UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
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Glucocorticoids regulate diverse functions important for the maintenance of central nervous system, cardiovascular, metabolic, and immune homeostasis. The actions of these hormones are mediated by the specific intracellular glucocorticoid receptors (GRs). Pathologic conditions associated with changes of tissue sensitivity to these hormones have been described. The syndrome of familial/sporadic glucocorticoid resistance is characterized by hypercortisolism without Cushing syndrome stigmata. Many of the patients present with hypertension, with or without hypokalemic alkalosis, as a result of elevated concentrations of cortisol and other salt-retaining steroids. The molecular defects of 4 kindreds and one sporadic case have been elucidated as inactivating mutations in the ligand-binding domain of the GR. In two patients in whom the GR was mutated at amino acid isoleucine 559 to aspartic acid (GRalphaI559N) and isoleucine 747 to methionine (GRalphaI747M), respectively, glucocorticoid resistance developed at the heterozygous state, with transdominant negative activity of each of the mutant receptors upon the wild-type protein. Retention of the wild-type receptor in the cytoplasm by the mutant receptor was found in the former, while inappropriate accumulation of p160-type coactivators on the promoter region of glucocorticoid-responsive genes, because of a defective interaction between the AF2 region of the mutant receptor and the LXXLL motif of the coactivators, was determined in the latter. These results suggest that the pathologic mechanisms of glucocorticoid resistance is quite broad, and this is reflected in the wide variability of the clinical picture in patients with the syndrome.
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PMID:Familial/sporadic glucocorticoid resistance syndrome and hypertension. 1238 45

Angiotensinogen (AGT) was the first gene to be genetically linked to hypertension in humans. Analysis of the gene sequence identified a number of polymorphisms, several of which were reported associated with increased blood pressure (BP) or other cardiovascular diseases. One haplotype of the human AGT (hAGT) gene consisting of an allele at the -6 (A vs. G) position in the promoter and the sequence encoding amino acid 235 (Thr vs. Met) attracted the most attention and has been the subject of numerous association studies. In this report, we addressed the physiological relevance of alleles at these two positions using an experimental mouse model system. Transgenic mice were generated by targeting each haplotype [-6G/235Met (GM) and -6A/235Thr (AT)] as a single copy transgene to the mouse hypoxanthine phosphoribosyl transferase locus, allowing direct comparison of the two transgenes in vivo. Our results indicate that both transgenes exhibit the same transcriptional activity and produce similar levels of hAGT protein in the plasma of the transgenic mice. BP analysis was performed in double transgenic mice generated by breeding each hAGT line to mice expressing a human renin gene. A small but significant increase in BP and relative heart weight was demonstrated by mice carrying the GM haplotype. Moreover, compensatory downregulation of endogenous renin expression was more pronounced in mice containing the GM variant. Our findings suggest that the AT and GM haplotypes of the hAGT gene have no effect on gene expression, but may affect the cardiovascular system and the regulation of BP differently.
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PMID:Physiological significance of two common haplotypes of human angiotensinogen using gene targeting in the mouse. 1238 94

Maternal malnutrition can lead to fetal abnormalities and increase susceptibility to disease in later life. Rat models have been developed to study the physiology and metabolism underlying this phenomenon. One particular model of 50 % protein restriction during pregnancy, the low-protein diet (LPD) supplemented with methionine, has been developed to investigate the underlying mechanisms. Recent studies have shown that rats fed a LPD during only the first 4 d of pregnancy produce offspring that develop hypertension. These results suggest that the very earliest stages of embryo development are susceptible to diet-induced heritable changes. We demonstrate a marked elevation of maternal serum homocysteine (hcy) concentrations during the initial phases of pregnancy in both rats and mice fed an LPD. Fetal growth and many of the circulating amino acids are similarly perturbed in both rats and mice fed the LPD during pregnancy, indicating that the response to the LPD diet is similar in rats and mice. These findings allow us to exploit the advantages of the mouse experimental system in future analyses aimed at understanding the molecular basis of fetal programming. Our present findings are discussed with particular reference to mechanisms which may initiate fetal programming, and to the feasibility of dietary interventions aimed at reducing early pregnancy loss and pre-eclampsia in man.
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PMID:Serum concentrations of homocysteine are elevated during early pregnancy in rodent models of fetal programming. 1242 27

