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)

A study of Ca-ATPase and Ca-pump activity of the erythrocyte membrane's inverted vesicles with different cytoskeletal protein status demonstrated that Ca-pump activity remained unchanged, and Ca-ATPase activity was increased by 20-40%, as compared to erythrocytes from the normotensive controls, in hypertensive patients in the absence of exogenous calmodulin. These differences are assumed to be due to disorders of erythrocyte membrane structure in primary hypertension resulting in less efficient Ca-pump operation in the inverted vesicles. In all types of membranes obtained from hypertensive patients' erythrocytes in conditions of iso-osmotic hemolysis, calmodulin-induced increment of peak Ca-ATPase and Ca-pump activity was 2 or 3 times as low as that of normotensive controls. These differences remained in evidence after the solubilization of membrane proteins with triton X-100. No differences in calmodulin influence on Ca-ATPase affinity to Ca2+ could be found. The membranes obtained in iso-osmotic conditions demonstrated no calmodulin effect on Ca-ATPase activity which is attributed to partial proteolysis of the enzyme's molecule.
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PMID:[The Ca pump and Ca ATPase in the erythrocytes of patients with hypertension: disorders detected in cytoskeletal membranes and in solubilized Ca ATPase]. 242 39

Previous studies on genetic rat hypertension have shown that polymorphism within the alpha-adducin gene may regulate blood pressure. Adducin is a cytoskeletal protein that may be involved in cellular signal transduction and interacts with other membrane-skeleton proteins that affect ion transport across the cell membrane. There is a high homology between rat and human adducin and pathophysiological similarities between the Milan hypertensive rat strain and a subgroup of patients with essential hypertension. Thus, we designed a case-control study to test the possible association between the alpha-adducin locus and hypertension. One hundred ninety primary hypertensive patients were compared with 126 control subjects. All subjects were white and unrelated. Four multiallelic markers surrounding the alpha-adducin locus located in 4p16.3 were selected: D4S125 and D4S95 mapping at 680 and 20 kb centromeric, and D4S43 and D4S228/E24 mapping at 660 and 2500 kb telomeric. Alleles for each marker were pooled into groups. Comparisons between control subjects and hypertensive patients were carried out by testing the allele-disease association relative to the marker genotype. The maximal association occurred for D4S95 (chi 2(1) 13.33), which maps closest to alpha-adducin. These data suggest that a polymorphism within the alpha-adducin gene may affect blood pressure in humans.
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PMID:Association of the alpha-adducin locus with essential hypertension. 787 56

Human primary hypertension is a polygenic disease; its phenotypic expression is modulated by the environment. Though the kidney can play a major role in the initiation and maintainance of hypertension, many questions remain open. Kidney cross-transplantation demonstrated that hypertension can be transplanted with the kidney in all strains of genetically hypertensive rats where such experiments have been carried out. Data consistent with those in rats were also obtained in humans. Many abnormalities in kidney function and ion transport were described in hypertensive rats and humans, but the logical sequence from genetic-molecular to cellular abnormality that causes hypertension via modification of kidney function is difficult to prove. We established this sequence in Milan hypertensive rats using a variety of experimental techniques (isolated kidney and renal cell function, cell membrane ion transport, cross-immunization with membrane proteins, molecular biology, genetic crosses and manipulation). Such studies led to the identification of a polymorphism in the cytoskeletal protein adducin. This polymorphism seems involved in blood pressure regulation both in rats and humans. Preliminary results suggest that adducin polymorphism affects kidney function by modulating the overall capacity of tubular epithelial cells to transport ions modifying the assembly of actin cytoskeleton.
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PMID:Renal mechanisms of genetic hypertension: from the molecular level to the intact organism. 874 91

Human essential hypertension is a polygenic disease whose phenotypic expression is modulated by the environment. Though the kidney could play a major role in the initiation and maintainment of hypertension, many questions remain open. Rat models of primary hypertension provided the substantial information with experiments on kidney cross-transplantation, showing that at least a portion of hypertension could be transplanted with the kidney in all strains where such an experiment has been carried out. Data consistent with those of rats have also been obtained in humans. Many abnormalities in kidney function and cell membrane ion transport have been described in hypertensive rats and humans, but the logical sequence of events from a genetic-molecular abnormality to a cellular abnormality which causes hypertension via a modification of kidney function is difficult to prove. We established this sequence in Milan hypertensive rats using a variety of experimental techniques such as the study of isolated kidney and renal cell function, cell membrane ion transport, cross-immunisation with membrane proteins, molecular biology, genetic crosses and manipulation. Such study led to the identification of a polymorphism in the cytoskeletal protein adducin. Recently, alpha-adducin variants have been associated to both primary hypertension and salt sensitive hypertension. Finally, recent findings strongly support the hypothesis that adducin variants may affect kidney function by modulating the overall capacity of the tubular epithelial cells to transport ions through both a modification in the assembly of actin cytoskeleton, and a modulation of sodium pump activity.
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PMID:Genetic determinants and renal mechanisms in essential hypertension. 900 89

