Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

19-Noraldosterone, which was recently shown to be synthesized and produced in the human adrenal gland, possesses potent mineralocorticoid and hypertensinogenic activities. 18,19-Dihydroxycorticosterone (18,19-(OH)2-B) and 18-hydroxy-19-norcorticosterone (18-OH-19-nor-B), a possible precursor of 19-noraldosterone, have been identified in human urine. These mineralocorticoid hormones are regulated by the renin-angiotensin system and synthesized in adrenal glomerulosa cells. Urinary 19-noraldosterone correlated with urinary 18,19-(OH)2-B, 18-OH-19-nor-B, 18-hydroxycorticosterone (18-OH-B), and aldosterone. Urinary excretion of 19-noraldosterone, 18,19-(OH)2-B, and 18-OH-19-nor-B were increased in patients with aldosterone-producing adenoma (APA) and in those with idiopathic hyperaldosteronism (IHA), but the two did not differ significantly. Urinary 18-OH-B and 18-hydroxycortisol (18-OH-F) were significantly higher in APA compared with IHA. Though urinary 18-OH-F and 18-OH-B concentrations were useful markers, urinary 19-noraldosterone, 18,19-(OH)2-B, and 18-OH-19-nor-B could not be used to distinguish the two subsets of primary aldosteronism. Urinary 19-noraldosterone did not differ in hypertensive and normotensive patients. However, urinary 19-noraldosterone was increased in some hypertensive patients. In spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP), urinary 19-noraldosterone was increased at the prehypertensive stage compared with Wistar-Kyoto (WKY) rats. Urinary 19-noraldosterone was decreased in 9-week-old SHR and SHRSP compared with WKY rats. However urinary 19-noraldosterone was higher in SHRSP than in SHR. These elevated levels of 19-noraldosterone may contribute to hypertension in some individuals and in experimental hypertensive rats.
Steroids 1995 Jan
PMID:Significance of 19-noraldosterone, a new mineralocorticoid, in clinical and experimental hypertension. 779 99

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)
Steroids 1995 Jan
PMID:Syndromes of glucocorticoid and mineralocorticoid resistance. 779 8

Primary aldosteronism is the commonest cause of potentially curable hypertension when diagnosed in both florid and less florid forms. Genetic screening, so far available only for glucocorticoid-suppressible hyperaldosteronism, permits diagnosis from birth, before any biochemical or clinical abnormalities appear. Biochemical screening using the aldosterone-to-renin ratio permits diagnosis in the absence of raised aldosterone or of hypokalemia. Primary aldosteronism occurs in several familial forms. As well as the variety described in 1966 which is ACTH-dependent and glucocorticoid-suppressible, and not so far associated with tumors, another variety described in 1991 is not glucocorticoid-suppressible and is frequently associated with aldosterone-producing adenomas (APAs). Primary aldosteronism due to adrenocortical hyperplasia, adenoma, or carcinoma can also occur as part of the multiple endocrine neoplasia syndromes, where normoplasia, hyperplasia, benign neoplasia, and malignant neoplasia can exist in the same patient in the same endocrine gland(s) at the same time. The morphology of adrenocortical hyperplasia causing primary aldosteronism ranges from glomerulosa-like (idiopathic hyperplasia of the adrenals) to fasciculata-like (glucocorticoid-suppressible hyperaldosteronism). The morphology of adrenocortical neoplasia causing primary aldosteronism can also be either predominantly glomerulosa-like or fasciculata-like, in our experience equally often. Varying morphology of APAs is associated with varying responses of aldosterone to angiotensin II. Tumors predominantly fasciculata-like are unresponsive to angiotensin II, whereas those predominantly glomerulosa-like are responsive to angiotensin II. Both subtypes can be seen in a single family. Primary aldosteronism represents a spectrum of genetic disorders resulting in hyperplasia or neoplasia, but all are associated with some degree of autonomy of aldosterone production, independent of the renin-angiotensin system.
Steroids 1995 Jan
PMID:Primary aldosteronism--some genetic, morphological, and biochemical aspects of subtypes. 779 13

