UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

beta-Adrenoceptor antagonists play an important role in the treatment of cardiovascular disease and have been used for three decades in the treatment of hypertension and ischemic heart disease. More recently they have been demonstrated to improve survival in patients with mild to moderate congestive heart failure. The beneficial effects of beta-adrenoceptor antagonists stems from their ability to limit the deleterious effects of adrenergic stimulation, which in the cardiovascular system is primarily transmitted through two subclasses of receptor, beta(1) and beta(2). The advances of the Human Genome Project have led to an increased appreciation that variations in genetic background may underlie a substantial portion of the clinical heterogeneity apparent in cardiovascular disease. This review examines the molecular, functional, and clinical significance of the most common polymorphisms of the beta(1 and beta(2)-adrenoceptors. Initial research in adrenoceptor variation focused on the beta(2)-adrenoceptor. Three common polymorphisms appear to influence receptor function: Arg16-->Gly, Glu(27)-->Gln, and Thr(164)-->Ile. In in vitro studies of agonist stimulation, Gly(16) receptors demonstrate enhanced downregulation, while Glu(27) variants are resistant to downregulation. There is much controversy and conflict among various clinical studies regarding the effect of these variants on vasoreactivity and hypertensive risk. The Ile(164) variant demonstrates decreased responsiveness to agonist activity both in vitro and in animal models. In studies of patients with congestive heart failure, this variant has been associated with poor functional capacity and decreased survival. More recent investigations have focused on the two common polymorphisms of the beta(1)-adrenoceptor: Ser(49)-->Gly, and Arg(389)-->Gly. In vitro studies of Arg(389) receptors demonstrate a gain of function, as agonist stimulation results in significantly higher intracellular levels of cyclic adenosine monophosphate when compared with the Gly(389) variant. Consistent with the in vitro data, clinical studies demonstrate increased responsiveness to beta-agonist stimulation, and an increased risk of hypertension among Arg(389) homozygotes. Further investigation of the clinical implications of these common variants of beta(1)- and beta2)-adrenoceptors are needed. Importantly, the pharmacogenetic impact of these variants on the effectiveness of beta-adrenergic blockade remains unknown.
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PMID:Clinical importance of beta-adrenoceptor polymorphisms in cardiovascular disease. 1208 43

This study investigates the association between the allelic distribution of two polymorphisms of the angiotensinogen (AGT) gene (T174M and M235T in the polypeptide chain) and blood pressure (BP) in a Mediterranean population in the south-west of Europe. The sample consists of 1322 participants from urban and rural areas, from the province of Albacete (218,462 inhabitants), located in the south-east of Spain. The subsample of this study, adjusted by age (over 18 years old) and sex, consists of 401 individuals. A case-control study is conducted which analyses 205 individuals from the group with the highest BP (fifth quintile) and 196 from the group with the lowest BP (first quintile). In addition, a comparative and associated analysis of these polymorphisms with BP level and family history of hypertension is carried out. The T174 allele proved to be more common in the fifth quintile group, although not statistically so. When the presence of threonine was analysed in both polymorphism positions (174 and 235), the TTTT genotype was found to be more common in the fifth quintile than in the first quintile. Moreover, the TTTT genotype was significantly more common in individuals with a family history of hypertension, indicating that it could be considered a predisposing factor to high BP in individuals from such families. In addition, the T174M-T235T genotype was more common in the first quintile group, and showed significant association (P=0.05) with the group that had no family history of hypertension.
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PMID:Threonines at position 174 and 235 of the angiotensinogen polypeptide chain are related to familial history of hypertension in a Spanish-Mediterranean population. 1211 11

