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)

Liddle's syndrome, a rare cause of hypokalemic hypertension, is characterized by a renal tubular sodium channel defect resulting in excessive sodium absorption and concomitant potassium wasting. In this disorder, although the clinical manifestations resemble primary aldosteronism, serum and urine aldosterone are suppressed. The syndrome is transmitted in an autosomal dominant pattern. It has been reported previously in white and oriental populations but not in the black individuals. We identified four patients (two of whom are black) in our nephrology clinic, with severe hypokalemic hypertension not correctly diagnosed for several years. All patients underwent an extensive work-up for secondary hypertension because of persistent severe hypertension (average blood pressure, 210/130 mm Hg) despite high-dose multi-drug therapy. Primary aldosteronism was excluded because of low serum aldosterone. Cushing's syndrome, pheochromocytoma, renal artery stenosis, and enzymatic deficiencies of cortisol synthesis (11 beta-hydroxylase, 17 alpha-hydroxylase, 5 beta-reductase, and 11 beta-hydroxysteroid dehydrogenase) were ruled out with extensive endocrine and radiologic studies. Once the diagnosis of Liddle's syndrome was suspected, all patients were treated with either triamterene or ameloride, with resolution of hypokalemia and correction of hypertension occurring within 5 to 7 days. Our findings suggest that Liddle's syndrome can occur in the black population. Although the actual incidence of this syndrome remains unknown, it may be significantly more common than we are led to believe since it is inherited in a Mendelian pattern. Whether there is a subset of low-renin, salt-sensitive black hypertensive patients who have the same or similar sodium channel defect remains to be elucidated.
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PMID:Liddle's syndrome, an underrecognized entity: a report of four cases, including the first report in black individuals. 777 90

The clinical manifestations associated with hyperandrogenism, such as hirsutism and acne, are disturbing to most patients. In addition to correcting androgen-related problems, concerns such as contraception or other metabolic problems (for example, lipid/lipoprotein abnormalities, diabetes, hypertension) associated with these disorders and the effects of unopposed estrogen on the endometrium also need to be considered. Oral contraceptives are a therapeutic modality that may address these multiple problems. The potential mechanisms of action by which oral contraceptives correct excess androgen states include gonadotropin suppression, reduction of circulating androgens, increased androgen binding, suppression of adrenal androgen secretion and inhibition of 5 alpha-reductase, and androgen receptor binding. In normal women, there is good evidence that these actions occur with the use of oral contraceptives. Among women with anovulatory hyperandrogenic states, such as polycystic ovary syndrome, the response to oral contraceptives in each of these areas is somewhat more variable. However, oral contraceptive preparations that are more estrogen dominant appear to produce many of the desired effects. From a clinical standpoint, 60-100% of women with hirsutism improve on oral contraceptives; acne shows improvement in a high percentage of women as well. The use of oral contraceptives also reduces the risk of endometrial hyperplasia that may be associated with anovulatory states. Finally, current low-dose preparations containing the newer progestins (for example, norgestimate and desogestrel) appear to be either neutral, or perhaps beneficial, with respect to their metabolic impact.
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PMID:The role of oral contraceptives in the treatment of hyperandrogenic disorders. 782 33

We compared corticosteroid metabolite excretion rates and patterns in a group of 68 subjects with untreated essential hypertension and a matched group of 48 normotensive control subjects. The ratio of tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone and the ratio of allotetrahydrocortisol to tetrahydrocortisol were significantly higher in the hypertensive group. This is qualitatively similar to the situation found in patients with the syndrome of apparent mineralocorticoid excess or subjects treated with licorice or carbenoxolone where hypertension is known to arise from deficiencies of 11 beta-hydroxysteroid dehydrogenase and 5 beta-reductase activities. The equivalent ratios for corticosterone metabolites were not different between groups, but total corticosterone metabolite excretion was higher in the hypertensive group. Plasma cortisol levels were lower in hypertensive than in control subjects, but corticosterone levels were higher. This evidence supports a previous suggestion that the activities of these two enzymes may be reduced in essential hypertension, but the contribution of these changes to hypertension is not known.
Hypertension 1995 Jan
PMID:Evidence of coexisting changes in 11 beta-hydroxysteroid dehydrogenase and 5 beta-reductase activity in subjects with untreated essential hypertension. 784 56

