Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P20020 (adenosine triphosphatase)
3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental evidence and observations in humans strongly support an interactive role of mutated alpha-adducin, sodium (Na(+))/potassium (K(+))-adenosine triphosphatase (ATPase) activity and endogenous ouabain in Na(+) homeostasis and the pathogenesis of hypertension. The Ouabain and Adducin for Specific Intervention on Sodium in HyperTension (OASIS-HT) trial is an early Phase II dose-finding study, which will be conducted across 39 European centers. Following a run-in period of 4 weeks without treatment, eligible patients will be randomized to one of five oral doses of rostafuroxin consisting of 0.05, 0.15, 0.5, 1.5, or 5.0 mg/day. Each dose will be compared to a placebo in a double-blind crossover experiment with balanced randomization. Treatment will be initiated with the active drug and continued with placebo or vice versa. Each double-blind period will last 5 weeks. The primary end point is the reduction in systolic blood pressure defined as the average of three clinic readings with the patient in the sitting position. Secondary end points include the reduction in diastolic blood pressure on clinic measurement, the decrease in the 24-h blood pressure, and the incidence of end points related to safety. Secondary objectives are to investigate the dependence of the blood pressure-lowering activity on the plasma concentration of endogenous ouabain and the genetic variation of the enzymes involved in the metabolism of this hormone, and the adducin cytoskeleton proteins. Eligible patients will have Grade I or II systolic hypertension without associated conditions and no more than two additional risk factors. In conclusion, OASIS-HT is a combination of five concurrent crossover studies, one for each dose of rostafuroxin to be studied. To our knowledge, OASIS-HT is the first Phase II dose-finding study in which a genetic hypothesis is driving primary and secondary end points.
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PMID:OASIS-HT: design of a pharmacogenomic dose-finding study. 1620 52

Diabetes mellitus induces a decrease in sodium potassium-adenosine triphosphatase (Na+/K(+)-ATPase) activity in several tissues in the rat and red blood cells (RBC) and nervous tissue in human patients. This decrease in Na+/K(+)-ATPase activity is thought to play a role in the development of long-term complications of the disease. Angiotensin enzyme inhibitors (ACEi) and angiotensin-II receptor antagonists (ARBs) reduce proteinuria and retard the progression of renal failure in patients with IDDM and diabetic rats. We investigated the effects of captopril and losartan, which are used in the treatment of diabetic nephropathy, on Na+/K(+)-ATPase activity. Captopril had an inhibitory effect on red cell plasma membrane Na+/K+ ATPase activity, but losartan did not. Our study draws attention to the inhibitory effect of captopril on Na+/K+ ATPase activity. Micro and macro vascular complications are preceeding mortality and morbidity causes in diabetes mellitus. There is a strong relationship between the decrease in Na+/K+ ATPase activity and hypertension. The non-sulphydryl containing ACEi and ARBs must be the choice of treatment in hypertensive diabetic patients and diabetic nephropathy.
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PMID:The effects of captopril and losartan on erythrocyte membrane Na+/K(+)-ATPase activity in experimental diabetes mellitus. 1751 48

Dopamine plays an important role in regulating renal function and blood pressure. Dopamine synthesis and dopamine receptor subtypes have been shown in the kidney. Dopamine acts via cell surface receptors coupled to G proteins; the receptors are classified via pharmacologic and molecular cloning studies into two families, D1-like and D2-like. Two D1-like receptors cloned in mammals, the D1 and D5 receptors (D1A and D1B in rodents), are linked to adenylyl cyclase stimulation. Three D2-like receptors (D2, D3, and D4) have been cloned and are linked mainly to adenylyl cyclase inhibition. Activation of D1-like receptors on the proximal tubules inhibits tubular sodium reabsorption by inhibiting Na/H-exchanger and Na/K-adenosine triphosphatase activity. Reports exist of defective renal dopamine production and/or dopamine receptor function in human primary hypertension and in genetic models of animal hypertension. In humans with essential hypertension, renal dopamine production in response to sodium loading is often impaired and may contribute to hypertension. A primary defect in D1-like receptors and an altered signaling system in proximal tubules may reduce dopamine-mediated effects on renal sodium excretion. The molecular basis for dopamine receptor dysfunction in hypertension is being investigated, and may involve an abnormal posttranslational modification of the dopamine receptor.
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PMID:Dopamine receptors and hypertension. 1862 55