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

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

Mutations in the serine-threonine kinases WNK1 and WNK4 [with no lysine (K) at a key catalytic residue] cause pseudohypoaldosteronism type II (PHAII), a Mendelian disease featuring hypertension, hyperkalemia, hyperchloremia, and metabolic acidosis. Both kinases are expressed in the distal nephron, although the regulators and targets of WNK signaling cascades are unknown. The Cl(-) dependence of PHAII phenotypes, their sensitivity to thiazide diuretics, and the observation that they constitute a "mirror image" of the phenotypes resulting from loss of function mutations in the thiazide-sensitive Na-Cl cotransporter (NCCT) suggest that PHAII may result from increased NCCT activity due to altered WNK signaling. To address this possibility, we measured NCCT-mediated Na(+) influx and membrane expression in the presence of wild-type and mutant WNK4 by heterologous expression in Xenopus oocytes. Wild-type WNK4 inhibits NCCT-mediated Na-influx by reducing membrane expression of the cotransporter ((22)Na-influx reduced 50%, P < 1 x 10(-9), surface expression reduced 75%, P < 1 x 10(-14) in the presence of WNK4). This inhibition depends on WNK4 kinase activity, because missense mutations that abrogate kinase function prevent this effect. PHAII-causing missense mutations, which are remote from the kinase domain, also prevent inhibition of NCCT activity, providing insight into the pathophysiology of the disorder. The specificity of this effect is indicated by the finding that WNK4 and the carboxyl terminus of NCCT coimmunoprecipitate when expressed in HEK 293T cells. Together, these findings demonstrate that WNK4 negatively regulates surface expression of NCCT and implicate loss of this regulation in the molecular pathogenesis of an inherited form of hypertension.
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PMID:Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. 1251 52

Mutations in WNK1 and WNK4, genes encoding members of a novel family of serine-threonine kinases, have recently been shown to cause pseudohypoaldosteronism type II (PHAII), an autosomal dominant disorder featuring hypertension, hyperkalemia, and renal tubular acidosis. The localization of these kinases in the distal nephron and the Cl(-) dependence of these phenotypes suggest that these mutations increase renal Cl(-) reabsorption. Although WNK4 expression is limited to the kidney, WNK1 is expressed in many tissues. We have examined the distribution of WNK1 in these extrarenal tissues. Immunostaining using WNK1-specific antibodies demonstrated that WNK1 is not present in all cell types; rather, it is predominantly localized in polarized epithelia, including those lining the lumen of the hepatic biliary ducts, pancreatic ducts, epididymis, sweat ducts, colonic crypts, and gallbladder. WNK1 is also found in the basal layers of epidermis and throughout the esophageal epithelium. The subcellular localization of WNK1 varies among these epithelia. WNK1 is cytoplasmic in kidney, colon, gallbladder, sweat duct, skin, and esophagus; in contrast, it localizes to the lateral membrane in bile ducts, pancreatic ducts, and epididymis. These epithelia are all notable for their prominent role in Cl(-) flux. Moreover, these sites largely coincide with those involved in the pathology of cystic fibrosis, a disease characterized by deranged epithelial Cl(-) flux. Together with the known pathophysiology of PHAII, these findings suggest that WNK1 plays a general role in the regulation of epithelial Cl(-) flux, a finding that suggests the potential of new approaches to the selective modulation of these processes.
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PMID:WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl- -transporting epithelia. 1252 52

Advanced pulmonary arterial hypertension is characterized by extensive vascular remodeling that is usually resistant to vasodilator therapy. Mevastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting step for cholesterol synthesis. HMG-CoA reductase inhibitors have been shown to upregulate the cyclin-dependent kinase inhibitor p27Kip1 and to block cell proliferation through cholesterol-independent pathways. The aim of this study was to determine the effect of mevastatin on DNA synthesis, cell cycle progression, and cell proliferation in rat pulmonary artery smooth muscle cells (PASMCs). We found that mevastatin induced G1 arrest and decreased DNA synthesis in rat PASMCs and did so in association with an increase in both total and cyclin E-bound p27Kip1. This caused a marked decrease in cyclin E kinase activity, which suggests an important role for p27Kip1 in the ability of mevastatin to induce G1 arrest. However, in PASMCs lacking functional p27Kip1, mevastatin still decreased cyclin E kinase activity, caused G1 arrest, and decreased DNA synthesis. In p27Kip1-deficient PASMCs, mevastatin induced a greater reduction of cyclin E protein levels (to 35% of control) than in wild-type cells (to 70% of control) and also reduced the phosphorylation of cdk2 on threonine 160. Mevastatin also caused apoptosis in both wild-type and p27Kip1-deficient PASMCs and was able to do so at a dose that did not induce cell cycle arrest. These data suggest that HMG-CoA reductase inhibitors can both inhibit cell proliferation and induce apoptosis in PASMCs through p27Kip1-independent pathways and may be important therapeutic agents in pulmonary arterial hypertension.
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PMID:Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a p27Kip1-independent pathway. 1260 Aug 84