1. The role of nigral tachykinin NK(1), NK(2) and NK(3) receptors in central cardiovascular regulation was studied by measuring the effects of selective agonists and antagonists on mean arterial pressure (MAP) and heart rate (HR) after bilateral microinjection into the substantia nigra of spontaneously hypertensive rats (SHR). Quantitative in vitro autoradiography was also performed in the midbrain of SHR and Wistar-Kyoto (WKY) with the NK(3) receptor ligand [(125)I]-HPP-Senktide. 2. Tachycardia was elicited by the NK(1) ([Sar(9),Met(O(2))(11)]SP) and NK(2) ([betaAla(8)]NKA(4-10)) agonists at 25 and 100 pmol while the NK(3) agonist (senktide, 50 and 100 pmol) had no significant effect. The three agonists had no effect on behaviour, and increases in MAP were elicited by the NK(1) agonist only. 3. Whereas antagonists at NK(1) (RP 67580, 500 pmol) and NK(2) (SR 48968, 500 pmol) receptors had no significant effect on MAP and HR, the NK(3) antagonist (R-820, 500 pmol) reduced MAP for over 3 h in SHR. That anti-hypertensive effect did not occur after intracerebroventricular or intravenous injection of R-820. Also, R-820 had no cardiovascular effect in WKY. 4. The affinity (K(D): 0.7 nM) and densities of specific NK(3) receptor binding sites measured in the substantia nigra, ventral tegmental area, hippocampus and amygdala were not significantly different in SHR and WKY. 5. It is concluded that endogenous tachykinins exert a tonic activity on NK(3) receptors in the substantia nigra of SHR to maintain high blood pressure. Hence, nigral tachykinin NK(3) receptors may represent a promising therapeutic target in the treatment of arterial hypertension.
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PMID:Implication of nigral tachykinin NK3 receptors in the maintenance of hypertension in spontaneously hypertensive rats: a pharmacologic and autoradiographic study. 1259 9

Homocysteine is a metabolic product of methyl group donation by the amino acid methionine. Moderate elevation of plasma homocysteine (>15 microM) is most commonly caused by B-vitamin deficiencies, especially folic acid, B(6) and B(12). Genetic factors, certain drugs and renal impairment may also contribute. Homocysteine has several potentially deleterious vascular actions. These include increased oxidant stress, impaired endothelial function, stimulation of mitogenesis, and induction of thrombosis. Homocysteine also appears to increase arterial pressure. In humans, experimental induction of hyperhomocysteinemia by methionine loading rapidly causes profound impairment of endothelium-dependent dilatation in both resistance and conduit arteries. This endothelial dysfunction can be reversed by administration of antioxidants. Epidemiological evidence suggests that homocysteine acts as an independent risk factor for atherosclerosis, thrombosis and hypertension. Prospective studies have shown that elevated plasma homocysteine concentrations in the top quintile of the population (>12 microM) increase risk of cardiovascular disease by about 2-fold. There are currently no data available from randomized, controlled trials of the effects of lowering plasma homocysteine on atherothrombotic events. Nonetheless, it would seem appropriate to screen for and treat hyperhomocysteinemia in individuals with progressive or unexplained atherosclerosis. Folic acid and vitamins B(6) and B(12) are the mainstay of therapy. Treatment of moderately elevated plasma homocysteine in patients without atherosclerosis should be deferred until the completion of randomized outcome trials.
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PMID:Hyperhomocysteinemia, vascular function and atherosclerosis: effects of vitamins. 1265 8

