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

1. The present study deals with the effect of maturation on the kinetic properties of renal Na(+)/K(+)-ATPase and its susceptibility to nitric oxide (NO)-deficient hypertension induced by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). 2. Immature (4-week-old) and adult (12-week-old) male Wistar rats were administered L-NAME (40 mg/kg per day) in their drinking water for 4 weeks. 3. The properties of the ATP- and Na(+)-binding sites of Na(+)/K(+)-ATPase were investigated by activation of the enzyme with increasing concentrations of the energy substrate ATP and/or cofactor Na(+). Unchanged values of K(m) suggest that energy utilization by the enzyme in the kidney of control rats remains unaffected during maturation. Conversely, the decrease in K(Na) values (the concentration of Na(+) necessary to achieve half-maximal reaction velocity) indicates improved affinity for Na(+) in the older group of control rats. 4. Application of L-NAME to all young animals had no significant effect on the functional properties of Na(+)/K(+)-ATPase. 5. In adult animals, the V(max) values remained unchanged after treatment with L-NAME, but the affinities of the ATP- and Na(+)-binding sites were decreased, as indicated by significant increase in K(m) and K(Na) values. 6. Maturation of control rats was accompanied by an increase in the Na(+) affinity of renal Na(+)/K(+)-ATPase without affecting ATP utilization. However, maturation increased the susceptibility of renal Na(+)/K(+)-ATPase to the harmful effects of L-NAME.
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PMID:Effect of maturation on renal Na+/K+-atpase and its susceptibility to nitric oxide-deficient hypertension in rats. 1758 Dec 18

Cardiac glycosides have been used for decades to treat congestive heart failure. The recent identification of cardiotonic steroids such as ouabain, digoxin, marinobufagenin, and telocinobufagin in blood plasma, adrenal glands, and hypothalamus of mammals led to exciting new perspectives in the pathology of heart failure and arterial hypertension. Biosynthesis of ouabain and digoxin occurs in adrenal glands and is under the control of angiotensin II, endothelin, and epinephrine released from cells of the midbrain upon stimulation of brain areas sensing cerebrospinal Na(+) concentration and, apparently, the body's K(+) content. Rapid changes of endogenous ouabain upon physical exercise may favor the economy of the heart by a rise of intracellular Ca(2)(+) levels in cardiac and atrial muscle cells. According to the sodium pump lag hypothesis, this may be accomplished by partial inhibition of the sodium pump and Ca(2+) influx via the Na(+)/Ca(2+) exchanger working in reverse mode or via activation of the Na(+)/K(+)-ATPase signalosome complex, generating intracellular calcium oscillations, reactive oxygen species, and gene activation via nuclear factor-kappaB or extracellular signal-regulated kinases 1 and 2. Elevated concentrations of endogenous ouabain and marinobufagenin in the subnanomolar concentration range were found to stimulate proliferation and differentiation of cardiac and smooth muscle cells. They may have a primary role in the development of cardiac dysfunction and failure because (i) offspring of hypertensive patients evidently inherit elevated plasma concentrations of endogenous ouabain; (ii) such elevated concentrations correlate positively with cardiac dysfunction, hypertrophy, and arterial hypertension; (iii) about 40% of Europeans with uncomplicated essential hypertension show increased concentrations of endogenous ouabain associated with reduced heart rate and cardiac hypertrophy; (iv) in patients with advanced arterial hypertension, circulating levels of endogenous ouabain correlate with BP and total peripheral resistance; (v) among patients with idiopathic dilated cardiomyopathy, high circulating levels of endogenous ouabain and marinobufagenin identify those individuals who are predisposed to progressing more rapidly to heart failure, suggesting that endogenous ouabain (and marinobufagenin) may contribute to toxicity upon digoxin therapy. In contrast to endogenous ouabain, endogenous marinobufagenin may act as a natriuretic substance as well. It shows a higher affinity for the ouabain-insensitive alpha(1) isoform of Na(+)/K(+)-ATPase of rat kidney tubular cells and its levels are increased in volume expansion and pre-eclampsia. Digoxin, which is synthesized in adrenal glands, seems to counteract the hypertensinogenic action of ouabain in rats, as do antibodies against ouabain, for example, (Digibind) and rostafuroxin (PST 2238), a selective ouabain antagonist. It lowers BP in ouabain- and adducin-dependent hypertension in rats and is a promising new class of antihypertensive medication in humans.
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PMID:Endogenous and exogenous cardiac glycosides and their mechanisms of action. 1761 Mar 45

