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: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activities of fumarase and 3-hydroxyacylCoA dehydrogenase (3-OHDH) were determined in homogenates of rat kidneys between day 21 of gestation and postnatal day 10 and in single isolated nephron segments at postnatal days 16, 21, and 30, and in adult segments. For 3-OHDH activity, main developmental changes were found in proximal convoluted (PCT) and straight tubules (PST) and were characterized by an overshoot of adult level from postnatal days 21 to 30 (59.7 +/- 3.0 and 37.5 +/- 3.4 at day 21 vs. adult values 27.1 +/- 1.5 and 22.7 +/- 1.5 mol.kg dry wt-1.h-1). When rats were precociously weaned on day 16 and fed a diet containing lipid to equal 13% of total caloric intake, a significant decrease in 3-OHDH activity was observed in some parts of the nephron. These changes could be prevented by maintaining early weaned animals on high-fat diet providing 70% of total calories as lipid. Results suggest that changes in fat content of diet during kidney maturation can in part regulate 3-OHDH activity in some nephron segments. Fumarase activity increased 2.6-fold in the medullary thick ascending limb between days 16 and 30; pattern of development was similar to the one reported for Na(+)-K(+)-ATPase activity in this segment. High levels of both enzymes were reached noticeably earlier during development in PCT and PST than in medullary thick ascending limb, which emphasizes metabolic heterogeneity of developing rat kidney nephron.
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PMID:Postnatal development of oxidative enzymes in various rat nephron segments: effect of weaning on different diets. 226 Jun 82

We determined the effect of dexamethasone on Na-K-ATPase activity in six nephron segments of the adrenalectomized rabbit. Treatment consisted of 1.4 micrograms dexamethasone X 100 g body wt-1 X day-1 for 7 days prior to the study of the nephron segments. Enzyme activity was determined in individual nephron segments by a microfluorometric assay. There was 40-50% less activity of Na-K-ATPase in the S1 portion of the proximal convoluted tubule (PCT, S1), the medullary thick ascending limb (MTAL), and the distal convoluted tubule (DCT) of adrenalectomized rabbits compared with that of control (sham-operated) animals. There was no significant difference in the enzyme activity in proximal straight tubules (PST, S2 and S3) and cortical thick ascending limb (CTAL) of adrenalectomized and control animals. Dexamethasone treatment produced a dexamethasone concentration of 5 +/- 0.8 nM in the plasma and increased Na-K-ATPase activity in PCT (S1), MTAL, and DCT of the adrenalectomized animals to the control levels without significantly affecting the enzyme activity in the PST (S2, S3) or CTAL. The concentration of dexamethasone in the plasma was such that the hormone should bind mainly to dexamethasone receptors (Kd = 5 nM) and very little to aldosterone receptors (Kd greater than 60 nM). Thus, glucocorticoids probably stimulate Na-K-ATPase in PCT, MTAL, and DCT through glucocorticoid (Type II) receptors and not through mineralocorticoid (Type I) receptors.
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PMID:Glucocorticoid effects on Na-K-ATPase in rabbit nephron segments. 298 45

The enzyme catechol-O-methyltransferase (COMT), which plays an important role for dopamine metabolism, is abundantly expressed in the kidney. To test whether the natriuretic effects of dopamine may be related to the rate of dopamine metabolism, rats were treated with nitecapone, a peripheral inhibitor of COMT. Nitecapone, given by gavage, induced a highly significant (5.6-fold) increase in sodium excretion, which was associated with an inhibition of the Na+,K+-ATPase activity in both the proximal convoluted and proximal straight tubules (PCT and PST, respectively). These effects were completely abolished if the rats were also treated with a specific dopamine 1 antagonist, SCH 23390. Furthermore, the natriuretic effect of nitecapone was also observed in rats on a high salt diet. The kidney-specific pro-drug to dopamine, glu-dopa, induced a significant, but less pronounced increase in urinary sodium excretion, associated with a dopamine-dependent inhibition of the Na+,K+-ATPase activity in the PCT but not in the PST. Nitecapone and glu-dopa had an additive natriuretic effect. It is concluded that COMT plays an important role in determining the natriuretic effects of the renal dopamine system.
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PMID:Inhibition of COMT induces dopamine-dependent natriuresis and inhibition of proximal tubular Na+,K+-ATPase. 929 Nov 95