The angiotensinogen (AGT) gene polymorphism M235T (a methionine to threonine amino acid substitution) has been investigated in association with essential hypertension (EHT) based on conventional measurement of blood pressure (BP); however, the results have been inconsistent. Recently, we have been conducting lines of genetic analysis on a general population of Ohasama Town in Iwate Prefecture, Japan, who measured their BP at home (Ohasama genetic analysis and home BP project). We here assessed the association between AGT M235T polymorphism and hypertension within the same population (1,245 subjects aged 40 years and over). AGT M235T polymorphism was determined by genotyping the AGT T+31C polymorphism, which has complete disequilibrium with the AGT M235T polymorphism. We defined subjects as hypertensive if they were being treated with antihypertensive medication and/or had home BP values of more than 135 mmHg in systole and/or 85 mmHg in diastole. The genotype frequencies were similar to those in previous Japanese studies. There was no significant difference among the genotypes in home BP values (p = 0.63/0.74 for systolic/diastolic blood pressure) or in prevalence of hypertension (MM: 44.7%; MT: 42.3%; TT: 39.6%; p = 0.61). No difference was noted in the frequency of familial history of hypertension. Pulse pressure, however, was significantly different among the genotypes (p = 0.049), and this association was prominent in the older (age260) population (p = 0.0018), but not noted in the younger population (60 > age > or = 40). In conclusion, the present analysis confirmed the lack of a significant effect of AGT M235T polymorphism on blood pressure level, but the difference in pulse pressure in the older population suggests that further investigations of this polymorphism should be made in the Japanese population.
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PMID:T+31C polymorphism (M235T) of the angiotensinogen gene and home blood pressure in the Japanese general population: the Ohasama Study. 1266 12

Stimulation of brain Na+ channels by Phe-Met-Arg-Phe-NH2 (FMRFamide) increases sympathetic nerve activity and blood pressure (BP) in Wistar rats. Blockade of brain ouabain-like compounds (OLC) by specific antibody Fab fragments prevents these responses to intracerebroventricular FMRFamide. In the present study, we evaluated the effects of high-salt intake on brain FMRFamide levels and the responses of BP and brain OLC to intracerebroventricular infusion of FMRFamide in Dahl salt-sensitive (SS) and salt-resistant (SR) rats. FMRFamide and OLC content was measured with the use of RIA and ELISA, respectively. A high-salt diet (1,370 micromol Na+/g) for 2 wk significantly increased BP in Dahl SS but not in SR rats. On a regular salt diet, Dahl SS and SR rats showed similar FMRFamide levels in the whole hypothalamus, pons and medulla, and spinal cord. A high-salt diet for 2 wk did not affect FMRFamide levels in these tissues in both Dahl SS and SR rats. In Dahl SS but not in SR rats, chronic intracerebroventricular infusion of FMRFamide (200 nmol. kg(-1).day(-1)) for 2 wk significantly increased BP (mean arterial pressure: 116 +/- 5 vs. 100 +/- 2 mmHg; P < 0.01). Chronic intracerebroventricular infusion of FMRFamide significantly increased hypothalamic and pituitary OLC in Dahl SS but not SR rats. These results indicate that Dahl SS rats exhibit enhanced central responses to FMRFamide. In Dahl SS but not in SR rats on a high-salt diet, enhanced Na+ entry through FMRFamide-activated brain Na+ channels may increase brain OLC release, thereby leading to hypertension.
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PMID:Stimulation of brain Na+ channels by FMRFamide in Dahl SS and SR rats. 1285 27