Glucocorticoid-remediable aldosteronism (GRA) is a hereditary cause of human hypertension in which aldosterone secretion is regulated by adrenocorticotropin (ACTH). A genetic mutation which causes GRA has recently been identified in our laboratory, a hybrid or chimeric gene fusing nucleotide sequences of the 11 beta-hydroxylase and aldosterone synthase genes. The finding that these chimeric gene duplications are sensitive and specific markers for GRA allows for a simple, direct genetic test for this disorder. In preliminary studies, we found a wide range of blood pressure levels (including normotension) in affected GRA subjects. Studies to data indicate that this is not related to environmental factors such as sodium intake. Another possibility is that chimeric gene expression is variable, with low blood pressure subjects having reduced gene expression. However, the data have not demonstrated differences in steroid levels in subjects with severe versus mild hypertension. In fact, it is likely that the wide range in blood pressure levels in affected subjects involves interaction of other systems which control blood pressure. Preliminary data in two kindreds suggest that blood pressure levels are reciprocally related to levels of urinary kallikrein excretion, supporting the notion that GRA is a hypertension-predisposing syndrome, with the resultant blood pressure the interaction of the gene mutation with other blood pressure regulatory systems. Although GRA is a mineralocorticoid excess state, as evidenced by profoundly suppressed levels of plasma renin activity, we have observed (contrary to the reported literature) that normokalemia is a typical finding. In one large normokalemic pedigree, preliminary findings indicate that these subjects have a normal capacity to excrete potassium.(ABSTRACT TRUNCATED AT 250 WORDS)
Steroids 1995 Jan
PMID:Glucocorticoid-remediable aldosteronism (GRA): diagnosis, variability of phenotype and regulation of potassium homeostasis. 779 15

In the course of my studies of patients with mineralocorticoid hypertensive disorders, unusual presentations led to unexpected findings, both clinically and in steroid etiologies and regulation. Unique circumstances permitted early studies in defining the autonomy of the aldosterone-producing adenoma. A chance referral brought the index case of 17 alpha-hydroxylase deficiency to the research center. New techniques were developed in unusual ways to measure the metabolites of deoxycorticosterone (DOC) using an anesthetic agent. Procedural delays were followed by the surreptitious transfer of a patient from one hospital to the research center after a benign DOC-secreting tumor had been removed. The delay of DOC and all 17-deoxysteroids to respond normally to ACTH stimulation suggested a possible second regulator of DOC. This observation led to studies that demonstrated divergent responses between DOC and cortisol in diverse conditions. An unexplained mineralocorticoid form of hypertension with suppression of renin and aldosterone, but normal DOC production, is seen in licorice intoxication. After licorice was discontinued we documented the delay in the recovery of the inhibited cortisol metabolism (14 days) and renin-angiotensin system (4 months). Licorice extract given to normal subjects on low sodium diets with and without ACTH suppression showed similar results. Other factors in licorice may thus be operative in terms of renin and aldosterone suppression.
Steroids 1995 Jan
PMID:My engagement with steroids: a review. 779 16

We have used several different approaches to study the role of steroids in hypertension, including rodent in vivo models, transgenic animals, and cell culture systems. Using the developing rodent fetus as a model for the ontogeny of regulation of glucocorticoid and mineralocorticoid synthesis, we found that in the developing rodent fetus, expression of both P450scc (cholesterol side chain cleavage) and P450c11 beta (11 beta-hydroxylase) mRNAs occur early, before there is complete organization of the fetal adrenal. Even after the zones of the adrenal are evident, the fetal adrenal still does not express the glomerulosa-specific P450c11AS (aldosterone synthase) mRNA. Stimulating maternal adrenal mineralocorticoid or glucocorticoid synthesis does not affect accumulation of fetal adrenal steroidogenic mRNAs, suggesting that the rodent fetal adrenal may be somewhat transcriptionally quiescent in vivo. We also used two different transgenic rodent systems to study the roles of steroids in hypertension. Using promoter-directed tumorigenesis in transgenic mice, we created transgenic mice that expressed SV40 T antigen under control of the P450scc promoter. Massive adrenal tumors, but not gonadal tumors, developed in all transgenic mice, and cells from these tumors were easily cultured. Using a novel selection tactic, we obtained several adrenocortical cell lines which have distinct characteristics, suggesting they were locked into various stages of differentiation; both expression of steroidogenic mRNAs and the steroids synthesized differ among the lines. Regulation of steroid synthesis and mRNA abundance also varies among cell lines. Several cell lines also express mouse renin, and its synthesis, secretion, and mRNA abundance is also hormonally regulated.(ABSTRACT TRUNCATED AT 250 WORDS)
Steroids 1995 Jan
PMID:Rodent models for studying steroids and hypertension: from fetal development to cells in culture. 779 17

11 beta-Hydroxysteroid dehydrogenase (11-HSD) catalyzes the interconversion of cortisol and cortisone. This activity is postulated to protect the type I (mineralocorticoid) receptor from excessive concentrations of cortisol, allowing aldosterone to function as a mineralocorticoid. An enzyme with 11-HSD activity was isolated from rat liver and the corresponding rat and human cDNA and genomic clones isolated. This enzyme is a member of the "short chain dehydrogenase" family. Using site-directed mutagenesis, it was demonstrated that two highly conserved residues, Tyr-179 and Lys-183, are required for enzymatic function. Elimination of the amino terminus or the two glycosylation sites also destroys enzymatic activity. This may be due to actual disruption of enzymatic function or to effects on intracellular localization or stability of the enzyme. Examination of patients with apparent mineralocorticoid excess, a syndrome of juvenile hypertension thought to represent 11-HSD deficiency, did not reveal any mutations in the gene for this enzyme. There is substantial evidence for a second 11-HSD isozyme with distinct kinetic properties that is expressed in the renal distal tubule and possibly other sites of mineralocorticoid action. Apparent mineralocorticoid excess may involve this enzyme.
Steroids 1995 Jan
PMID:Functional studies of 11 beta-hydroxysteroid dehydrogenase. 779 18

