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)

We have isolated a hamster adrenal P45OC11 cDNA which shared 90 and 84% homology, respectively, with the nucleotide sequence and the amino acid sequence of the hamster adrenal P450aldo. Both P450C11 and P450aldo cDNA coding sequences were inserted in the plasmid pBluescript SK, transcribed and then translated using a rabbit reticulocyte system in the presence of [35S]methionine. The reaction products were immunoprecipitated with an anti-bovine P450C11 antibody for P450C11 and with an anti-hamster P450aldo for P450aldo. Immunoprecipitated proteins were analyzed by polyacrylamide gel electrophoresis. A single 35S-labeled protein band was detected for P450C11 and for P450aldo, respectively. P450C11 and P450aldo cDNAs were then both inserted into the expression vector pCMV5 containing a viral sequence specific for the attachment of ribosomes to mRNA. These constructions were transfected in COS-1 cells. 24 h after transfection, the presence of P450C11 and P450aldo mRNAs was determined by Northern blot analysis. In a time study experiment we found that P450C11 transformed the labeled-steroid into [14C]corticosterone, [14C]19-OH-deoxycorticosterone and [14C]18-OH-deoxycorticosterone in ratios of 1:1.11:0.07, after 2 h of incubation; no [14C]aldosterone could be detected. Cells transfected with plasmids harboring the P450aldo cDNA transformed [14C]deoxycorticosterone to [14C]corticosterone, [14C]aldosterone, [14C]18-OH-corticosterone, [14C]18-OH-deoxycorticosterone, [14C]19-OH-deoxycorticosterone and [14C]11-dehydrocorticosterone in ratios of 1:0.25:0.45:0.04:0.04:0.04 after 12 h of incubation. These results indicate that one P450 catalyzes the ultimate step of glucocorticoid formation and a separate P450 is involved in the final steps of aldosterone formation in hamster adrenals. The capacity of the hamster adrenal P450C11 to hydroxylate at positions 11beta and 19 in nearly equal ratio makes this animal an excellent model to study the mechanism of synthesis and inhibition of 19-OH-deoxycorticosterone, the precursor of 19-nor-deoxycorticosterone, a very potent mineralocorticoid involved in the development of essential hypertension.
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PMID:The hamster adrenal cytochrome P450C11 has equipotent 11beta-hydroxylase and 19-hydroxylase activities, but no aldosterone synthase activity. 864 11

Alterations in Ca2+ homeostasis have been proposed to be a primary factor in the pathogenesis of essential hypertension. In this disease increased intracellular Ca2+ levels have repeatedly been reported in various cell types. Because of its prominent role in cellular calcium homeostasis in vascular smooth muscle cells, modifications of the plasma membrane Ca2+-ATPase (PMCA) pump have been suggested to contribute to an increased contractile tone of small blood vessels. This pump is a calmodulin-dependent Ca2+-ATPase that ejects Ca2+ from the cytosol into the extracellular space. Recently a mutational thymidine (T)-->guanosine (G) transversion in isoform 1 of the PMCA has been identified resulting in the substitution of a methionine (Met) by an arginine (Arg) at amino acid position 267 in a highly conserved domain of the pump molecule. The aim of our study was to determine the prevalence of this polymorphism in the normal population and to investigate whether the Met-267 Arg occurs more frequently in patients with essential hypertension than in normotensives. To detect the mutational change we modified a method based on the technique of amplification-created restriction sites (ACRS) using three base exchanges in the diagnostic primer. Samples from 100 hypertensive and 60 normotensive subjects revealed a thymidine at nucleotide position 981. These data suggest that ACRS is feasible in spite of extensive primer modifications (e.g., three mismatched bases) in contrast to the previously used one or two and may therefore be conceptually suitable to detect almost any base changes in the genome. The described T-->G transversion is a rare polymorphism and is presumably not related to common forms of essential hypertension.
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PMID:Investigation of the Met-267 Arg exchange in isoform 1 of the human plasma membrane calcium pump in patients with essential hypertension by the amplification-created restriction site technique. 902 Mar 86