The coexistence of hypercholesterolemia and hypertension often requires concomitant drug treatments. Thus, it is interesting to evaluate the efficacy, safety, and tolerability of the new lipid-lowering agent fluvastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)-reductase inhibitor, in patients receiving concomitant antihypertensive/cardiovascular drug treatments. A retrospective analysis was based on data from controlled clinical trials in which 1815 patients were treated with fluvastatin and 783 patients received placebo. The daily dose of fluvastatin was > or = 20 mg. At least one of the following drug treatments was taken by 445 of the fluvastatin-treated patients (24.5%) and 181 of those receiving placebo (23.1%): beta-adrenergic-receptor blockers (fluvastatin: n = 182; placebo: n = 84); diuretics (fluvastatin: n = 168; placebo: n = 72); calcium antagonists (fluvastatin: n = 161; placebo: n = 69); and angiotensin-converting enzyme (ACE) inhibitors (fluvastatin: n = 101; placebo: n = 30). The majority of patients received monotherapy with one of the above-mentioned antihypertensive agents (fluvastatin: 69%; placebo: 65%). The efficacy of fluvastatin in modifying low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol and triglyceride levels was not consistently different in patients taking a given antihypertensive compared with the overall group and the patients not taking the antihypertensive agent. In patients taking fluvastatin and antihypertensives, confirmed (measured at two consecutive occasions) increases more than three times the upper limit of normal in aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) occurred in only two patients. One case involved the concomitant use of a beta-blocker (ASAT and ALAT) and the other a diuretic (ALAT).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Safety and tolerability of fluvastatin with concomitant use of antihypertensive agents. An analysis of a clinical trial database. 790 74

11 beta-Hydroxysteroid dehydrogenase (11-HSD) catalyzes the conversion of cortisol to cortisone and corticosterone to 11-dehydrocorticosterone. This activity may be required to confer normal ligand specificity upon the mineralocorticoid receptor. Although an isozyme of 11-HSD was previously isolated from rat liver, a different isozyme is apparently expressed in mineralocorticoid target tissues. We isolated a sheep kidney cDNA clone encoding this isozyme by expression screening using Xenopus oocytes. The cDNA is 1.8 kilobase pairs in length and encodes a protein of 427 amino acid residues with a predicted M(r) of 46,700. When expressed in oocytes, this enzyme functions as an NAD(+)-dependent 11 beta-dehydrogenase with very high affinity for steroids, but it has no detectable reductase activity. It is 37% identical in amino acid sequence to an NAD(+)-dependent isozyme of 17 beta-hydroxysteroid dehydrogenase but only 20% identical to the NADP(+)-dependent liver isozyme of 11-HSD. It is expressed at high levels in the kidney and adrenal and at lower levels in the colon. The corresponding gene is present in a single copy in the sheep genome. In humans, this gene is a candidate locus for the syndrome of apparent mineralocorticoid excess, a form of hypertension postulated to result from 11-HSD deficiency in mineralocorticoid target tissues.
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PMID:NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase. Cloning and characterization of cDNA from sheep kidney. 792 4