Human essential hypertension is a polygenic disease whose phenotypic expression is modulated by the environment. Though the kidney could play a major role in the initiation and maintainment of hypertension, many questions remain open. Rat models of primary hypertension provided the substantial information with experiments on kidney cross-transplantation showing that at least a portion of hypertension could be transplanted with the kidney in all strains where such experiment has been carried out. Data consistent with those of rats have also been obtained in humans. Many abnormalities in kidney function and cell membrane on transport have been described in hypertensive rats and humans but the logical sequence of events going from a genetic-molecular abnormality to a cellular abnormality which causes hypertension via a modification of kidney function is difficult to prove. We established this sequence in Milan hypertensive rats using a variety of experimental techniques such as the study of isolated kidney and renal cell function, cell membrane ion transport, cross-immunisation with membrane proteins, molecular biology, genetic crosses and manipulation. Such study led to the identification of a polymorphism in the cytoskeletal protein adducin and to the demonstration of its role in blood pressure control. Recently, alpha-adducin variants have been associated to both human primary hypertension and salt sensitive hypertension. Finally, recent findings strongly support the hypothesis that adducin variants may affect kidney function by modulating the overall capacity of the tubular epithelial cells to transport ions through both a modification in the assembly of actin cytoskeleton, and a modulation of sodium pump activity.
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PMID:Renal genetic mechanisms of essential hypertension. 937 22

The individual variation in the efficacy of and tolerability to antihypertensive drugs in human essential hypertension is linked to the genetic heterogeneity of this multifactorial disease. Different approaches have been pursued in the attempt to correlate a specific responsiveness to the therapy with some phenotypic traits of the patients, such as the renin-angiotensin profile or the characteristics of cell ion transports. More recently, a genetic approach to the study of the mechanisms underlying hypertension has led to the identification of some quantitative trait loci or genes that influence blood pressure in both animal models and patients. Also, individual variation to therapy can now be studied from the genetic point of view using pharmacogenomics, that is, the study of the genes or loci which are involved in determining the responsiveness to a given drug. Only a few examples of this approach are available to date. Our group has identified a polymorphism of the genes for the cytoskeletal protein, adducin, which is linked to both rat and human hypertension, sodium sensitivity and to the pressor responsiveness to diuretic therapy. These results, together with the indication that adducin can play a functional role by modulating the cellular sodium transport, have led to the identification of a new antihypertensive compound, which could be a candidate for the selective treatment of those patients in whom alterations of the renal sodium handling are associated with specific genetic traits such as the polymorphism for adducin.
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PMID:Pharmacogenomics: a new approach to individual therapy of hypertension? 952 26

A Gly460Trp variant of the cytoskeletal protein alpha-adducin has recently been implicated in the etiology of essential hypertension (HT) in a study involving southern European whites. We attempted to replicate this finding in a well-characterized, extensively studied group of 112 white Australians with essential HT, with strong family history (two HT parents), early-onset, moderate to severe disease, and of British extraction. Controls were 196 normotensive (NT) white subjects whose parents were both NT older than age 50 years. A mismatch polymerase chain reaction method involving BanII was developed for genotyping. Frequency of the Trp460 allele was 0.23 in the HT and 0.24 in the NT groups (chi2 = 0.2, P = .7). No association was observed with blood pressure, body mass index, age, plasma renin, angiotensinogen, angiotensin converting enzyme, cholesterol, triglycerides, or HDL or LDL cholesterol. Our results therefore provide no support for a role for the alpha-adducin variant in hypertension, at least in our severely affected Anglo-white group with strong family history of HT.
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PMID:The Gly460Trp variant of alpha-adducin is not associated with hypertension in white Anglo-Australians. 1037 74

