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)

In 51 patients with stage II essential hypertension (mild and moderate arterial hypertension), a cross-over study was carried out to estimate the efficacy of the use of ketanserin (KS), an antagonist of serotonin receptors, as compared to the efficacy of placebo, the beta-adrenoblocker propranolol (PP), the diuretic triampur and the beta 1-adrenoblocker prazosin. When administered in the daily dose 40-80 mg, KS produced an antihypertensive effect in 43.7% of the patients. The efficacy of KS administered once or twice a day did not practically differ. The side effects of the monotherapy were unmarked and required the drug withdrawal only in 2 patients (4%). KS produced no material shifts in the biochemical parameters with the exception of a slight increase of the activity of alanine transferase and led to a certain reduction of carbohydrate tolerance. In patients who responded to KS, the drugs belonging to the other three groups appeared effective as well. Both KS combined with triampur and KS combined with PP provided a higher antihypertensive effect than monotherapy with each of those drugs. The combination of KS and prazosin produced the same effect as monotherapy with prazosin.
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PMID:[A cross-over study of ketanserin compared to placebo, beta-adrenergic blockader, diuretic and alpha 1-adrenergic blockader. Cooperative research in the USSR (the Cooperative Program to Study New Preparations in the Prevention of Arterial Hypertension). Working Group (4)]. 168 78

The study was carried out on 23 samples of amniotic fluid taken (by amniocentesis) between 35th and 39th week from pregnant women with arterial hypertension (13 cases of hypertension induced by pregnancy, 5 cases of primary hypertension and 5 cases of hypertension accompanying renal diseases). Seven women undergoing the study gave birth to newborns with symptoms of delayed intrauterine growth below 16 centiles (group examined), 16 mothers gave birth to eutrophic babies (control group). The amniotic fluid of the two groups was studied for the following biochemical indexes: alanine and aspartate aminotransferase alkaline total and thermostabile phosphatase, ceruloplasmin, alpha-amylase, general protein, beta-lipoproteins, cholesterol, uric acid, urea and creatinine. No significant changes were found in the parameters determined between the group examined and the control group.
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PMID:[Biochemical studies of the amniotic fluid in arterial hypertension in relation to intrauterine growth retardation. I. Parameters of the proteins, lipids, enzymes and renal maturity]. 263 82

To evaluate the role of the renin-angiotensin system and sodium depletion in the hypotensive response to 1-sarcosine-8-alanine-angiotensin II (saralasin), 15 male patients with essential hypertension were studied on a diet containing 120 mEq of sodium and 100 mEq of potassium per day. After a 5-day control period, all subjects had a mild pressor response to the saralasin infusion (p less than 0.01). After 5 days of the diuretic metolazone (5 mg/day), eight of the 15 patients had a vasodepressor response; these responders had a significantly greater increase in plasma renin activity and angiotensin II concentrations than did the non-responders. Sodium deficit differed markedly (p less than 0.001) between the two groups (361 +/- 121 mEq (SD) vs 52 +/- 26 mEq sodium, respectively). The addition of spironolactone (400 mg/day) for 5 days resulted in saralasin responsiveness in all but two patients, both of whom had small sodium deficits. Thus, variability in the natriuretic response to diuretics may affect saralasin testing and limit its clinical utility.
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PMID:Angiotensin II, plasma renin and sodium depletion as determinants of blood pressure response to saralasin in essential hypertension. 698 3

The renin-angiotensin-aldosterone system plays an important role in large artery structure and blood pressure homeostasis. Among the genes coding for different components of this system, the aldosterone synthase (CYP11B2) gene could play an important role, but has been less investigated. We examined the role of two variations of the aldosterone synthase gene (CYP11B2), one located in the promoter of the gene, T-344C, the other in the 7th exon, the T4986C (Val/Ala), on plasma levels of renin and aldosterone, blood pressure, and arterial stiffness in subjects with essential hypertension. Subjects of European origin (n = 216) were examined during a 1-day hospitalization. Treatment, if any, was interrupted for at least 21 days before. Arterial stiffness was evaluated by measuring pulse wave velocity. Renin and aldosterone levels were evaluated by using a radioimmunoassay. The two polymorphisms were in complete linkage disequilibrium, as suggested by the presence of only three haplotypes in this population (T-344T4986, T-344C4986, and C-344T4986). The mean age and blood pressure values were similar in the different genotypes. Presence of the -344C allele was associated with elevated levels of plasma aldosterone: 90 +/- 8 pg/mL for TT (n = 67), 110 +/- 6 pg/mL for TC (n = 107), and 129 +/- 10 pg/mL for CC (n = 42) (test of codominant effect, P < .002 after adjustment for age and 24-h Na+ urine excretion). Pulse wave velocity was also increased in the -344C allele carriers: 11.3 +/- 0.4 m/sec, 12.7 +/- 0.3 m/sec, 12.0 +/- 0.5 m/sec in the TT, TC, and CC genotypes, respectively. No association was found between the T4986C polymorphism and the studied variables. In patients with essential hypertension, a variant on the promoter region of the aldosterone synthase gene is associated with significant differences in plasma aldosterone levels and arterial stiffness. These differences are not associated with variations in blood pressure levels.
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PMID:Genetic determination of plasma aldosterone levels in essential hypertension. 968 48

CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) are 93% identical mitochondrial enzymes that both catalyze 11beta-hydroxylation of steroid hormones. CYP11B2 has the additional 18-hydroxylase and 18-oxidase activities required for conversion of 11-deoxycorticosterone to aldosterone. These two additional C18 conversions can be catalyzed by CYP11B1 if serine-288 and valine-320 are replaced by the corresponding CYP11B2 residues, glycine and alanine. Here we show that such a hybrid enzyme also catalyzes conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. These latter two steroids are present at elevated levels in individuals with glucocorticoid suppressible hyperaldosteronism (GSH) and some forms of primary aldosteronism. Their production by the recombinant CYP11B enzyme is enhanced by substitution of further amino acids encoded in exons 4, 5, and 6 of CYP11B2. A converted CYP11B1 gene, containing these exons from CYP11B2, would be regulated like CYP11B1, yet encode an enzyme with the activities of CYP11B2, thus causing GSH or essential hypertension. In a sample of 103 low renin hypertensive patients, 218 patients with primary aldosteronism, and 90 normotensive individuals, we found a high level of conversion of CYP11B genes and four cases of GSH caused by unequal crossing over but no gene conversions of the type expected to cause GSH.
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PMID:Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. 981 82

We investigated the relationship between peroxisome proliferator-activated receptor gamma (PPARgamma) Pro12Ala substitution and insulin resistance in subjects with normal insulin secretory capacity, since it has been reported that PPARgamma may affect not only insulin resistance but also insulin secretion. We examined 81 Japanese male patients with untreated essential hypertension using the glucose clamp technique. We found 77 subjects with Pro/Pro and 4 subjects with Pro/Ala genotype, and the glucose disposal rate was not significantly different between the two groups. Fasting plasma glucose, fasting immunoreactive insulin, total cholesterol, HDL cholesterol, and triglyceride were not significantly different between the two groups. There were also no significant differences between groups in homeostasis model assessment of insulin resistance (HOMA-R) values, area under the curve (AUC) for plasma glucose, or AUC for IRI in 75 g OGTT. Because insulin sensitivity is likely to be determined by polygenic factors, we also investigated beta3 adrenergic receptor Trp64Arg polymorphism as a possible determinant of insulin resistance. In conclusion, no significant association was observed between PPARgamma2 substitution and insulin sensitivity in the present cohort of Japanese hypertensive patients.
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PMID:PPARgamma2 pro12Ala polymorphism and insulin resistance in Japanese hypertensive patients. 1192 22

Spirolactones harboring various C7 substituents are aldosterone antagonists, and some of them are used in the treatment of essential hypertension. They bind to the human mineralocorticoid receptor and render it transcriptionally inactive. Structural analysis using a three-dimensional homology model of the ligand-binding domain of the receptor has revealed that the Met852 residue of the ligand-binding cavity faces the C7 substituent of spirolactones. We therefore tested the binding capacities of C7-substituted spirolactones in an in vitro system expressing either the mutant receptor, in which Met852 was replaced by alanine, or the wild-type receptor. The M852A mutation had almost no effect on the binding of C7-substituted spirolactones to mineralocorticoid receptor but dramatically reduced the capacity of the receptor to bind steroids with no C7 substituent (aldosterone, cortisol, deoxycorticosterone, and canrenone). cis-trans Cotransfection assays revealed that two spirolactones characterized by having a propyl group [7 alpha-propyl-17 alpha-hydroxy-3-oxo-preg-4-ene-21-carboxylic acid gamma-lactone (RU26752)] or a thioacetyl group (spironolactone) at the C7 position acquired agonist properties when bound to the mutant receptor. In contrast, mexrenone and eplerenone, both of which harbor an acetyl group at the C7 position, retained antagonist properties when bound to the mutant receptor. Overall, these findings indicate that Met852 acts as an organizer residue that plays two major roles: 1) it allows steroids with no substituent at the C7 position to be accommodated within the ligand-binding cavity; and 2) it is involved in the steric hindrance that prevents C7-substituted spirolactones from folding the receptor in its active state.
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PMID:The Met852 residue is a key organizer of the ligand-binding cavity of the human mineralocorticoid receptor. 1571 62