The expression of mineralocorticoid receptors (MR) and 11 beta-hydroxysteroid dehydrogenase (11HSD) activity has been investigated in the epidermis and appendages of the human skin. Aldosterone binds to MR and regulates sodium transport in tight epithelia. Mineralocorticoid selectivity is achieved through coexpression of MR and 11HSD, which prevents permanent MR occupancy by glucocorticoids. Some forms of hypertension may involve abnormalities of MR and/or 11HSD. However, their direct assessment in humans remains difficult in the kidney or colon. This led us to explore this system in human skin easily accessible to biopsy. In situ hybridization with specific MR complementary ribonucleic acid probes and immunohistochemistry using three different anti-MR antibodies showed that MR was expressed at both the messenger ribonucleic acid and protein levels in the keratinocytes of the epidermis, in the sweat and sebaceous glands, and in the hair follicles. A significant 11HSD activity was found in isolated sweat gland ducts (5 fmol/3-mm length.10-min incubation with 10 nmol/L corticosterone as substrate) and was very low in the epidermis. In both structures, reductase activity was 10 times lower than that of dehydrogenase. Studies on the cofactor specificity of the enzyme showed a nicotinamide-adenine-dinucleotide preference in sweat glands, contrasting with a nicotinamide-adenine-dinucleotide phosphate dependence in epidermis. Human skin appears as a new target for aldosterone because it coexpresses MR and 11HSD. Our findings present the possibility to explore the functionality of the MR system in human tissue and its implications in various physiopathological situations.
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PMID:Human skin as target for aldosterone: coexpression of mineralocorticoid receptors and 11 beta-hydroxysteroid dehydrogenase. 796 26

Patients with primary hypercholesterolemia and established coronary artery disease (CAD) with additional associated risk factors for atherosclerosis are considered for lipid-lowering drug therapy at lower levels of total and/or low-density lipoprotein cholesterol (LDL-C) than are patients with isolated hypercholesterolemia. As regards prevention of cardiovascular morbid events, high-risk patients are expected to receive the most benefit from lipid-lowering treatment. Thus, it is of interest to evaluate the efficacy, safety, and tolerability of the new lipid-lowering agent fluvastatin, a new, wholly synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, in patients at high risk. A retrospective analysis was based on data from controlled clinical trials in which 1,815 patients were treated with fluvastatin at a daily dose of > or = 20 mg and 783 patients received placebo. Of the fluvastatin-treated patients, 328 (18.1%) had CAD compared with 136 (17.4%) patients taking placebo. Within these groups, 186 fluvastatin patients and 75 placebo patients had at least one of the following additional risk factors: hypertension, obesity, and/or fasting blood glucose levels above the upper limit of normal (ULN). Patients at high risk, as defined above, were compared with patients without CAD or any risk factors (fluvastatin, n = 837; placebo, n = 375). The effect of 40 mg of fluvastatin on LDL and high-density lipoprotein cholesterol (HDL-C), and triglycerides tended to be enhanced in patients at high risk (HR) compared with those at low risk (LR). Changes from baseline in HR patients were: LDL-C, -26.6%; HDL-C, 6.4%; triglycerides, -13%. Changes in LR patients were: LDL-C, -24.8%; HDL-C, 4.4%; triglycerides, -6%. All of these changes were highly significant (0.001 < p < 0.01). No patient in the HR group experienced a confirmed (measured on two consecutive occasions) increase > 3 x ULN in aspartate (ASAT) or alanine (ALAT) aminotransferases, nor any notable increases in creatine kinase > 10 x ULN. The tolerability of fluvastatin, as assessed by analysis of adverse events, was not consistently influenced by concomitant high risk. This exploratory analysis of the efficacy and safety profile of fluvastatin in patients at high risk for atherosclerosis suggests that such treatment is efficacious, safe, and well tolerated. The observed tendency toward an improved efficacy in the high-risk group will need further confirmation using data from prospective studies in such patients.
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PMID:Fluvastatin in primary hypercholesterolemia: efficacy and safety in patients at high risk. An analysis of a clinical trial database. 801 71

