Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 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.
J Steroid Biochem Mol Biol 1996 Jan
PMID:The hamster adrenal cytochrome P450C11 has equipotent 11beta-hydroxylase and 19-hydroxylase activities, but no aldosterone synthase activity. 864 11

Intracellular free Ca2+ concentration has been shown to be elevated in platelets of patients with essential hypertension. This study was designed to characterize Ca(2+)-pump activity of the platelet membranes (surface and intracellular) in these patients A double-blind study was carried out. Untreated and treated (on beta-blockers) essential hypertensives were studied in comparison with normotensive control subjects. First degree blood relatives of essential hypertensives were also studied. The Ca2+ activation kinetics of the enzyme showed a significant decrease in the Vmax (for the plasma- and intracellular membranes) and Km (for the intracellular membranes) in the essential hypertensive patients. Increased platelet membrane cholesterol content was observed in these patients. Lowered Ca2(+)-efflux by Ca2(+)-ATPase may lead to elevated intracellular free Ca2(+)-levels in platelet of essential hypertensives. A lowered Ca2(+) -ATPase activity may emerge as a marker for essential hypertension.
Mol Cell Biochem 1996 Mar 09
PMID:Platelet calcium pump activity in essential hypertensives and their first-degree relatives. 870 74

In essential hypertension it has been hypothesized that there is a generalized derangement in cellular Ca2+ homeostasis. The aim of this study was to assess whether there is functional evidence for increased vulnerability to Ca overload in cardiomyocytes derived from age-matched (11-week) normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rat (SHR) strains. Contraction cycles of isolated ventricular cardiomyocytes were recorded using a rapid digital imaging technique and were evaluated by computation of a range of normalized parameters. Significant differences in the basal contractile cycles of SHR and WKY ventricular cardiomyocytes recorded under control conditions (36 degrees C, 3 Hz, 1 mM Ca2+) were detected. SHR myocytes exhibited a reduction in maximum shortening attained (SHR/WKY = 0.79) and in maximum rates of shortening (SHR/WKY = 0.85) and lengthening (SHR/WKY = 0.87). In the SHR there was a small delay in excitation-contraction coupling latency and an abbreviation of the contractile cycle (SHR/WKY = 0.87). The time to peak contraction was not different in the two strains and was not altered by the inotropic interventions studied. No functional evidence for an increased susceptibility of the SHR myocytes to uncompensated "Ca2+ leakiness" was observed during repeated challenge of elevated extracellular Ca2+. In both strains, the relative increase in maximum shortening of myocytes to isoproterenol (10(-8) M) was similar, suggesting that differential sensitivity to adrenergic modulation is due to factors other than altered cardiomyocyte responsiveness. Diminished basal cardiomyocyte contractile function may represent an intrinsic feature of impaired cardiovascular function in this form of genetically determined hypertension.
J Mol Cell Cardiol 1996 Apr
PMID:Contractile function of cardiomyocytes from the spontaneously hypertensive rat. 873

Although considerable evidence lends credence to the association between insulin resistance, hyperinsulinemia and essential hypertension, the precise nature of this relationship remains unexplained. In the present investigation, we examined the proposition that these metabolic defects contribute causally to the development of high blood pressure. If these metabolic abnormalities were responsible for the development of hypertension, then drug interventions that improve these defects should also decrease high blood pressure. Since previous studies have demonstrated that vanadium compounds enhance insulin action and lower plasma insulin levels in nondiabetic rats, we examined the effects of these compounds on insulin sensitivity, plasma insulin concentration and blood pressure in two hyperinsulinemic models of experimental hypertension. The animal models studied were the genetically predisposed spontaneously hypertensive rat and the fructose-hypertensive rat, where hypertension is induced in normotensive rats by feeding them a high fructose diet. Vanadium compounds caused marked and sustained decreases in plasma insulin concentration and blood pressure in both the animal models studied. Furthermore, the effect of the drugs on blood pressure was reversed by restoring plasma insulin levels in the drug-treated rats to those observed in their untreated counterparts. These data suggest that either hyperinsulinemia contributes to the development of hypertension in both the spontaneously hypertensive and the fructose-hypertensive rats or that the underlying mechanism is closely related to the expression of both these disorders.
Mol Cell Biochem
PMID:Antihypertensive effects of vanadium compounds in hyperinsulinemic, hypertensive rats. 892 40

