Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excessive production of 16beta-hydroxydehydroepiandrosterone (16beta-OH-DHEA) has been suggested as a cause of low-renin essential hypertension. The mineralocorticoid effect of 16beta-OH-DHEA was reported to be one-fortieth that of aldostereone in the rat bioassay. Using kidney slices from adrenalectomized rats, the affinity of 16beta-OH-DHEA and a series of related compounds for mineralocorticoid receptors has been determined. In studies done at both 4 C and 37 C, the affinity of 16beta-OHDHEA for mineralocorticoid receptors was found to be less than 0.1% that of aldosterone (P less than 0.01). Various related steroids and/or potential metabolites similarly showed negligible affinity for the aldosterone receptor. In addition, In addition, 16beta-OHDHEA showed no significant affinity for renal dexamethasone-binding sites (Type II glucocorticoid receptors), corticosterone-binding sites (Type III glucocorticoid receptors), dihydrotestosterone binding sites, or estradiol binding sites. In in vivo competition experiments, the concurrent administration of 50 mug deoxycorticosterone reduced (3H)aldosterone binding to 20-30% of control levels; 50 mug 16beta-OH-DHEA did not compete for (3H)aldosterone binding sites. In in vivo bioassay electrolyte excretion was found-in contrast to that of aldosterone-to be variable. Within a given group, certain rats reproducibly responded to 16beta-OH-DHEA by sodium retention and kaliuresis; in others no response was observed. In vitro binding studies comparing "responders" with "non-responders" demonstrated that in neither group did 16beta-OH-DHEA have significant affinity for renal mineralocorticoid receptors. Accordingly, the mechanism whereby 16beta-OHDHEA produces changes in urinary electrolyte excretion appears independent of classical mineralocorticoid effector mechanisms. The conditions under which this effect is seen await eludication.
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PMID:16Beta-hydroxydehydroepiandrosterone: the dichotomy between renal receptor binding and urinary electrolyte activity. 18 63

Renin-aldosterone profiling was used to classify patients with hypertension: 243 patients with essential hypertension were classified by renin-urinary sodium indexing; 107 were reclassified by response to administration of furosemide and intravenous saline; 45 were further classified by response to a low-sodium diet. Arbitrary "normal ranges" were determined in 89, 32, and 38 volunteers, respectively. Patients with low-renin apparently do not have "high-volume" hypertension. Rather, they show a primary renal abnormality in renin secretion and become relatively deficient in angiotensin II and aldosterone when they are subjected to diuresis. They can maintain aldosterone secretion under normal conditions because their adrenal aldosterone receptor is supersensitive to angiotensin II. No evidence of abnormal sympathetic neural activity was found among the renin subgroups. Renin-aldosterone profiling in current clinical practice seems useful mainly in the detection of patients with curable forms of secondary hypertension. Aldosterone/renin ratios may be particularly helpful in diagnosis when obtained after a patient has undergone expansion or contraction of his extracellular fluid volume.
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PMID:Renin-aldosterone profiling in hypertension. 33 42

11 beta-OHSD is an enzyme complex consisting of 11 beta-DH, converting cortisol to cortisone in man and an 11-keto-reductase performing the reverse reaction. Congenital deficiency of 11 beta-DH should be considered in any child presenting with mineralocorticoid hypertension and suppression of the renin-angiotensin-aldosterone axis. The keystone to diagnosis is the demonstration of a reduced daily production rate of cortisol and an increase in its plasma half-life. In the majority of cases diagnosis can be made from a urinary steroid metabolite profile indicating a high excretion of cortisol relative to cortisone metabolites. Cortisol is the responsible mineralocorticoid, and as such treatment with the pure glucocorticoid dexamethasone will prevent life-threatening hypokalemia, although additional anti-hypertensive drugs are usually required to control blood pressure. Liquorice and carbenoxolone, for years thought to be direct "agonists" of the mineralocorticoid receptor, in fact cause sodium retention through inhibition of 11 beta-DH. The demonstration of 11 beta-DH activity in the vasculature raises the possibility that it locally modules access of glucocorticoids to mineralocorticoid and possibly glucocorticoid receptors in the vessel wall. It remains possible that subtle alterations of this cortisol-cortisone shuttle are responsible for other forms of hypertension which are currently classified under the umbrella diagnosis of essential hypertension.
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PMID:The cortisol-cortisone shuttle and hypertension. 195 52