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) catalyzes the conversion of cortisol to cortisone and plays an important role in the mammalian kidney in regulating cortisol access to the mineralocorticoid receptor. 11 beta HSD-deficient states, such as the syndrome of apparent mineralocorticoid excess (AME), and licorice ingestion result in hypertension in which cortisol acts as a mineralocorticoid. A gene and complementary DNA sequence encoding type I human 11 beta HSD have been described, but this gene is normal in patients with AME. Separate 11 beta HSD isoforms have been described in rat and rabbit kidney, but 11 beta HSD has not been characterized in human kidney. Kinetic analysis of 11 beta HSD activity in human fetal kidney microsomes revealed only a high affinity isoform (apparent Km, 60 nmol/L for cortisol, 13 nmol/L for corticosterone), the activity of which was exclusively nicotinamide adenine dinucleotide (NAD) dependent. No 11-oxo-reductase activity was seen in either renal homogenates or microsomes. 11 beta-Dehydrogenase activity was inhibited by glycyrrhetinic acid (the active ingredient in licorice) in a competitive fashion, with a Ki of 8.7 nmol/L. This 11 beta HSD isoform was clearly distinct from the type I h11 beta HSD enzyme, in that COS-1 cells transfected with type I h11 beta HSD complementary DNA expressed a low affinity (apparent Km, 2.13 mumol/L) isoform, the activity of which was NAD phosphate dependent. 11-Oxo-reductase activity was present in intact transfected cells (apparent Km for cortisone, 0.36 mumol/L), but not in cell lysates. In contrast to the cloned, low affinity, type I h11 beta HSD enzyme, human kidney contains a high affinity NAD-dependent 11 beta HSD isoform. It seems probable that this isoform is responsible for protecting the renal mineralocorticoid receptor from glucocorticoid excess, and a defect in its activity may explain AME.
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PMID:Human kidney 11 beta-hydroxysteroid dehydrogenase is a high affinity nicotinamide adenine dinucleotide-dependent enzyme and differs from the cloned type I isoform. 804 66

Patients with insulin-dependent diabetes mellitus (IDDM) are at an increased risk for coronary heart disease. Factors that may enhance the risk include dyslipidemia, hypertension, and hyperglycemia. Until recently, the importance of dyslipidemia in IDDM was ignored because the prevalence of high cholesterol levels was similar to that in the nondiabetic population. However, unique abnormalities in the composition and metabolism of lipoproteins may occur in IDDM patients. Management of IDDM patients, therefore, should include control of dyslipidemia as well as control of hyperglycemia and hypertension. The therapeutic goals for serum cholesterol reduction in IDDM patients should be lower than that for nondiabetic patients, and the goals for children should be even lower than those for adults. Both very-low-density lipoprotein and low-density lipoprotein (LDL) levels should be the targets for therapeutic interventions and not just the LDL alone. Because of the unique features of dyslipidemia in IDDM patients, the therapeutic options may not be the same as that for nondiabetic patients. Hyperglycemia should be controlled by matching daily energy intake and activity with appropriately timed doses of insulin. The diets should be low in saturated fats and cholesterol. If dyslipidemia persists despite diet and hyperglycemia management, drug therapy may be initiated. For IDDM children > or = 10 years of age with elevated LDL-cholesterol levels, the first-line therapy should be bile acid sequestrants. For adults with IDDM, bile acid sequestrants also may be the drugs of choice, particularly for normotriglyceridemic patients. Nicotinic acid therapy should be avoided. Among other drugs, hydroxymethyl-glutaryl coenzyme A reductase inhibitors may be preferable for patients with elevated LDL cholesterol and borderline hypertriglyceridemia. Fibric acid derivatives should be used for markedly hypertriglyceridemic patients. The role of probucol for dyslipidemia in IDDM patients is not clear.
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PMID:Management of dyslipidemia in IDDM patients. 817 52

The syndrome of apparent mineralocorticoid excess (AME) is currently understood to reflect impaired peripheral metabolism of cortisol, which is then able to activate the non-selective mineralocorticoid (MC) receptor. The failure of glucocorticoid inactivation at the MC target tissue level in AME involves abnormal activity of 11 beta-hydroxysteroid dehydrogenase, with impaired conversion of cortisol to cortisone, and also of 5 beta-reductase. We have discovered a new form of AME (Type II) in four patients with the same clinical picture of hypertension, hypokalemia, and suppressed renin-angiotensin-aldosterone system, but in whom this conversion seems either to be normal (since cortisol to cortisone metabolite ratio is normal) or to be impaired in both directions, leaving the ratio unchanged. Both types are characterized by a profound decrease in cortisol turnover quotient and Ring A reduction constant. Short-term dexamethasone treatment is effective in correcting the MC-derived abnormalities, while in the long term the addition of other antihypertensive drugs may be required to control the severity of hypertension.
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PMID:Apparent mineralocorticoid excess type II. 819 52


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