The XL-I form of xenobiotic-metabolizing medium-chain fatty acid:CoA ligase was purified to apparent homogeneity from bovine liver mitochondria. The procedure gave rise to a 435-fold increase in specific activity, with a yield of 12%. The enzyme eluted from a gel filtration column as a single peak with an apparent molecular weight of ca. 55,000. It ran as a single band on SDS-polyacrylamide gel electrophoresis (SDS-PAGE) which had an apparent molecular weight of 62 kDa. N-Terminal sequence analysis of the enzyme gave no sequence, which indicates a blocked N-terminus. To obtain sequence data, the enzyme was cleaved at methionine residues using CNBr. The resulting peptides were separated by SDS-PAGE. The cleavage pattern revealed two large peptides with molecular weights of ca. 10,000 and 12,000, plus several smaller peptides of lesser intensity. The 10 kDa and 12 kDa peptides were electroblotted onto Trans-Blot, and then sequenced directly from the blot. The N-terminal sequences of these two peptides are presented. When compared with known sequences it was discovered that these two peptides both have high homology with regions of the SA essential hypertension protein. This suggests a role for a carboxylic acid:CoA ligase in the control of high blood pressure.
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PMID:Purification and partial sequencing of the XL-I form of xenobiotic-metabolizing medium chain fatty acid:CoA ligase from bovine liver mitochondria, and its homology with the essential hypertension protein. 921 7

Despite advances in the understanding of monogenic hypertensive disorders, the genetic contribution to essential hypertension has yet to be elucidated. The position of tyrosine hydroxylase (TH) as the rate-limiting enzyme in catecholamine biosynthesis renders it a candidate gene for the etiology of hypertension. The TH gene contains an internal, informative microsatellite marker (TCAT)9. We undertook (1) an association study in a group of well-characterized hypertensive subjects (HT) and control subjects (NT) and (2) an affected sibling pair (ASP) study using sibships from our local family practices. Two hundred twenty-seven hypertensive patients (pretreatment systolic/diastolic blood pressure [BP] range, 139/94 to 237/133 mm Hg; age range [SD], 30 to 71 [8.5] years) were age- and gender-matched with 206 control subjects (BP range, 96/62 to 153/86 mm Hg; age range, 40 to 70 [7.6] years). One hundred thirty-six affected sibling pairs were recruited for our linkage study; 73 young borderline hypertensive subjects (YHT) (pretreatment BP range, 123/76 to 197/107 mm Hg; age range, 20 to 51 [9.4] years) were also recruited in whom recent pretreatment norepinephrine and epinephrine levels were available. All subjects were white. The TH short tandem repeat (STR) was amplified using specific polymerase chain reaction cycling conditions in all subjects, and products were run on an ABI 373A sequencer. TH alleles were assigned using Genescan and Genotyper software. Five TH alleles were present and designated A through E. Allele frequencies in the NT population (A, B, C, D, and E: 0.24, 0.17, 0.13, 0.20, and 0.26, respectively) were significantly different from the HT cohort (A, B, C, D, and E: 0.24, 0.19, 0.11, 0.11, and 0.35, respectively), P<0. 0005 (Pearson's test chi2=19.94; 4 df). The E allele appears overrepresented in the HT group, whereas the D allele appears to be overrepresented in the NT group. TH genotype frequencies were also significantly different between cases and controls (P<0.001; chi2=36. 57; 14 df). Both groups were in Hardy-Weinberg proportion. There was a trend (NS) for the D allele to be associated with a lower BP when BP was analyzed as a quantitative trait. ASP linkage data was analyzed using Splink, a nonparametric program. Expected values for sharing 0, 1, and 2 alleles (Z0, Z1, and Z2, respectively) may be expected to be 25%, 50%, and 25%, respectively, by chance (assuming identity by descent). These probabilities were calculated by Splink as 34, 68, and 34, respectively, and compared with observed values of 36.8, 67.9, and 31.3, respectively; thus, there was no excess sharing of TH alleles among affected sibling pairs (P=0.59; logarithm of odds ratio score, 0.0). TH allele frequencies in our YHT group (A, B, C, D, and E: 0.24, 0.20, 0.12, 0.15, and 0.29, respectively) were similar to those of our NT cohort (P>0.05). There was a trend for lower pretreatment plasma norepinephrine levels with the D allele in this YHT cohort. A common and potentially functional variant at codon 81(Val-->Met) within exon 2 of the TH gene (which we show to be in linkage disequilibrium with TH-STR) was also typed in our YHT but did not associate with catecholamine levels and is therefore unlikely to account for our findings with D and E TH-STR. In conclusion, the TH locus strongly associates with essential hypertension in a case-control model using well-characterized hypertensive and control groups. An ASP linkage model was negative, presumably because of lack of power. This study suggests that the TH gene, or a nearby gene, may be involved in the etiology of essential hypertension.
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PMID:Positive association of tyrosine hydroxylase microsatellite marker to essential hypertension. 977 62