The blood-brain barrier (BBB) impedes the influx of intravascular compounds from the blood to the brain. Few blood-borne macromolecules are transferred into the brain because vesicular transcytosis in the endothelial cells is considerably limited and the tight junction is located between the endothelial cells. At the first line of the BBB, the endothelial glycocalyx which is a negatively charged, surface coat of proteoglycans, and adsorbed plasma proteins, contributes to the vasculoprotective effects of the vessels wall and are involved in maintaining vascular permeability. In the endothelial cytoplasm of cerebral capillaries, there is an asymmetrical array of metabolic enzymes such as alkaline phosphatase, acid phosphatase, 5'-nucleotidase, adenosine triphosphatase, and nucleoside diphosphatase and these enzymes contribute to inactivation of substrates. In addition, there are several types of influx or efflux transporters at the BBB, such as P-glycoprotein (P-gp), multidrug resistance associated protein, breast cancer resistance protein, organic anion transporters, organic cation transporters, organic cation transporter novel type transporters, and monocarboxylic acid transporters. P-gp, energy-dependent efflux transporter protein, is instrumental to the barrier function. Several findings recently reported indicate that endothelial P-gp contributes to efflux of undesirable substances such as beta-amyloid protein from the brain or periarterial interstitial fluid, while P-gp likely plays a crucial role in the genesis of multiple vascular abnormalities that accompany hypertension. In this review, influx and efflux mechanisms of drugs at the BBB are also reviewed and how medicines pass the BBB to reach the brain parenchyma is discussed.
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PMID:Mechanisms of the penetration of blood-borne substances into the brain. 1994 73

Due to their implication in numerous diseases like cancer, cystic fibrosis, epilepsy, hyperinsulinism, heart failure, hypertension, and Alzheimer disease, membrane proteins (MPs) represent around 50% of drug targets. However, only 204 crystal structures of MPs have been solved. Structural analysis requires large quantities of pure and active proteins. The majority of medically and pharmaceutically relevant MPs are present in tissues at low concentration, which makes heterologous expression in large-scale production-adapted cells a prerequisite for structural studies. The yeast Saccharomyces cerevisiae is a convenient host for the production of mammalian MPs for functional and structural studies. Like bacteria, they are straightforward to manipulate genetically, are well characterized, can be easily cultured, and can be grown inexpensively in large quantities. The advantage of yeast compared to bacteria is that they have protein-processing and posttranslational modification mechanisms related to those found in mammalian cells. The recombinant rabbit muscle Ca(2+)-ATPase (adenosine triphosphatase), the first heterologously expressed mammalian MP for which the crystal structure was resolved, has been produced in S. cerevisiae. In this chapter, the focus is on expression of recombinant human integral MPs in a functional state at the plasma membrane of the yeast S. cerevisiae. Optimization of yeast culture and of MP preparations is detailed for two human receptors of the Hedgehog pathway: Patched and Smoothened.
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PMID:Heterologous expression of human membrane receptors in the yeast Saccharomyces cerevisiae. 2009 41

The bufodienolides are cardiac glycosides which have the ability to inhibit the enzyme, Na(+)/K(+) ATPase (sodium potassium adenosine triphosphatase). They are cardiac inotropes, cause vasoconstriction (and, potentially, hypertension) and are natriuretic. Evidence has accrued over time which supports the view that they are mechanistically involved in volume expansion-mediated hypertension. In this communication, the authors summarize data which support the view that the bufodienolides and, in particular, marinobufagenin (MBG) are involved in the pathogenesis of preeclampsia. In a rat model of the syndrome, MBG causes hypertension, proteinuria, intrauterine growth restriction and increased weight gain. All of these phenotypic characteristics are prevented by an antagonist to MBG, resibufogenin (RBG). The "preeclamptic" animals also develop a vascular leak syndrome, resulting in hemoconcentration. Abnormalities in the MAPK (mitogen-activated protein kinase) system play a role in the mechanism by which MBG produces the abnormalities in the pregnant rat. Studies to discover the relevance of these findings to human preeclampsia are currently underway in several laboratories and clinics.
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PMID:Marinobufagenin, resibufogenin and preeclampsia. 2016 72