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.
J Mol Med (Berl) 1997 Jan
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

Transbilayer movement of erythrocyte membrane cholesterol is impaired in patients affected with essential hypertension. This is an inherited disorder, but environmental factors are also involved. Dietary fats might play a role in the prevention and/or treatment of such abnormality in the kinetic pools of membrane cholesterol. We tested this hypothesis by using a diet (in which 30% of the energy came from fat) rich in olive oil or in high-oleic sunflower oil (as natural sources of monounsaturated fatty acids, MUFAs) and determining their influence on the movement of cholesterol into the lipid bilayer of the erythrocyte membrane after a four-week period. We concluded that dietary olive oil is helpful in normalizing the impaired transbilayer movement of membrane cholesterol in erythrocytes of eight normocholesterolaemic and eight hypercholesterolaemic hypertensive patients. However, the effects cannot be attributed exclusively to the content of MUFAs (mainly oleic acid) in the diet, as high-oleic sunflower oil was unable to induce favourable changes.
Cell Mol Life Sci 1997 Jun
PMID:Intake of olive oil can modulate the transbilayer movement of human erythrocyte membrane cholesterol. 923 Sep 25

The role of renin binding protein (RnBP) in human (patho)physiology, despite its biochemical characterization, is as yet unclear. RnBP has been shown to bind and inactivate renin, a key player of the blood pressure regulating renin-angiotensin system. This renders the RnBP gene a promising candidate gene in human hypertension. Herein, a molecular genetic approach was employed to investigate if RnBP might affect renin, prorenin and/or blood pressure levels. Sequencing of the human Xq28 chromosomal region provided the precise chromosomal location and full genomic sequence of the RnBP gene. All 11 exons, adjacent intronic splice sites and the promoter region were sequenced in 20 patients with essential hypertension of early onset and possible X-linked inheritance and in four normotensive individuals. The only variant found was a single base exchange polymorphism 61 base pairs upstream of the intron 6/exon 7 boundary (T61C). Several cardiovascular parameters, the renin, and prorenin levels and the T61C allele status were determined in 505 Caucasian individuals. Male individuals without medication who were hemizygous for the C allele were characterized by lower prorenin levels (196 +/- 15 versus 256 +/- 12 mU/l, P = 0.05) and a significantly higher renin/prorenin ratio (10.7 +/- 1.5 versus 7.7 +/- 0.3%, P = 0.002), whereas no variations in circulating renin, blood pressure, heart rate and left ventricular mass index were associated with the C allele. No significant association was observed in women. The data do not exclude a role of RnBP in essential hypertension. The complete genomic structure of the RnBP gene, including the identified repetitive sequence elements, provides an essential tool for further studies of the RnBP gene in hypertensive patients with a different genetic background.
Hum Mol Genet 1997 Sep
PMID:Human renin binding protein: complete genomic sequence and association of an intronic T/C polymorphism with the prorenin level in males. 928 90