A tailored or individualized antihypertensive therapy represents the new frontier for the treatment of essential hypertension and its organ complications. Indeed, individual variation in the efficacy and tolerability of antihypertensive drugs in human essential hypertension is currently experienced by all physicians and is linked to the genetic heterogeneity of this multifactorial disease. Different approaches have been pursued in the attempt to correlate specific responsiveness to the therapy with phenotypic traits of the patients, but with poor results. More recently, the genetic approach to the study of the mechanisms underlying hypertension has led to the identification of some quantitative trait loci or genes that influence blood pressure both in animal models and in patients. But the relevance of these polymorphisms for defining and classifying patients in terms of therapy responsiveness must be analyzed in a more complex context that takes into account the crucial aspects of environmental influences, stage of disease, previous treatments, efficacy, tolerance, and duration of the treatment. Only a few examples of a pharmacogenomic approach to hypertension therapy are now available. In particular, the association of different variants of ACE, angiotensinogen, and G-protein genes with the blood pressure response to drugs interfering with RAS or beta-adrenergic receptor has been studied. However, the results of these studies cannot be considered conclusive, since not all the criteria have been fully applied for proper assessment of an association between genetic polymorphism and drug response. Our group has identified a polymorphism of the genes coding for the cytoskeletal protein, adducin, which is associated with both rat and human hypertension, sodium sensitivity, and the antihypertensive effects of diuretics. A modification of the renal Na-KATPase leading to an increase of tubular sodium reabsorption seems to be the most likely underlying mechanism. A new antihypertensive compound has been developed that can correct the abnormality of the renal Na-KATPase and the blood pressure increase associated with adducin polymorphism in the rat. At present, the antihypertensive activity of this compound is under evaluation in patients with different adducin genotypes.
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PMID:Genetic mapping and tailored antihypertensive therapy. 1099 45

A primary renal alteration due to a genetic polymorphism of the cytoskeletal protein adducin associated with an up-regulation of the renal Na-K pump and increased levels of ouabainlike factor (OLF) has been identified as a possible causes of hypertension in Milan rats (MHS). This adducin polymorphism has also been found to be associated with hypertension and the blood pressure changes related to renal Na handling in humans and increased OLF levels have been found in a relevant portion of hypertensive patients. Increased activity and expression of the Na-K pump has also been observed under the following 'in vitro' and 'in vivo' conditions: rat renal cells transfected with the 'hypertensive' variant of adducin, as compared with normal cells; normal rat renal cells incubated for 5 days with 10(-9) M ouabain and normal rats made hypertensive by a chronic infusion of low doses of ouabain (OS rats). An up-regulation of the Na-K pump seems therefore to be a common biochemical alteration induced both by an adducin polymorphism and/or chronic exposure to low concentrations of ouabain (or OLF). A new antihypertensive compound, PST 2238, that selectively antagonizes the pressor effect and the alteration of the renal Na-K pump induced both by an adducin polymorphism and OLF, is described. The ability of PST 2238 to lower blood pressure and normalize the Na-K pump both in MHS and OS rats suggests that this compound could be useful in the treatment of those forms of essential hypertension in which renal Na-handling alterations are associated with either adducin polymorphisms and/or increased OLF levels.
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PMID:PST 2238: a new antihypertensive compound that modulates the Na-K pump 'in vivo' and 'in vitro'. 1101 14

Abnormal erythrocyte sodium-lithium countertransport is common in a subgroup of patients with essential hypertension and a strong family history of hypertension and cardiovascular disease. We have previously shown that the abnormality in sodium-lithium countertransport is associated with tropomyosin, a cytoskeletal protein required to stabilize actin filament formation. Leukocyte trafficking events, which depend on cytoskeletal reorganization, are also altered in patients with essential hypertension with abnormal sodium-lithium countertransport. The aim of this study was to determine whether there is an abnormality in isoforms of tropomyosin that are common to erythrocytes and leukocytes. Analysis of reticulocyte RNA by reverse transcription (RT) and polymerase chain reaction (PCR) showed expression of TPMN and TPM5b isoforms of tropomyosin. No other isoforms were expressed. These isoforms were also detected in RNA from leukocytes. In patients with essential hypertension with abnormal erythrocyte sodium-lithium countertransport compared with normal control subjects, there was a higher TPMN/TPM5b ratio of protein in erythrocytes (median 3.8 [range 1.8 to 6.6] versus 2.9 [1.9 to 4.0], P<0.001) and of RNA in leukocytes (3.7 [1.7 to 8.2] versus 2.6 [1.2 to 4.3], P<0.01). Furthermore, the protein ratio of TPMN/TPM5b in erythrocytes showed significant correlation with the V(max)/K(m) ratio of sodium-lithium countertransport across the patient groups (r=-0.42; P<0.01). Therefore, altered tropomyosin expression may be the underlying abnormality associated with blood cell membrane changes in essential hypertension and implicates the cytoskeleton in the pathogenesis of the disease in a major subgroup of patients.
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PMID:Altered tropomyosin expression in essential hypertension. 1257 6


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