Phosphatidylinositol 3-kinase (PI3K) activity is increased in aortae from deoxycorticosterone (DOCA)-salt rats and enhanced PI3K activity contributes to the arterial hyperreactivity in these animals. Because PI3K activity is increased in DOCA-salt hypertension, we postulated that phosphorylation of Akt and glycogen synthase kinase 3 (GSK-3), serine threonine kinases that are downstream of PI3K, would be increased in DOCA-salt hypertension. In this study, we focused on GSK-3. Because GSK-3 activity is reduced by phosphorylation, we expected that its activity would be reduced in DOCA-salt hypertensive arteries and that reduced GSK-3 activity could contribute to enhanced adrenergic signaling and vascular smooth muscle hypertrophy that augment the heightened contractile response in DOCA-salt hypertension. Surprisingly, we observed a decrease in phosphorylation of GSK-3, indicating an increase in GSK-3 activity. To determine whether increased GSK-3 activity contributes to altered arterial reactivity in DOCA-salt animals, we measured isometric contraction to norepinephrine (NE) in the presence and absence of PI3K or GSK-3 inhibition. Addition of LY294002 (20 micromol/L), a PI3K inhibitor, resulted in a rightward shift in response to NE and normalized the NE-induced contractions in the DOCA hypertensive vessels. SB415286, a GSK-3 inhibitor, resulted in a slight rightward shift in response to NE in the DOCA-salt vessels. Thus, enhanced GSK-3 activity modestly augments the effects of PI3K but does not appear to contribute greatly to the altered arterial reactivity in DOCA-salt hypertension.
Hypertension 2003 Apr
PMID:PI3-kinase-induced hyperreactivity in DOCA-salt hypertension is independent of GSK-3 activity. 1262 35

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

Four types of monogenic hypertension belong to the group of mineralocorticoid hypertension, which are characterized by high renal water and sodium retention and resulting suppression of plasma renin activity (PRA), high urinary potassium secretion and consecutive low plasma potassium:1. increased production of the hormone aldosterone: glucocorticoid-remediable aldosteronism (GRH), 2. prereceptor disorder with loss of selectivity of the mineralocorticoid receptor: apparent mineralocorticoid excess (AME), 3. receptor disorder with constitutive activation of the mineralocorticoid receptor: "Geller syndrome", 4. postreceptor disorder with enhanced function of the epithelial sodium channel: Liddle's syndrome. While in GRH high synthesis of aldosterone results in high plasma aldosterone and low PRA, in the primary renal malfunctions of the AME, constitutive activation of the mineralocorticoid receptor and the Liddle's syndrome both plasma aldosterone and PRA are low. These forms of hypertension are rather rare in their complete expression, but they point to candidate genes whose mutations may predispose to hypertension. A point mutation of the ENaC beta-subunit (T594M) occurs rather frequent in people of African origin, with 5%. Therefore it is suggested to analyze the genotype of black hypertensive patients as a prerequisite for a rational amiloride therapy. Contrarily, the rather frequent (A[2139]G) polymorphism of the promoter of the alpha-subunit is supposed to mark a lower risk of hypertension. Mutations in the serine-threonine kinases WNK1 or WNK4 cause pseudohypoaldosteronism type II. WNK1 and WNK4 are expressed in the distal part of the nephron. Stimulation of sodium reabsorption by aldosterone is normal but without influence on hyperkalemia. An extrarenal disorder is suggested to be the cause of autosomal-dominant hypertension with brachydactyly: the patients react with a severely impaired baroreflex und show neurovascular contact. The mutation causing this syndrome is not known.
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PMID:[Monogenic hypertension]. 1271 44

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