The bufadienolides are a group of steroid hormones that circulate in blood and are excreted in urine. They have the ability to inhibit the adenosine triphosphatase sodium-potassium pump (Na(+)-K(+)-ATPase), with predilection for its alpha1 isoform. This capability enables them to share with other cardiac glycosides the facility to cause an increase in sodium excretion, produce vasoconstriction resulting in hypertension, and act as cardiac inotropes. Bufadienolides have been implicated in instances of volume expansion-mediated hypertension, syndromes in which they are considered capable of causing a vascular leak, interfering with cellular proliferation, and inhibiting cellular maturation. An antagonist to the most well-studied bufadienolide, marinobufagenin, is resibufogenin, a compound that provides promise for the treatment of disorders in which excessive levels of marinobufagenin are present and are etiopathogenetic.
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PMID:Emerging role of the bufadienolides in cardiovascular and kidney diseases. 2041 1

Dopamine receptor, via D(1)-like and D(2)-like receptors, increases sodium excretion in kidney. We have reported positive interactions between D(3) and D(1) receptors in renal proximal tubule (RPT) cells. These reports, however do not preclude that there may be also interaction between D(3) and D(5) receptors, because of the lack of selective D(1) and D(5) receptor agonists or antagonists. We hypothesize that D(3) receptors can regulate D(5) receptors, and that D(3) receptor regulation of D(5) receptors in RPTs is impaired in spontaneously hypertensive rats (SHRs). It showed that a D(3) receptor agonist, PD128907, by the activation of protein kinase C activity, increased the expression of D(5) receptors in a concentration- and time-dependent manner in RPT cells from Wistar-Kyoto (WKY) rats. The stimulatory effect of the D(3) receptor on D(5) receptor expression was impaired in RPT cells from SHRs. The effect of D(3) receptor on D(5) receptor is functionally relevant; stimulation of D(5) receptor decreases Na(+)-K(+) adenosine triphosphatase (ATPase) activity in WKY cells. Pretreatment with D(3) receptor agonist for 24 h enhances the D(5) receptor expression and D(5) receptor-mediated inhibitory effect on Na(+)-K(+) ATPase activity in WKY cells, but decreases them in SHR cells. The effect of D(3) receptor on D(5) receptor expression and function was also confirmed in the D(5) receptor-transfected HEK293 cells. It indicates that activation of D(3) receptor increases D(5) receptor expression and function. Altered regulation of D(3) receptor on D(5) receptors may have a role in the pathogenesis of hypertension.
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PMID:D3 dopamine receptor regulation of D5 receptor expression and function in renal proximal tubule cells. 2229 82

We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na(+)-Ca(2+) exchanger isoform 1 mRNA was decreased in vascular smooth muscle cells of KO mice. However, ATP2B4 expression was increased in KO mice. The cultured vascular smooth muscle cells of KO mice showed increased intracellular calcium concentration not only in basal condition but also in phenylephrine-stimulated condition. Furthermore, phenylephrine-induced vasoconstriction was significantly increased in vascular rings of the femoral artery of KO mice. These results suggest that ATP2B1 plays important roles in the regulation of blood pressure through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells.
Hypertension 2012 Apr
PMID:Mice lacking hypertension candidate gene ATP2B1 in vascular smooth muscle cells show significant blood pressure elevation. 2231 9

The ability of cells to maintain sharp ion gradients across their membranes is the foundation for the molecular transport and electrical excitability. Across animal species and cell types, Na(+),K(+)-adenosine triphosphatase (ATPase) is arguably the most powerful contributor to this phenomenon. By producing a steep concentration difference of sodium and potassium between the intracellular and extracellular milieu, Na(+),K(+)-ATPase in the tubules provides the driving force for renal sodium reabsorption. Pump activity is downregulated by natriuretic hormones, such as dopamine, and is upregulated by antinatriuretic hormones, such as angiotensin. In the past decade, studies have revealed a novel and surprising role: that Na(+),K(+)-ATPase is a transducer of signals from extracellular to intracellular compartments. The signaling function of Na(+),K(+)-ATPase is activated by ouabain, a mammalian steroid hormone, at far lower concentrations than those that inhibit pump activity. By promoting growth and inhibiting apoptosis, activation of Na(+),K(+)-ATPase exerts tissue-protective effects. Ouabain-stimulated Na(+),K(+)-ATPase signaling has recently shown clinical promise by protecting the malnourished embryonic kidney from adverse developmental programming. A deeper understanding of the tissue-protective role of Na(+),K(+)-ATPase signaling and the regulation of Na(+),K(+)-ATPase pumping activity is of fundamental importance for the understanding and treatment of kidney diseases and kidney-related hypertension.
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PMID:2011 Homer Smith Award: To serve and protect: classic and novel roles for Na+, K+ -adenosine triphosphatase. 2274 76


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