Hypertension is a significant risk factor for heart attack and stroke and represents a major public health burden because of its high prevalence (e.g. 15-20% of the European and American populations). Although blood pressure is known to have a strong genetic determination, the genes responsible for susceptibility to essential hypertension are mostly unknown. Loci involved in blood pressure regulation have been found by linkage in experimental hereditary hypertensive rat strains, but their relationship to human hypertension has not been extensively investigated. One of the principal blood pressure loci has been mapped to rat chromosome 10 and we have undertaken an investigation of the homologous region on human chromosome 17 in familial essential hypertension. Affected sib-pair analysis and parametric analysis with ascertainment correction gave significant evidence of linkage ( P <0.0001 in some analyses) near two closely linked microsatellite markers, D17S183 and D17S934, that reside 18 cM proximal to the ACE locus in the homology region. Our results indicate that chromosome 17q could contain a susceptibility locus for human hypertension and show that comparative mapping may be a useful approach for identification of such loci in humans.
Hum Mol Genet 1997 Nov
PMID:Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10. 932 71

Familial factors are believed to be important in determining the high sodium-lithium countertransport activity (defined as >0.40 mmol Li/(h x l cell) at external sodium concentration of 140 mmol/L (Nae 140)) which is observed in a proportion of patients with essential hypertension. However, environmental factors such as pregnancy and dyslipidemia also affect activity. High sodium-lithium countertransport activity (Nae 140) in essential hypertension is mainly due to a low Michaelis constant (Km) and is associated with a high Vmax/Km ratio. In contrast, dyslipidemias affect Vmax. This study aimed to determine if there was evidence that Km and Vmax/Km ratios are influenced by familial factors. Sodium-lithium countertransport kinetics were measured in the 47 first degree relatives of 12 hypertensive probands with abnormal sodium-lithium countertransport kinetics and 35 normotensive control subjects. Sodium-lithium countertransport was measured as Na-stimulated Li efflux from lithium loaded erythrocytes. The relatives had significantly reduced Km and increased Vmax/Km compared to normal subjects. Eleven relatives had high sodium-lithium countertransport activity (Nae 140), associated with low Km and high Vmax/Km. The 14 relatives that were hypertensive had abnormalities of sodium-lithium countertransport kinetics. The results of this study suggest that familial factors are important in determining the Km and Vmax/Km of sodium-lithium countertransport activity. Studies aimed at determining the inheritance of sodium-lithium countertransport and its use as an intermediate phenotype of essential hypertension must measure its kinetic determinants to reduce the risk of confounding effects from other variables.
Biochem Mol Med 1997 Oct
PMID:Na-Li countertransport kinetics in the relatives of hypertensive patients with abnormal Na-Li countertransport activity. 936 6

Endothelin receptor antagonists have been proposed for the treatment of a variety of disorders in which the endothelins may act as pathogenic mediators, such as congestive heart failure, systemic and pulmonary hypertension, and cerebral vasospasm. Bosentan (Ro 47-0203) is a nonpeptide competitive antagonist, which can be a good tool for studying the endothelin system because it may be administered either acutely or chronically. It is specific for the endothelin system and blocks the actions of endothelin at both mammalian receptors (A and B). In experimental models of heart failure bosentan acts as a vasodilator and neurohormonal blocker that improves overall left ventricular performance and reduces renal dysfunction. Furthermore, in chronic studies, bosentan attenuates cardiac remodeling and significantly improves survival. In patients with chronic heart failure bosentan produces pulmonary and systemic vasodilation and may enhance conventional treatment with angiotensin-converting enzyme inhibitors. Long-term studies are being conducted to characterize the full therapeutic potential of bosentan in chronic heart failure. In experimental models bosentan reverses established pulmonary hypertension. Preclinical efficacy has also been demonstrated in essential hypertension, where bosentan can reduce blood pressure and end-organ damage. Clinical trials in hypertensive patients indicate that bosentan reduces blood pressure without heart rate increase or neurohumoral stimulation. Finally, bosentan is being considered for the treatment of cerebral vasospasm following subarachnoid hemorrhage. Bosentan reverses experimentally induced vasospasm of the basilar artery, and preliminary trials indicate that it can increase cerebral blood flow after aneurysmal subarachnoid hemorrhage.
J Mol Med (Berl) 1999 Apr
PMID:Endothelin antagonism with bosentan: a review of potential applications. 1035 41


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