A major biologically active Na,K-ATPase inhibitor in the mammalian body may be ouabain-like compound. We investigated the potential roles of circulating ouabain-like compound in the regulation of Na+ and K+ homeostasis in terms of Na+ and K+ distribution between the cells and the extracellular fluid (internal balance). First, we developed a population of rats immunized against ouabain to block the action of ouabain-like compound. We measured plasma and intracellular Na+ and K+ concentrations in skeletal muscle and determined Na+ (extracellular-to-intracellular concentration ratio) and K+ (intracellular-to-extracellular concentration ratio) gradients in immune rats. We examined also the ability to respond to hypertonic NaCl load in immune rats. Consistent lower plasma K+ levels and steeper Na+ and K+ gradients were observed in immune rats. K+ handling in response to hypertonic NaCl load was altered, and lower plasma K+ level was maintained in immune rats. Second, we used PST-2238, a newly developed anti-ouabain agent, to block the action of ouabain-like compound and examined its effect on plasma Na+ and K+ concentrations. Chronic administration of PST-2238 significantly lowered plasma K+ levels in rats with subtotal nephrectomy. These findings collectively suggest that ouabain-like compound may determine at least in part the internal Na+ and K+ distribution and the transmembrane cation gradients in vivo in rats.
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PMID:Role of ouabain-like compound in the regulation of transmembrane sodium and potassium gradients in rats. 932 18

The inhibition of the long-term pressor effect of ouabain may be useful for the therapy of essential hypertension. Here, for the first time, a selective inhibitor of the ouabain pressor effect is described. In vitro, 17beta-(3-furyl)-5beta-androstane-3beta, 14beta, 17alpha-triol (PST 2238) displaced ouabain from its binding sites on purified sodium, potassium ATPase enzyme (Na-K ATPase) (IC50 1.7 x 10(-6) M) without interacting with other receptors involved in blood pressure regulation or hormonal control. In cultured renal cells, incubation with ouabain (10(-10) to 10(-8) M) for 5 days stimulated the Na-K pump at Vmax, whereas PST 2238 showed the same effect at micromolar concentration. The ouabain-dependent increase in the Na-K pump rate was abolished by PST 2238 at concentrations from 10(-14) to 10(-9) M. In rats made hypertensive by chronic infusion of 50 microg/kg/day of ouabain, PST 2238 given p.o at very low doses (0.1-1 microg/kg/day for 4 weeks) abolished the increase in blood pressure and renal Na-K ATPase activity caused by ouabain. PST 2238 did not affect either blood pressure or renal Na-K ATPase activity in normotensive rats. In conclusion, PST 2238 is a very potent compound that normalizes both blood pressure and alterations in the Na-K pump caused by ouabain. Thus it represents the prototype of a new class of antihypertensive drugs that could be effective in forms of hypertension sustained by the concomitant increase of endogenous ouabain levels and alterations in the Na-K pump.
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PMID:PST2238: a new antihypertensive compound that antagonizes the long-term pressor effect of ouabain. 953 97

A genetic alteration in the adducin genes is associated with hypertension and up-regulation of the expression of renal Na, K-ATPase in Milan-hypertensive (MHS) rats, in which increased ouabain-like factor (OLF) levels are also observed. PST 2238, a new antihypertensive compound that antagonizes the pressor effect of ouabain in vivo and normalizes ouabain-dependent up-regulation of the renal Na-K pump, was evaluated for its ability to lower blood pressure and regulate renal Na,K-ATPase activity in MHS genetic hypertension. In this study, we show that PST 2238, given orally at very low doses (1 and 10 microg/kg for 5-6 weeks), reduced the development of hypertension in MHS rats and normalized the increased renal Na,K-ATPase activity and mRNA levels, whereas it did not affect either blood pressure or Na,K-ATPase in Milan-normotensive (MNS) rats. In addition, a similar antihypertensive effect was observed in adult MHS rats after a short-term treatment. In cultured rat renal cells with increased Na-K pump activity at Vmax due to overexpression of the hypertensive variant of adducin, 5 days of incubation with PST 2238 (10(-10-)-10(-9) M) lowered the pump rate to the level of normal wild-type cells, which in turn were not affected by the drug. In conclusion, PST 2238 is a very potent compound that in MHS rats reduces blood pressure and normalizes Na-K pump alterations caused by a genetic alteration of the cytoskeletal adducin. Because adducin gene mutations have been associated with human essential hypertension, it is suggested that PST 2238 may display greater antihypertensive activity in those patients carrying such a genetic alteration.
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PMID:PST 2238: A new antihypertensive compound that modulates Na,K-ATPase in genetic hypertension. 1002 44

