essential hypertension, as judged by prolonged half-lives of [11 alpha-3H]cortisol (44 +/- 4 versus 58 +/- 4 minutes, control subjects versus hypertensive patients; P < .02). However, this did not correlate with the dermal vasoconstrictor response. We conclude that vasoconstrictor sensitivity to glucocorticoids is increased in essential hypertension and that this may initiate and/or sustain the increased peripheral vascular resistance that characterizes this disease. The mechanism of increased sensitivity remains uncertain, but it will be important to establish whether it relates to genetic abnormalities of the glucocorticoid receptor that have been observed in animal models and young individuals who are predisposed to essential hypertension.
Hypertension 1996 Feb
PMID:Increased vasoconstrictor sensitivity to glucocorticoids in essential hypertension. 856 40

The intravascular renin-angiotensin system is an endocrine system designed to maintain cardiovascular homeostasis in response to hypotension. Under normal conditions, angiotensinogen concentrations circulating in the plasma are rate limiting for the maximum velocity of angiotensin I formation. In the liver, the major site of circulating angiotensinogen synthesis, angiotensinogen expression is under exquisite hormonal control. We review the mechanisms by which hormones effect transcriptional control of angiotensinogen expression. Adrenal-derived glucocorticoids produce the translocation of the glucocorticoid receptor into the nucleus. It in turn binds to two glucocorticoid response elements and stimulates angiotensinogen gene transcription. Inflammation activates angiotensinogen transcription as a result of the macrophage-derived cytokines interleukin-1 and tumor necrosis factor-alpha. These cytokines change the abundance of two transcription factor families that bind a single regulatory site in the angiotensinogen promoter, the acute-phase response element. These proteins include the nuclear factor-kappaB complex and the CCAAT/enhancer binding protein family. Activation of the renin-angiotensin system, through production of angiotensin II, results in feedback stimulation of angiotensinogen synthesis (the "positive feedback loop"). We have discovered that the nuclear factor-kappaB transcription factor is regulated by angiotensin II, a finding that provides a mechanism for the transcriptional component of angiotensinogen gene synthesis in the positive feedback loop. These studies underscore the concept that induction of the angiotensinogen gene by diverse physiological stimuli is mediated through changes in the nuclear abundance of sequence-specific transcription factors. The intracellular convergence of cytokine- and angiotensin II-induced signaling pathways on the nuclear factor-kappaB transcription factor provides a point for "cross talk" between angiotensin- and cytokine-activated second messenger pathways.
Hypertension 1996 Mar
PMID:Mechanisms for inducible control of angiotensinogen gene transcription. 861 88

The objective of this study was to examine the role of dexamethasone on the expression of angiotensin II (Ang II) receptors in cultured rat mesangial cells. Dexamethasone caused concentration- and time-dependent decreases in 125I-[Sar1,Ala8]Ang II binding that were prevented by glucocorticoid receptor inhibition with mifepristone. A lag time of 24 hours and a dexamethasone concentration of at least 10 nmol/L were necessary for this effect to occur. Dexamethasone-induced reduction of 125I-[Sar1,Ala8]Ang II binding resulted from decreased Ang II type 1 (AT1) receptor density. No change in the apparent dissociation constant was observed. Dexamethasone also markedly inhibited Ang II-dependent inositol phosphate accumulation. Both reverse transcription-polymerase chain reaction and Northern blot analysis using specific short probes from the 3' noncoding region of the cDNA demonstrated the presence of AT1A and AT1B receptor mRNAs in rat mesangial cells, with a slight predominance of AT1B. Therefore, we studied the effect of dexamethasone on the expression of these two subtypes in rat mesangial cells. Dexamethasone produced a time-dependent decrease of AT1B receptor mRNA that was apparent after 6 hours of incubation, whereas AT1A receptor mRNA did not change. Mifepristone also suppressed the dexamethasone-induced decrease in AT1B receptor mRNA. In conclusion, glucocorticoids diminish Ang II receptor density at the mesangial cell surface through a mechanism that implies successive interaction with the glucocorticoid receptor and specific reduction in AT1B receptor mRNA expression. This differential regulation of both AT1 receptor subtypes might allow glucocorticoids to exert adjusted effects in their various target tissues.
Hypertension 1996 Apr
PMID:Regulation of angiotensin II receptor subtypes by dexamethasone in rat mesangial cells. 861 62