The activities of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) and 5 beta-reductase were analyzed in 39 normotensive controls and 128 patients with essential hypertension. The activity of 11 beta-HSD was obtained by dividing the 24-hour urinary tetrahydrocortisone by the sum of tetrahydrocortisol (THF) and allotetrahydrocortisol (aTHF), whereas the activity of 5 beta-reductase was obtained by dividing the 24-hour urinary THF by aTHF. The activity of 5 beta-reductase was significantly lower in essential hypertensives compared with normotensive controls (P < 0.05). However, the activity of 11 beta-HSD did not differ between normotensive controls and essential hypertensives. A positive correlation between the activities of 11 beta-HSD and 5 beta-reductase was observed in essential hypertensives (r = 0.60, P < 0.01). Neither 11 beta-HSD nor 5 beta-reductase activity correlated with indices of renal mineralocorticoid receptor activation, which were assessed by determination of plasma potassium and urinary excretion of sodium as well as potassium. Taken together, these results suggest that disturbances of one of the inactivation pathways of cortisol may contribute to the pathogenesis of hypertension.
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PMID:The activities of 5 beta-reductase and 11 beta-hydroxysteroid dehydrogenase in essential hypertension. 770 42

Exogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase (e.g. glycyrrhetinic acid, a constituent of licorice) raise blood pressure by allowing cortisol to activate mineralocorticoid receptors. Endogenous 11 beta-dehydrogenase inhibitors called glycyrrhetinic acid-like factors (GALFs), have been extracted from urine. Increased GALFs could explain the impairment of 11 beta-dehydrogenase in essential hypertension and ectopic ACTH syndrome. We extracted urine on Sep-Paks and quantified GALFs by their inhibition of 11 beta-dehydrogenase bioactivity in microsomes from rat liver. GALFs have no diurnal rhythm and were no different after dexamethasone treatment, in patients with low ACTH, on in 4 patients with ectopic ACTH secretion. In 79 subjects, GALF excretion did not correlate with blood pressure. In 17 subjects, GALF excretion did not correlate with indices of mineralocorticoid receptor activation on 11 beta-dehydrogenase activity. We conclude that GALFs are not ACTH dependent and have no measurable effect on 11 beta-dehydrogenase in vivo. In hypertension associated with impaired 11 beta-dehydrogenase activity GALFs are unlikely to play a pathophysiological role.
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PMID:Endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase in hypertension. 785 15

Mean mineralocorticoid receptor number in mononuclear leukocytes of patients with increased plasma aldosterone (Conn's syndrome, nephrovascular hypertension, preeclampsia) is lower than in controls and this reduction could be the consequence of a down-regulation of the receptor. A similar pattern is evident also in situations of excess of other mineralocorticoids (Cushing's syndrome, chronic licorice ingestion). In essential hypertension 20% of cases have reduced number of mineralocorticoid receptors in mononuclear leukocytes without increase of aldosterone and normal serum potassium. We postulate that in some cases with essential hypertension the reduction of mineralocorticoid receptors is an index of mineralocorticoid excess due to mineralocorticoids other than aldosterone.
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PMID:Regulation of aldosterone receptors in hypertension. 811 17

11 beta-hydroxysteroid dehydrogenase (11 beta HSD) has both dehydrogenase (11 beta DH) and reductase (11 beta R) activities, which catalyse the interconversion of cortisol and cortisone, and prednisolone and prednisone. This enzyme confers specificity on the mineralocorticoid receptor by local oxidation of cortisol to cortisone. Using radiolabelled cortisol 11 beta HSD activity has been shown to be lower in some cases of essential hypertension. This study investigated a novel approach to estimating 11 beta HSD activity in vivo. Plasma steroid kinetics were investigated following oral hydrocortisone (a substrate for 11 beta DH) and prednisone (a substrate for 11 beta R) in five normotensive volunteers after dexamethasone suppression of endogenous steroid production. This approach was evaluated by inducing partial deficiency of 11 beta HSD in the volunteers who took liquorice (to inhibit 11 beta DH) and then carbenoxolone (to inhibit both 11 beta DH and 11 beta R). The ratio of cortisol to prednisolone (formed from prednisone) provided a measure of the activity of both 11 beta DH and 11 beta R. At 75 min after the steroid bolus the ratio increased from 1.1 (0.6-1.3) (median, range) under control conditions to 1.2 (0.8-1.7) after liquorice (P = 0.01, n = 5), and 2.0 (1.3-5.9) after carbenoxolone (P = 0.02, n = 5). It may therefore be applied to the measurement of 11 beta HSD activity in vivo in large numbers of hypertensive patients without the use of radioisotopes.
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PMID:A non-isotopic method for estimating 11 beta hydroxysteroid dehydrogenase activity in vivo. 929 6