The adipocyte-derived leucine aminopeptidase (A-LAP)/ER aminopeptidase-1 is a multi-functional enzyme belonging to the M1 family of aminopeptidases. It was reported that the polymorphism Lys528Arg in the human A-LAP gene is associated with essential hypertension. In this study, the role of Lys528 in the enzymatic activity of human A-LAP was examined by site-directed mutagenesis. Among non-synonymous polymorphisms tested, only Lys528Arg reduced enzymatic activity. The replacement of Lys528 with various amino acids including Ala, Met, His and Arg caused a significant decrease in the enzymatic activity. Molecular modeling of the enzyme suggested that Lys528 is located near the entrance of the substrate pocket. These results suggest that Lys528 is important for maximal activity of A-LAP by maintaining the appropriate structure of the substrate pocket of the enzyme. The reduced enzymatic activity of A-LAP may cause high blood pressure and the observed association between the polymorphism and hypertension.
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PMID:Reduced activity of the hypertension-associated Lys528Arg mutant of human adipocyte-derived leucine aminopeptidase (A-LAP)/ER-aminopeptidase-1. 1651 16

Major advances are being made in identifying the structure and behaviour of regulatory cascades that control the activity of cation-Cl(-) cotransporters and certain Na(+), K(+) and Cl(-) channels. These transporters play key roles in regulating arterial blood pressure as they are not only responsible for NaCl reabsorption in the thick ascending limb and distal tubule of the kidney, but are also involved in regulating smooth muscle Ca(2+) levels. It is now apparent that defects in these transporters, and particularly in the regulatory cascades, cause some monogenetic forms of hypertension and may contribute to essential hypertension and problems with K(+) homoeostasis. Two families of kinases are prominent in these processes: the Ste-20-related kinases [OSR1 (oxidative stress-responsive kinase 1) and SPAK (Ste20/SPS1-related proline/alanine-rich kinase)] and the WNKs [with no lysine kinases]. These kinases affect the behaviour of their targets through both phosphorylation and by acting as scaffolding proteins, bringing together regulatory complexes. This review analyses how these kinases affect transport by activating or inhibiting individual transporters at the cell surface, or by changing the surface density of transporters by altering the rate of insertion or removal of transporters from the cell surface, and perhaps through controlling the rate of transporter degradation. This new knowledge should not only help us target antihypertensive therapy more appropriately, but could also provide the basis for developing new therapeutic approaches to essential hypertension.
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PMID:Cotransporters, WNKs and hypertension: important leads from the study of monogenetic disorders of blood pressure regulation. 1722 94

In order to determine whether Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) gene contributes to susceptibility to primary hypertension and metabolic lipid disorders, 482 unrelated subjects from Inner Mongolia were studied, including 137 healthy normotensive (controls) and 345 hypertensive subjects. PCR-RFLP was used to determine the genotypes of Pro12Ala variants of the PPARgamma2 gene, and direct sequencing was used to check the results. The frequency of the Ala allele was lower in patients with hypertension (1.3%) than in controls (3.6%). The incidence of the Ala allele was significantly lower in patients with hypertension (P = 0.018) and in those with elevated blood lipids (P = 0.040), compared to the control group. Total plasma cholesterol, triglycerides and high-density lipoprotein cholesterol were significantly higher (P < 0.05), and low-density lipoprotein cholesterol was significantly lower (P < 0.05) in primary hypertension patients than in the control group. We conclude that the Ala allele is involved in genetic susceptibility to hypertension and metabolic lipid disorders in the Han population of Inner Mongolia.
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PMID:Association of the PPARgamma2 gene Pro12Ala variant with primary hypertension and metabolic lipid disorders in Han Chinese of Inner Mongolia. 2062 56


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