Ouabain is Na(+)/K(+)-ATPase inhibitor and an endogenous regulator of blood pressure, it has dual effect on vascular endothelial cells(VEC) cell growth and VEC apoptosis is contributed to vascular dysfunction involved in vascular remolding. However, the precise mechanisms of apoptosis induced by ouabain remained unclear. The objective of this study was to identify the differently expressed proteins involved in VEC apoptosis induced by ouabain in order to explore cellular and subcellular mechanisms related to ouabain actions. Human umbilical vein endothelial cells (HUVEC) were exposed to increasing concentrations (0.1 nM to 10 microM) of ouabain at 12-48 h intervals. Cell viability tests revealed that high concentrations of ouabain inhibited cell growth. Flow cytometry and caspase-3 activity analysis confirmed that apoptosis was primarily responsible for ouabain induced cell death. Two-dimensional electrophoresis in conjunction with mass spectrometry revealed that the ouabain-induced apoptosis was accompanied by regulated expression of programmed cell death protein 6, cytochrome C1, endothelin converting enzyme, claudin-1, reticulon-4, galectin-1, ras-related protein rab-11B, calnexin, profilin-1 and heat shock protein 60 (HSP60). Further study on cytochrome c and HSP60 demonstrated that levels of mitochondria and cytosol cytochrome c and HSP60 changed in response to ouabain treatment. Data showed that mitochondria proteins such as HSP60 interferes with HSP60-Bax interactions played an important role in ouabain induced apoptosis. These data bring new sights into physiological role for ouabain in VEC apoptosis and vascular remodeling, thus provide new strategies for new anti-cardiovascular disease drug development or the identification of biomarkers for vascular dysfunction in ouabain related hypertension.
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PMID:Proteomics investigation of protein expression changes in ouabain induced apoptosis in human umbilical vein endothelial cells. 1824 27

Marinobufagenin (MBG) is an endogenous mammalian cardiotonic steroid that is involved in the inhibition of the sodium pump Na(+)/K(+)-ATPase. Increased plasma levels of MBG have been reported in patients with volume expansion-mediated hypertension and preeclampsia. We have recently demonstrated that MBG impairs both the proliferation and growth factor-induced migration of human first trimester cytotrophoblast (CTB) cells, crucial for proper placental development. However, the intracellular signaling mechanisms regulating the MBG-induced impairment of CTB differentiation, migration and invasion are unknown. The human extravillous CTB cell line SGHPL-4 was utilized for this study. The phosphorylation of MAP kinase protein ERK1/2 was evaluated by Cellular Activation of Signaling ELISA (CASE) in control CTB cells and those treated with MBG. MBG at concentrations of 10 and 100nM inhibited CTB cell proliferation, migration and invasion (60%, 50% and 50%, respectively). MBG also caused a significant decrease in the phosphorylation of ERK1/2. In addition, MBG decreased proliferation, migration, and ERK1/2 activity in another motile cell line, CHO cells. Another sodium pump inhibitor, ouabain, similarly decreased proliferation and ERK1/2 activity in CTB and CHO cells. These data suggest that the changes observed in cell function may be mediated by inhibition of Na(+)/K(+)-ATPase. We demonstrate that the MBG-induced impairment of CTB cell proliferation, migration and invasion is associated with decreased ERK1/2 activity which may be mediated by inhibition of Na(+)/K(+)-ATPase.
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PMID:Marinobufagenin inhibits proliferation and migration of cytotrophoblast and CHO cells. 1827 54

Marinobufagenin (MBG) is an endogenous mammalian cardiotonic steroid involved in the inhibition of Na(+)/K(+)-ATPase. Increased plasma levels have been reported in patients with volume expansion-related hypertension. We have recently demonstrated that MBG impairs first trimester cytotrophoblast (CTB) cell proliferation, migration, and invasion, which may play a role in the development of preeclampsia. However, whether apoptosis contributes to altered CTB cell function by MBG remains unknown. Using the human extravillous CTB cell line SGHPL-4, we examined the effect of MBG and a similar Na(+)/K(+)-ATPase inhibitor, ouabain, on the phosphorylation status of Jnk, p38, and Src. Additionally, we measured apoptosis by caspase 9 and 3/7 activity and by annexin-V staining. We also investigated interleukin-6 (IL-6) secretion with or without p38 and Jnk inhibition. MBG significantly increased the phosphorylation of Jnk, p38, and Src and increased the expression of caspase 9 and 3/7 indicating the activation of apoptosis. MBG treatment also stimulated the expression of the early apoptosis marker, annexin-V, which was prevented by Jnk and p38 inhibition. MBG also stimulated the secretion of IL-6, which was attenuated by p38 inhibition. Ouabain had similar effects to those of MBG, suggesting that the apoptotic effects on CTB cells may be mediated by inhibition of Na(+)/K(+)-ATPase. In conclusion, the MBG-induced impairment of CTB function occurs via activation of Jnk, p38, and Src leading to increased apoptosis and IL-6 secretion. These observations may have clinical applicability with respect to the therapy of preeclampsia.
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PMID:Examination of the cellular mechanisms by which marinobufagenin inhibits cytotrophoblast function. 1843 1