The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) inactivates glucocorticoids in the kidney and thus prevents glucocorticoids from occupying the non-selective mineralocorticoid receptor in epithelial tissues. Mutations in the HSD11B2 gene have been found to cause the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disease characterized by severe hypertension. Thus, this locus could also be an ideal candidate involved in the etiology of primary hypertension. We identified a polymorphism in exon 3 characterized by a GAG to GAA transition at codon 178, with the loss of an Alu I restriction site and analysed it in an association study using end-stage renal disease patients, diabetic or essential hypertensive patients and control subjects. Two-hundred and eighty nine subjects and patients were analysed; the genotype was determined by amplification of genomic DNA and subsequent digestion with Alu I restriction enzyme. The prevalence of the Alu I allele was 8.6% in healthy control subjects (n = 116). This prevalence was lower (chi 2 P = 0.035 vs. controls) than the 18.0% in a group of renal transplant patients (n = 61). The corresponding values for patients with diabetes mellitus (n = 25), hypertension (n = 41) and patients on dialysis (n = 46) were 4.0%, 4.8% and 4.3%, respectively. There was no correlation between blood pressure and the marker in non-ESRD subjects. These data indicate the presence of a polymorphic marker in exon 3 of the HSD11B2 gene; this marker is associated with end-stage renal disease but not with essential hypertension in humans.
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PMID:A new polymorphic restriction site in the human 11 beta-hydroxysteroid dehydrogenase type 2 gene. 958 99

There is increasing evidence for important cardiovascular effects of aldosterone via classical mineralocorticoid receptors in the heart. Administration of aldosterone with excess salt produces both cardiac hypertrophy and interstitial cardiac fibrosis in rats, and concomitant administration of potassium canrenoate at a dose that only modestly lowers blood pressure completely blocks the cardiac effects of aldosterone. In the present study, we examined the effect on left ventricular hypertrophy of adding a low dose of the mineralocorticoid receptor antagonist spironolactone (25 mg/d) to an angiotensin-converting enzyme inhibitor (enalapril maleate) in patients with essential hypertension. Eighteen untreated patients with moderate to severe essential hypertension based on the WHO/ISH guidelines participated in this study. Subjects were treated with either an angiotensin-converting enzyme inhibitor alone (group I: 10 patients, 4 men and 6 women, mean age 56 +/- 18 yr) or an angiotensin-converting enzyme inhibitor plus spironolactone (group II: 8 patients, 3 men and 5 women, mean age 59 +/- 14 yr) for 9 mo. Left ventricular mass index, various echocardiographic variables, mean blood pressure, plasma renin activity, and plasma aldosterone concentration before treatment were similar in the two groups. Blood pressure of both groups decreased significantly and similarly after antihypertensive treatment (group I, 136 +/- 9/82 +/- 9 mmHg; group II, 133 +/- 9/85 +/- 10 mmHg). Left ventricular mass index also decreased significantly in both groups (group I, -10.2 +/- 7.1%; group II, -18.1 +/- 6.9%). The extent of reduction was significantly greater in the spironolactone group (group II) (p < 0.05 vs. group I). In group II patients, spironolactone did not cause any side effects during the observation period. We conclude that spironolactone may have beneficial effects on left ventricular hypertrophy in patients with essential hypertension who are receiving an angiotensin-converting enzyme inhibitor.
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PMID:Effects of spironolactone and angiotensin-converting enzyme inhibitor on left ventricular hypertrophy in patients with essential hypertension. 1022 46

11beta-Hydroxysteroid dehydrogenases (11beta-HSD) interconvert cortisol, the physiological glucocorticoid, and its inactive metabolite cortisone in humans. The diminished dehydrogenase activity (cortisol to cortisone) has been demonstrated in patients with essential hypertension and in resistance vessels of genetically hypertensive rats. 11beta-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2) catalyzes only 11beta-dehydrogenation. However, a functional relationship between diminished vascular 11beta-HSD2 activity and elevated blood pressure has been unclear. In this study we showed the expression and enzyme activity of 11beta-HSD2 and 11beta-HSD type 1 (which is mainly oxoreductase, converting cortisone to cortisol) in human vascular smooth muscle cells. Glucocorticoids and mineralocorticoids increase vascular tone by upregulating the receptors of pressor hormones such as angiotensin II. We found that physiological concentrations of cortisol-induced increase in angiotensin II binding were significantly enhanced by the inhibition of 11beta-HSD2 activity with an antisense DNA complementary to 11beta-HSD2 mRNA, and the enhancement was partially but significantly abolished by a selective aldosterone receptor antagonist. This may indicate that impaired 11beta-HSD2 activity in vascular wall results in increased vascular tone by the contribution of cortisol, which acts as a mineralocorticoid. In congenital 11beta-HSD deficiency and after administration of 11beta-HSD inhibitors, suppression of 11beta-HSD2 activity in the kidney has been believed to cause renal mineralocorticoid excess, resulting in sodium retention and hypertension. In the present study we provide evidence for a mechanism that could link impaired vascular 11beta-HSD2 activity, increased vascular tone, and elevated blood pressure without invoking renal sodium retention.
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PMID:11beta-hydroxysteroid dehydrogenase in cultured human vascular cells. Possible role in the development of hypertension. 1033 8


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