The role of glucocorticoids in the intrauterine programming of hypertension was assessed in the progeny of rats fed either 18 g casein/100 g diet (control diet) or 9 g casein/100 g diet (low protein diet), before conception and throughout pregnancy. Rats exposed to the low protein diet had significantly (P < 0.05) higher systolic blood pressures than control animals, when weaned. These rats had elevated brain and liver activities of specific glucocorticoid-inducible marker enzymes, relative to controls. Glycerol 3-phosphate dehydrogenase activity was also higher (377%) in whole brains of newborn rats exposed to low protein diet in utero, but no similar effect of corticosteroids was noted in brains of d 20 fetuses. Weanling rats of the low protein group exhibited a blunted diurnal pattern of adrenocorticotrophin (ACTH) concentrations in plasma. Plasma corticosterone concentrations were unaltered by prenatal dietary experience and exhibited a normal pattern of diurnal variation. Brain regional 11beta-hydroxysteroid dehydrogenase activities were unaltered by prenatal dietary experience, as was binding of 3H-corticosterone to type I glucocorticoid receptors in hippocampus, hypothalamus and liver. Type II glucocorticoid receptor binding capacity and receptor numbers in male rats were apparently elevated in hippocampus of low protein-exposed rats and were significantly lower in liver (P < 0.05), relative to control rats. Programming of the hypothalamic-pituitary-adrenal axis is inferred, and the observation that binding of steroid to type II receptor sites in vascular tissue is increased in low protein exposed rats may provide a direct mechanism for modulation of blood pressure by glucocorticoids in this model.
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PMID:Maternal protein restriction influences the programming of the rat hypothalamic-pituitary-adrenal axis. 864 31

1. The role of genetically determined changes in adrenal steroid production, metabolism and action in the pathogenesis of cardiovascular disease in man is considered by studying three loci that are important in corticosteroid function. 2. Variation at the glucocorticoid receptor locus can be identified as a biallelic restriction fragment length polymorphism (Bcl1); subjects with contrasting genotypes show altered skin vasoconstrictor responses to topically applied budesonide without any significant change in leucocyte receptor binding characteristics. 3. In a case control study of patients with essential hypertension, we have shown evidence of reduced 11 beta-hydroxysteroid dehydrogenase activity, with an elevated ratio of cortisol to cortisone metabolites in urine. 4. The genes encoding 11 beta-hydroxylase and aldosterone synthase are highly homologous. Studies in the Milan hypertensive rat show variation at this locus, which may account for the increased steroid synthesis noted in the hypertensive strain; in man, a chimaeric gene comprising 5' regulatory regions from 11 beta-hydroxylase and 3' coding sequence from aldosterone synthase accounts for the autosomal dominant condition Dexamethasone Suppressible Hyperaldosteronism. Variation in the precise location of the crossover site between the two genes does not account for the observed phenotypic heterogeneity in this condition. 5. Measurement of basal plasma steroid levels in subjects with essential hypertension show an increased ratio of 11-deoxycortisol/cortisol, consistent with reduced activity of 11 beta-hydroxylase in the zona fasciculata. 6. In summary, three loci involved in corticosteroid synthesis, metabolism and action can independently affect cardiovascular phenotypes; their roles in determining pathophysiological changes, including hypertension, remain to be studied.
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PMID:Corticosteroids in essential hypertension: multiple candidate loci and phenotypic variation. 871 73

1. We tested the hypothesis that dehydroepiandrosterone (DHEA), which prevents dexamethasone-induced hypertension in rats, may block adrenocorticotrophin (ACTH) hypertension, which has been presumed due to corticosterone excess. The blood pressure and metabolic effects of DHEA (18 mg/kg per day) were examined in sham and ACTH-treated (0.5 mg/kg per day) conscious Sprague-Dawley rates (n = 20). 2. ACTH but not sham injection increased blood pressure, water intake and urine output and decreased bodyweight. 3. DHEA administration for 10 days did not alter blood pressure or metabolic effects in either sham or ACTH-treated rats. 4. DHEA, which is known to block dexamethasone-induced hypertension, did not modify ACTH-induced hypertension in the rat. This suggests either that ACTH-induced hypertension is not simply a consequence of glucocorticoid activity or that the action of DHEA in dexamethasone hypertension is not through blocking the glucocorticoid receptor.
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PMID:Dehydroepiandrosterone does not prevent adrenocorticotrophin-induced hypertension in conscious rats. 871 85


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