To evaluate whether increased levels of reactive oxygen species (ROS) are involved in the pathogenesis of essential hypertension (EH) and non-insulin-dependent diabetes mellitus (NIDDM), both resting and stimulated levels of intracellular ROS were measured in lymphocytes from patients with EH (n = 10), NIDDM (n = 16) and age-matched healthy individuals (control subjects, n = 19). ROS was monitored with the dye, dihydrorhodamine-123 (DHR; 1 micromol/L) in the presence or absence of superoxide dismutase (superoxide scavenger), sodium azide (singlet oxygen/hydrogen peroxide scavenger), genistein (tyrosine kinase inhibitor), or bisindolylmaleimide (protein kinase C inhibitor). Simultaneous monitoring of cytosolic [Ca2+]i was done with fura-2. Resting ROS levels were significantly higher in NIDDM (4.71+/-0.25 nmol/10(6) cells; mean +/- SEM, P<.05) compared with EH (4.03+/-0.22 nmol/10(6) cells) or controls (4.05+/-0.15 nmol/10(6) cells). The formyl-Met-Leu-Phenylalanine-(fMLP)-induced ROS generation was significantly higher in NIDDM (21.92+/-2.23 nmol/10(6) cells; P<.05) compared with EH (14.58+/-1.90 nmol/10(6) cells) or control (16.06+/-1.22 nmol/10(6) cells). The fMLP-induced ROS increase was significantly reduced in the presence of sodium azide in all groups (P<.01) but was largely unaffected in the presence of SOD. Genistein and bisindolylmaleimide significantly inhibited the fMLP-induced ROS in all groups. The fMLP-induced [Ca2+]i increase was significantly higher in NIDDM (71+/-12 nmol/L, P <.01) compared with EH (42+/-4 nmol/L) and control subjects (35+/-3 nmol/L). Phytohemagglutinin was more effective in increasing [Ca2+]i than ROS. It is concluded that ROS may play a role in the metabolic syndrome of NIDDM but not in EH.
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PMID:Reactive oxygen species in essential hypertension and non-insulin-dependent diabetes mellitus. 1061 78

A common variant at codon 235 of the angiotensinogen gene with methionine to threonine amino acid substitution (AGT M235T) has been reported as a genetic risk for essential hypertension. However, the frequency of AGT T235 was heterogeneous among races, and a positive association between AGT M235T and hypertension was not settled. To examine the association in a general population of Japanese (n=4013), we introduced the TaqMan polymerase chain reaction method and examined the relation between hypertension and T+31C polymorphism, which was in absolute linkage disequilibrium with AGT M235T. The C+31 allele of AGT was significantly associated with the positive family history of hypertension (FH) but not with the presence of hypertension or blood pressure. The subjects with CC tended to have hypertensive relatives, especially a hypertensive father or siblings, and its statistical significance was stronger in men. Adjustment of confounding factor did not alter the results of simple association study, suggesting that this positive association with FH is independent and significant. Our findings revealed that the TaqMan polymerase chain reaction method is a powerful tool for genetic association study with a large number of subjects and that AGT T+31C is significantly associated with paternal FH.
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PMID:T+31C polymorphism of angiotensinogen gene and essential hypertension. 1123 Feb 86

Essential hypertension has a familial predisposition, but the phenotype of elevated blood pressure has delayed penetrance. Because the kidney is a crucial determinant of blood pressure homeostasis, we studied early glomerular alterations in still-normotensive young subjects at genetic risk of hypertension. Thirty-nine normotensive adults (mean age 29 to 31 years), stratified by genetic risk (parental family history [FH]) of hypertension (26 with positive FH [FH+], 13 with negative FH [FH-]), underwent intravenous infusion of mixed amino acids. Before and during amino acid administration, we measured glomerular filtration rate (GFR), putative second messengers of amino acids (nitric oxide [NO.] metabolites and cGMP), serum insulin and amino acid concentrations, and the FE(Li)+ as an index of renal proximal tubular reabsorption. The FH+ group had a blunted GFR rise in response to amino acids (2.43+/-8.16% versus 31.0+/-13.4% rise, P:=0.0126). The amino acid-induced change in GFR correlated (r=0.786, P:<0.01) with the change in urinary NO. metabolite excretion; a diminished rise in urinary NO. metabolite excretion in the FH+ group (P:=0.0105) suggested a biochemical mechanism for the different GFR responses between FH groups: a relative inability to convert arginine to NO. The FH+ group had a far lower initial cGMP excretion at baseline (261+/-21.1 versus 579+/-84.9 nmol. h(-1)/1.73 m(2), P:=0.001), although cGMP did not change during the amino acid infusion (P:=0.703). FH status, baseline GFR, and baseline serum insulin jointly predicted GFR response to amino acids (P:=0.0013), accounting for approximately 45% of the variance in GFR response. Decline in FE(Li)+, an inverse index of proximal tubular reabsorption, paralleled increase in GFR (r=-0.506, P:=0.01), suggesting differences in proximal tubular reabsorption during amino acids between the FH groups. GFR response to amino acid infusion was blunted in the FH+ group despite significantly higher serum concentrations of 6 amino acids (arginine, isoleucine, leucine, methionine, phenylalanine, and valine) in the FH+ group, suggesting a novel form of insulin resistance (to the amino acid-translocating action of insulin) in FH+ subjects. We conclude that blunted glomerular filtration reserve in response to amino acids is an early-penetrance phenotype seen even in still-normotensive subjects at genetic risk of hypertension and is linked to impaired formation of NO. in the kidney. Corresponding changes in GFR and fractional excretion of Li(+) suggest that altered proximal tubular reabsorption after amino acids is an early pathophysiologic mechanism. Resistance to the amino acid-translocating actions of insulin may play a role in the biological response to amino acids in this setting. This glomerular reserve phenotype may be useful in genetic studies of renal traits preceding or predisposing to hypertension.
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PMID:Early alteration in glomerular reserve in humans at genetic risk of essential hypertension: mechanisms and consequences. 1124 15