A primary impairment of the kidney sodium excretion has been documented both in hypertensive patients (EH) and genetic animal models (Milan hypertensive rat [MHS]) carrying mutations of the cytoskeletal protein adducin and/or increased plasma levels of endogenous ouabain (EO). Ouabain (OU) itself induces hypertension in rats and both OU and mutated adducin activate the renal Na/K-ATPase function both in vivo and in cultured renal cells (NRK). A new antihypertensive agent, PST 2238, able to selectively interact with these alterations has been developed. PST lowers blood pressure (BP) by normalizing the expression and activity of the renal Na-K pump selectively in those rat models carrying the adducin mutation (MHS) and/or increased EO levels (OS) at oral doses of 0.1-10 micro g/kg. In NRK cells either transfected with mutated adducin or incubated with 10(-9) M OU, PST normalizes the Na-K pump activity. Recently, an association between EO and cardiac complications has been observed in both EH and rat models consistent with a prohypertrophic activity of OU. OS rats showed a 10% increase of left ventricle and kidney weights as compared with controls, and PST 2238 (1 micro g/kg OS) prevented both ventricle and renal hypertrophy. This effect was associated with the ability of PST to antagonize the OU-dependent activation of growth-related genes, in the membrane subdomains of caveolae. In conclusion, PST is a new antihypertensive agent that may prevent cardiovascular complications associated with hypertension through the selective modulation of the Na-K pump function.
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PMID:Antihypertensive compounds that modulate the Na-K pump. 1276 20

The design, synthesis, and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as potential positive inotropic compounds are reported. Following our model of superposition between cassaine and digitoxigenin, digitalis-like activity has been elicited from a non-digitalis steroidal structure by suitable modifications of the 5alpha,14alpha-androstane skeleton. The strong hydrophobic interaction of the digitalis or cassaine polycyclic cores can be effectively obtained with the androstane skeleton taken in a reversed orientation. Thus, oxidation of C-6 and introduction in the C-3 position of the potent pharmacophoric group recently introduced by us, in the 17 position of the digitalis skeleton, namely, O-(omega-aminoalkyl)oxime, led to a series of substituted androstanes able to inhibit the Na(+),K(+)-ATPase, most of them with an IC(50) in the low micromolar level, and to induce a positive inotropic effect in guinea pig. Within this series, androstane-3,6,17-trione (E,Z)-3-(2-aminoethyl)oxime (22b, PST 2744) induced a strong positive inotropic effect while being less arrhythmogenic than digoxin, when the two compounds were compared at equiinotropic doses.
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PMID:Structure-based design and synthesis of novel potent Na+,K+ -ATPase inhibitors derived from a 5alpha,14alpha-androstane scaffold as positive inotropic compounds. 1290 68

In addition to inhibition of the Na-K ATPase, ouabain activates a signal transduction function, triggering growth and proliferation of cultured cells even at nanomolar concentrations. An isomer of ouabain (EO) circulates in mammalians at subnanomolar concentrations, and increased levels are associated with cardiac hypertrophy and hypertension. We present here a study of cardiac and renal hypertrophy induced by ouabain infused into rats for prolonged periods and relate this effect to the recently described ouabain-induced activation of the Src-EGFr-ERK signaling pathway. Ouabain infusion into rats (15 microg/kg/day for 18 weeks) doubled plasma ouabain levels from 0.3 to 0.7 nm and increased blood pressure by 20 mm Hg (p < 0.001), cardiac left ventricle (+11%, p < 0.05), and kidney weight (+9%, p < 0.01). These effects in vivo are associated with a significant enrichment of alpha1, beta1, gammaa Na-K ATPase subunits together with Src and EGFr in isolated renal caveolae membranes and activation of ERK1/2. In caveolae, direct Na-K ATPase/Src interactions can be demonstrated by co-immunoprecipitation. The interaction is amplified by ouabain, at a high affinity binding site, detectable in caveolae but not in total rat renal membranes. The high affinity site for ouabain is associated with Src-dependent tyrosine phosphorylation of rat alpha1 Na-K ATPase. The antihypertensive compound, PST 2238, antagonized all ouabain-induced effects at 10 microg/kg/day in vivo or 10(-10)-10(-8) m in vitro. These findings provide a molecular mechanism for the in vivo pro-hypertrophic and hypertensinogenic activity of ouabain, or by analogy those of EO in humans. They also explain the pharmacological basis for PST 2238 treatment.
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PMID:Organ hypertrophic signaling within caveolae membrane subdomains triggered by ouabain and antagonized by PST 2238. 1516 29

Sigma-Tau is developing PST-2238, the prototype of a new class of hypertensive steroidal ATPase modulators, for the potential treatment of hypertension [169159]. Phase II trials were ongoing in early 2002 [441505].
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PMID:PST-2238 Sigma-Tau. 1557 Apr 67


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