Several association studies of candidate genes for preeclampsia and essential hypertension have led to discordant results, partly because of small sample sizes. Using a large population-based sample of pregnant women, we conducted an association study of 10 polymorphisms in 9 genes and aimed (1) to validate 10 published associations with preeclampsia or essential hypertension, (2) to investigate candidate polymorphisms previously associated with preeclampsia for association with essential hypertension and similarly with polymorphisms previously associated with essential hypertension. From a prospective sample of 3391 nulliparous French Canadian pregnant women, we identified 180 cases of preeclampsia, 203 cases of essential hypertension that were matched with normotensive control subjects (n=310 and 357, respectively). Polymorphisms were genotyped by allele-specific PCR. Among our candidate polymorphisms, the Met allele of Thr174Met of AGT was associated with preeclampsia (P=0.0033). Haplotype analysis revealed that the A-Met-Thr (G1035A-Thr174Met-Met235Thr) haplotype was associated with a 2.1-fold increased risk of preeclampsia (95% CI, 1.4 to 3.4; P=0.0008). In conclusion, we observed a strong association between a specific AGT haplotype and preeclampsia in our population, without replicating previous published associations with either preeclampsia or essential hypertension. Our data support a role for AGT in genetic susceptibility to preeclampsia.
Hypertension 2004 Jan
PMID:Implication of an AGT haplotype in a multigene association study with pregnancy hypertension. 1463 22

About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and getting larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a "new" risk factor, is being viewed with mounting interest. Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B12, and vitamin B6 deficiencies and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10% of total risk. Elevated plasma homocysteine levels (>12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10% of the general population and in up to 40% of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence over-proportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial anti-thrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stress. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and lifestyle factors have an impact on homocysteine metabolism. Folic acid deficiency is considered the most common cause of hyperhomocysteinemia. An adequate intake of at least 400 microg of folate per day is difficult to maintain even with a balanced diet, and high-risk groups often find it impossible to meet these folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated homocysteine levels in high-risk individuals in general and patients with manifest vascular disease in particular. Subjects of both populations should first have a baseline homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma homocysteine level of <10 micromol/l. Based on various calculation models, reduction of elevated plasma homocysteine concentrations may theoretically prevent up to 25% of cardiovascular events. Supplementation is inexpensive, potentially effective, and devoid of adverse effects and, therefore, has an exceptionally favorable benefit/risk ratio. The results of ongoing randomized controlled intervention trials must be available before screening for, and treatment of, hyperhomocysteinemia can be recommended for the apparently healthy general population.
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PMID:DACH-LIGA homocystein (german, austrian and swiss homocysteine society): consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations. 1465 16

Homocysteine is a sulphur aminoacid with a free thiol group which is not present in dietary protein. This aminoacid is a secondary f methionine by-product from cysteine metabolism. The pathogenic mechanisms of homocysteine in vascular damage have not been clarified. At present, it is no possible to develop an atherogenic and thrombogenic hypothesis. Yet high levels of homocysteine can cause endothelial damage, with increased thrombosis and atherosclerosis. Hyperhomocysteinemia has been reported in patients with diabetes mellitus type 1 and type 2; the prevalence and secondary cardiovascular risk is higher in patients with diabetes type 2 than those with diabetes type 1. In patients with diabetes mellitus type 1, microvascular and macrovascular complications and neuropathy are found to be increased in those with hyperhomocysteinemia. In patients with diabetes mellitus type 2, the relationship between hyperhomocysteinemia, macrovascular complications and renal disease is unclear; however, a higher prevalence of macrovascular complications in diabetic patients with hyperhomocisteinemia is associated with a higher prevalence of renal disease. Moreover, patients with hyperhomocysteinemia have hypertension and dyslipemia. Multivariate regression analyses have shown an independent relationship between homocysteine and macrovascular complications. The relationship between retinopathy and homocysteine has not been clarified. In summary, hyperhomocysteinemia could be a risk factor accounting for chronic complications in diabetic patients. Nevertheless, it is necesary to perform more prospective and intervention studies to clarify the independent risk of homocysteine and thus assay alternative treatments.
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PMID:[Homocysteine in patients with diabetes mellitus]. 1473 72

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