Compelling evidence is accumulating indicating a pathophysiological role of the serum-and-glucocorticoid-inducible-kinase-1 (SGK1) in the development and complications of diabetes. SGK1 is ubiquitously expressed with exquisitely high transcriptional volatility. Stimulators of SGK1 expression include hyperglycemia, cell shrinkage, ischemia, glucocorticoids and mineralocorticoids. SGK1 is activated by insulin and growth factors via PI3K, 3-phosphoinositide dependent kinase PDK1 and mTOR. SGK1 activates ion channels (including ENaC, TRPV5, ROMK, KCNE1/KCNQ1 and CLCKa/Barttin), carriers (including NCC, NKCC, NHE3, SGLT1 and EAAT3), and the Na(+)/K(+)-ATPase. It regulates the activity of several enzymes (e.g., glycogen-synthase-kinase-3, ubiquitin-ligase Nedd4-2, phosphomannose-mutase-2), and transcription factors (e.g., forkhead-transcription-factor FOXO3a, beta-catenin and NF-kappaB). A common SGK1 gene variant ( approximately 3 - 5% prevalence in Caucasians, approximately 10% in Africans) is associated with increased blood pressure, obesity and type 2 diabetes. In patients suffering from type 2 diabetes, SGK1 presumably contributes to fluid retention and hypertension, enhanced coagulation and increased deposition of matrix proteins leading to tissue fibrosis such as diabetic nephropathy. Accordingly, targeting SGK1 may favourably influence occurrence and course of type 2 diabetes.
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PMID:Targeting SGK1 in diabetes. 1976 91

Heterocyclic indazole derivatives are claimed in patent WO2008138448 as inhibitors of the serum- and glucocorticoid-inducible-kinase 1 (SGK1) and drugs for the pharmacological treatment of SGK1-related diseases, such as diabetes, obesity, metabolic syndrome, systemic and pulmonary hypertension, cardiac fibrosis, hypertrophy and insufficiency, arteriosclerosis, glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, deranged electrolyte excretion, fibrosing and inflammatory disease (e.g., liver cirrhosis, lung fibrosis, rheumatism, arthrosis, Crohn s disease, chronic bronchitis, radiation fibrosis, sclerodermia, cystic fibrosis, scar formation and Alzheimer' disease), tumor growth, peptic ulcers and some disorders hitherto not conclusively shown to involve SGK1. Most of the claims are supported by the literature. SGK1 is ubiquitously expressed and its expression is stimulated by hyperglycemia, cell shrinkage, ischemia, glucocorticoids, mineralocorticoids and several inflammatory mediators including TGF-ss. SGK1 is activated by insulin and growth factors via the phosphatidylinositol-3-kinase pathway. SGK1 regulates ion channels (including ENaC, KCNE1/KCNQ1), carriers (including NCC, NHE3, SGLT1), Na(+)/K(+)-ATPase, enzymes (including glycogen-synthase-kinase-3) and transcription factors (including FOXO3a, ss-catenin, NF-kappaB). A gain-of-function SGK1 gene variant, carried by approximately 3 - 5% of Caucasians and approximately 10% of Africans, is associated with increased blood pressure, obesity and type 2 diabetes. In vitro and in vivo experiments suggested a critical role of SGK1 in renal fluid retention and hypertension, glucose-induced obesity, coagulation and increased matrix protein formation.
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PMID:Heterocyclic indazole derivatives as SGK1 inhibitors, WO2008138448. 2002 Dec 89