An association between mineralocorticoids and hypertension has been recognized for over 50 years, although the mechanisms involved are not entirely clear. In addition to the hypertension seen in cases of frank mineralocorticoid excess, such as in an aldosterone-producing adenoma, many essential hypertensive patients respond to treatments mitigating mineralocorticoid action, even though circulating levels of these steroids are within normal ranges. It has been a decade since David Bohr hypothesized that a center within the brain, probably in the AV3V area, was responsible for the orchestration of the multiple homeostatic mechanisms controlling blood pressure. It was proposed that the "set point" for such a center was dependent upon intracellular Ca + + and/or another ion content or transport across cell membranes, and was altered by mineralocorticoids and in some forms of genetic hypertension. The focus of this paper is the role of the central nervous system in mineralocorticoid hypertension. The importance of these data resides in the possibility that the central mechanisms involved in mineralocorticoid hypertension may also be operant in the pathogenesis of other forms of hypertension, as well as in the normal control of blood pressure.
Steroids 1995 Jan
PMID:Mineralocorticoid modulation of central control of blood pressure. 779 19

There is emerging evidence that cortisol plays a significantly greater role in human hypertension than previously thought. Apart from the well recognized role of cortisol in the hypertension of Cushing's syndrome, local cortisol excess has been recognized as responsible for rare forms of hypertension such as apparent mineralocorticoid excess and licorice abuse and more recently implicated in the hypertension of chronic renal failure, hypertension related to low birth weight and essential hypertension. Although cortisol-induced hypertension is characterized by sodium retention and volume expansion, studies with synthetic glucocorticoids or sodium restriction suggest that the hypertension is, to a substantial degree, independent of sodium and volume. Increase in cardiac output is not essential for cortisol-induced blood pressure rise but the precise role of increases in total or regional peripheral resistance as a primary mechanism has nto been determined. Increased pressor responsiveness, particularly to catechols, is a prominent feature but whether these changes are sufficient to account for the hypertension remains unclear. There is no evidence for increased sympathetic nervous activity as judged by measurements of plasma catcholamines, neuropeptide-Y, or resting noradrenaline spillover rate. Responses to mental stress or maximal hand-grip are unchanged and baroreflex sensitivity is increased. Octreotide profoundly reduced the elevated plasma insulin concentrations seen with cortisol administration but had no effect on the rise in blood pressure.
Steroids 1995 Jan
PMID:Mechanisms of cortisol-induced hypertension in humans. 779 21

Recognition of the pathogenesis of secondary forms of hypertension is often considered the key to appropriate choice of treatment. We here present the results of a prolonged clinical follow-up (from 1 to 20 years) of a large number of patients with mineralocorticoid excess syndromes (MES), including over 100 patients with primary aldosteronism (PA), 3 cases with dexamethasone-suppressible aldosteronism (DSA), 3 cases of apparent mineralocorticoid excess (AME) Type II, and 4 patients with 17-hydroxylase deficiency (17OHDS). The patients with PA have been divided in two subgroups, one of 69 cases followed between 1973 and 1982, and the second of 37 patients studied between 1983 and 1992; 33 further cases were not evaluated due to poor compliance. In group I, 26 patients underwent surgery (23 unilateral adenoma, 1 primary hyperplasia, 2 bilateral nodular hyperplasia); at 5 years 50% had normal blood pressure, 25% had mild hypertension and 25% had moderate to severe hypertension. Forty-three patients with either adenoma (APA) or idiopathic aldosteronism (IHA) received long-term spironolactone treatment. Among them, 13 required the addition of thiazide and/or beta-blockers, while 13 were switched to an amiloride/thiazide combination (+/- beta blockers) due to side-effects to spironolactone (gynecomastia 6/20 males, menstrual upset or breast pain in 7/23 females). In group II, 12 patients underwent surgery (11 adenoma, 1 primary hyperplasia) with a similar outcome at 3 years as in group I; 25 patients were put on either K canrenoate (11) or Ca++ channel blockers (14) with or without KCl supplementation; in 8 cases these two drugs were combined according to blood pressure levels achieved during the follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)
Steroids 1995 Jan
PMID:Long-term treatment of mineralocorticoid excess syndromes. 779 22


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