The natriuretic peptide (NP) family is involved in regulation of blood pressure and fluid volume. We recently characterized the exon/intron organization of the human type A NP receptor (hNPRA) gene. The aim of this study was to isolate the genetic markers according to the organization of this gene, and to study the association between this gene and essential hypertension. Using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, we identified a novel missense mutation, M3411, consisting of a methionine (ATG) to isoleucine (ATC) substitution at nucleotide 1023 in exon 3. Computer-aided three-dimensional structural analysis suggested that M341 exists in the loop between two alpha-helices, and that the mutation may influence receptor activities by altering the conformation of the alpha-helices. We performed an association study of the mutation in 210 essential hypertension (EH) patients and 210 normotensive controls. The overall distribution of alleles was not significantly different between the control and EH groups. However, the C/C homozygous genotype was found only in the EH group. The ratio of plasma brain natriuretic peptide (BNP)/mean blood pressure of the C/C genotype was significantly higher than that of the G/G genotype or the G/C genotype. We conclude that the significance of homozygous M3411 mutation in exon 3 is worth investigating for its possible association with EH.
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PMID:A novel missense mutation of exon 3 in the type A human natriuretic peptide receptor gene: possible association with essential hypertension. 1213 18

Several candidate genes, chosen from the renin- angiotensin system, were examined for their association with essential hypertension. The genes of the renin- angiotensin system (RAS) are good candidates for such an approach because this system is well known to be involved in the control of blood pressure. One of these candidate genes is the gene encoding for angiotensinogen (the most important gene of the RAS associated with essential hypertension in the most population, is the gene for angiotensin-converting enzyme- ACE). One DNA polymorphism within exon 2- with threonine instead of methionine at position 235 (M235T) was found to be significantly associated with hypertension. The objective of this study is the analysis of M235T polymorphism in angiotensinogen gene in Romanian patients with essential hypertension as well as controls. We examined 38 patients with essential hypertension and 21 normotensive patients. In order to identify the M235T angioteninogen variant, we used the following methods: DNA extraction, PCR amplification and enzymatic digestion of the PCR product using Tth 111I restriction endonuclease enzyme. In the study groups, the M235T variant (Met?Thr in aminoacid position 235) was found more frequently in hypertensive patients (81,57%), than in control subjects (66,66%). We identified 52,63% M235T heterozygotes in the hypertensive group compared with 47,61% in the control group, and 28,94% T235T homozygotes in the hypertensive group compared with 19,04% in the control group. The results of our study suggest an association of the M235T polymorphism in the gene encoding angiotensinogen with essential hypertension.
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PMID:Essential arterial hypertension and polymorphism of angiotensinogen M235T gene. 1216 9

A single nucleotide polymorphism of mitochondrial 5178A/C, causing a Met to Leu replacement within the NADH dehydrogenase subunit, is reported to be associated with longevity. The purpose of the present study was to assess the contribution of mitochondrial polymorphisms, particularly the 5178A/C genotype, to the susceptibility to acute myocardial infarction (AMI) in a Japanese study population. There were 4 groups: 150 patients with AMI, 150 with essential hypertension, 100 with diabetes mellitus, and 150 subjects matched for age and sex who served as the control group. Mitochondrial 5178A/C was detected by the polymerase chain reaction restriction fragment length polymorphism method. The allelic frequency of 5178C was significantly higher in the AMI group than in the control group, and this difference was more marked in younger patients. There were differences in allelic frequencies among the essential hypertension group, diabetes mellitus group and control group, but a higher frequency of the C allele was seen in the AMI group compared with the essential hypertension and diabetes mellitus groups. This particular polymorphism was found to be associated with development of AMI, especially in younger patients and constitutes a new risk factor for AMI.
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PMID:Mitochondrial 5178A/C genotype is associated with acute myocardial infarction. 1252 Jan 45


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