The enzyme kinetics of cardiac Na(+)/K(+)-ATPase were used for characterizing the ATP- and Na(+)-binding sites after administration of red wine polyphenolic compounds (Provinol) during developing and sustained hypertension. Hypertension was induced in rats (LN group) by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 40 mg*kg(-1)*day(-1)). Provinol (40 mg*kg(-1)*day(-1)) was applied during developing hypertension (LNPF4 group) and sustained hypertension (LNPF7/3 group). Provinol reduced the number of active Na(+)/K(+)-ATPase molecules in cardiac tissue, as indicated by decreased V(max) values (by 33% in LNPF4 and 26% in LNPF7/3 compared with LN). Concerning qualitative properties of the enzyme, Provinol induced different effects on the ATP- and Na(+)-binding sites of Na(+)/K(+)-ATPase. The ATP-binding site was impaired by Provinol, as indicated by increased K(m) value (by 52% in LNPF4 vs. LN), suggesting worsened utilization of substrate by the enzyme. In sustained hypertension, however, Provinol had no effect on the ATP-binding site, as indicated by unchanged K(m) value (LNPF7/3 vs. LN). On the other hand, the Na(+)-binding site was protected by Provinol, as suggested by decreased K(Na) value (by 72% in LNPF4 and 69% in LNPF7/3 vs. LN), indicating an increased affinity of the enzyme for sodium. Thus, Provinol appeared to stimulate the extrusion of Na(+) from cardiac cells, especially in the physiologically important range of sodium concentrations (2-10 mmol*L(-1)), during both developing and sustained hypertension.
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PMID:Dual effect of polyphenolic compounds on cardiac Na+/K+-ATPase during development and persistence of hypertension in rats. 2002 41

1. Abnormal renal sodium handling is considered a major contributing factor in hypertension associated with chronic ouabain treatment. However, the molecular mechanisms involved in abnormal renal sodium handling have not been elucidated. Therefore, we investigated whether chronic ouabain treatment perturbs dopamine D(1) receptor function. 2. The expression and phosphorylation levels of the D(1) receptor in cells of the human proximal tubule cell line (HK-2) were determined using western blot analysis and reverse transcription polymerase chain reaction. The activity of the renal sodium/potassium pump (Na(+)/K(+)-ATPase) was measured using a colourimetric assay, and cyclic adenosine monophosphate accumulation was determined by performing a radioimmunoassay. 3. We showed that chronic ouabain treatment decreased the protein and mRNA expression levels of the D(1) receptor and increased the basal phosphorylation of the D(1) receptor in HK-2 cells. We also showed that in the presence of ouabain, HK-2 cells did not reveal the cyclic adenosine monophosphate accumulation and Na(+)/K(+)-ATPase inhibition induced by the D(1) receptor agonist fenoldopam. 4. We hypothesize that the ouabain-induced decrease in renal D(1) receptor function is responsible for the increase in renal sodium reabsorption, which eventually leads to ouabain-induced hypertension.
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PMID:Dopamine-mediated inhibition of renal Na+/K+-ATPase in HK-2 cells is reduced by ouabain. 2013 39

Na(+)-transport regulating mechanisms classically considered to reflect renal control of sodium homeostasis and BP, i.e. aldosterone-mineralocorticoid receptors (MR)-epithelial sodium channels (ENaC)-Na(+)/K(+)-ATPase have now been demonstrated to also be present in the central nervous system. This pathway is being regulated independently of the peripheral/renal pathway and contributes to regulation of cerebrospinal fluid [Na(+)] by the choroid plexus, of brain tissue [Na(+)] by the ependyma and to neuronal responses to e.g. Na(+) or angiotensin II. Increases in CSF [Na(+)] by central infusion of Na(+)-rich aCSF or by high salt intake in Dahl S or SHR cause sympatho-excitation and hypertension. These responses appear to depend on activation of a CNS cascade starting with aldosterone-MR-ENaC-"ouabain," the latter lowering neuronal membrane potential leading to enhanced angiotensin II release in e.g. the PVN. Specific CNS blockade of any of the steps in this cascade from aldosterone synthase blockade to AT(1)-receptor blockade prevents the sympathetic hyperactivity and hypertension on high salt intake, irrespective of the presence of a "salt-sensitive kidney." We propose that in salt-sensitive hypertension an increase in CSF [Na(+)] causes a local increase in aldosterone biosynthesis which activates an aldosterone dependent neuromodulatory pathway which enhances activity of angiotensinergic sympatho-excitatory pathways leading to hypertension.
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PMID:The central role of the brain aldosterone-"ouabain" pathway in salt-sensitive hypertension. 2023 Aug 92


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