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)

The present study was aimed at investigating the role of endogenous nitric oxide (NO) in regulating Na,K-ATPase activity in the kidney. The expression of alpha-1 and beta-1 subunits; and the enzymatic activity of Na,K-ATPase were determined in the kidney of rats treated with an NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). Following the treatment with L-NAME in the drinking water for 4 weeks, Na,K-ATPase activity was increased while tissue nitrite/nitrate levels were decreased in the kidney. Supplementation with L-arginine prevented the L-NAME-induced changes. The expression of either alpha-1 or beta-1 subunit protein of Na,K-ATPase, assessed by Western blot analysis, was not affected by L-NAME-treatment. An acute in vitro treatment of the kidney with L-NAME also caused an increase of Na,K-ATPase activity; which was again prevented by cotreatment with L-arginine. On the contrary, treatment with sodium nitroprusside significantly decreased Na,K-ATPase activity. These results suggest that the endogenous NO plays a direct inhibitory role on Na,K-ATPase activity in the kidney.
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PMID:Effects of nitric oxide synthesis inhibition on the Na,K-ATPase activity in the kidney. 1060 Feb 80

Nebivolol is a recently developed beta-blocker provided with vasodilator properties. Because the mechanism of the putative endothelium-dependent effect of this beta-adrenoceptor blocker has not been completely elucidated, the aim of this study was to investigate the effects of nebivolol on an isolated resistance vascular bed and on cell messengers and constitutive nitric-oxide synthase activity (cNOS) in endothelial cells. Experiments were carried out using the rat mesenteric vascular bed and cultured bovine coronary postcapillary venular endothelial cells from bovine heart (CVEC). In mesenteric vascular bed preconstricted by 30 microM noradrenaline and 0.3 microM U46619, dl-nebivolol induced a concentration-dependent relaxing effect at concentrations between 3 and 30 microM; this effect was changed to a concentration-dependent vasoconstrictor response either in endothelium-denuded preparations or in intact preparations pretreated with 100 microM N(omega)-nitro-L-arginine methyl ester plus 3 microM indomethacin. The vasorelaxant effect of dl-nebivolol in preconstricted preparations was completely blocked by pretreatment either with the phospholipase C inhibitor U73122 (1 microM) or with the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin (1 microM) for 30 min. The cellular level of the inositol trisphosphate metabolite inositol monophosphate in coronary postcapillary venular endothelial cells was not affected by dl-nebivolol in the concentration range 100 nM to 1 microM, but it was concentration dependently increased after exposure for 15 min to 10 and 30 microM dl-nebivolol. The activity of cNOS was almost doubled after a 5-min exposure to 10 microM dl-nebivolol and was significantly impaired by thapsigargin and N(omega)-nitro-L-arginine methyl ester treatment, although it was unaffected by N(omega)-nitro-D-arginine methyl ester. These findings demonstrate that nebivolol, in micromolar concentrations, induces vasorelaxation through activation of inositol phosphate metabolism and stimulation of cNOS activity in endothelial cells.
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PMID:Inositol phosphate metabolism and nitric-oxide synthase activity in endothelial cells are involved in the vasorelaxant activity of nebivolol. 1064 Mar 8

The present study was aimed at investigating the role of endogenous nitric oxide (NO) in regulating Na,K-ATPase activity in the kidney. The expression of alpha-1 and beta-1 subunits; and the enzymatic activity of Na,K-ATPase were determined in the kidney of rats treated with an NO synthase inhibitor, N(G)-nitro- l -arginine methyl ester (l -NAME). Following the treatment with l -NAME in the drinking water for 4 weeks, Na,K-ATPase activity was increased while tissue nitrite/nitrate levels were decreased in the kidney. Supplementation with l -arginine prevented the l -NAME-induced changes. The expression of either alpha-1 or beta-1 subunit protein of Na,K-ATPase, assessed by Western blot analysis, was not affected by l -NAME-treatment. An acute in vitro treatment of the kidney with l -NAME also caused an increase of Na,K-ATPase activity; which was again prevented by cotreatment with l -arginine. On the contrary, treatment with sodium nitroprusside significantly decreased Na,K-ATPase activity. These results suggest that the endogenous NO plays a direct inhibitory role on Na,K-ATPase activity in the kidney. 2000 Academic Press@p$hr Copyright 2000 Academic Press.
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PMID:EFFECTS OF NITRIC OXIDE SYNTHESIS INHIBITION ON THE Na,K-ATPase ACTIVITY IN THE KIDNEY. 1071 37

Bone resorption by osteoclasts is modified by agents that affect cyclic guanosine monophosphate (cGMP), but their relative physiological roles, and what components of the process are present in osteoclasts or require accessory cells such as osteoblasts, are unclear. We studied cGMP regulation in avian osteoclasts, and in particular the roles of nitric oxide and natriuretic peptides, to clarify the mechanisms involved. C-type natriuretic peptide drives a membrane guanylate cyclase, and increased cGMP production in mixed bone cells. However, C-type natriuretic peptide did not increase cGMP in purified osteoclasts. By contrast, osteoclasts did produce cGMP in response to nitric oxide (NO) generators, sodium nitroprusside or 1-hydroxy-2-oxo-3,3-bis(3-aminoethyl)-1-triazene. These findings indicate that C-type natriuretic peptide and NO modulate cGMP in different types of bone cells. The activity of the osteoclast centers on HCI secretion that dissolves bone mineral, and both NO generators and hydrolysis-resistant cGMP analogues reduced bone degradation, while cGMP antagonists increased activity. NO synthase agonists did not affect activity, arguing against autocrine NO production. Osteoclasts express NO-activated guanylate cyclase and cGMP-dependent protein kinase (G-kinase). G-kinase reduced membrane HCI transport activity in a concentration-dependent manner, and phosphorylated a 60-kD osteoclast membrane protein, which immunoprecipitation showed is not an H+-ATPase subunit. We conclude that cGMP is a negative regulator of osteoclast activity. cGMP is produced in response to NO made by other cells, but not in response to C-type natriuretic peptide. G-kinase modulates osteoclast membrane HCI transport via intermediate protein(s) and may mediate cGMP effects in osteoclasts.
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PMID:Nitric oxide regulation of cGMP production in osteoclasts. 1073 42

Simvastatin is an inhibitor of HMG-CoA reductase used in the treatment of hypercholesterolemia. In the present study simvastatin-induced contraction was observed in rat aortic thoracic rings, this effect increased when the endothelium was removed and when NO synthase was blocked by L-NOARG (3 x 10(-5) M). The contractile effect of simvastatin on intact aortic rings diminished when cyclo-oxygenase was inhibited with indomethacin (10(-5) M). Also in the presence of endothelium, pretreatment with mevalonate (1 mM), the product of HMG-CoA reductase activity, significantly inhibited the contraction. In other experiments carried out on endothelium-removed preparations and in medium containing the calcium antagonist, diltiazem (10(-5) and 10(-6) M), the contraction dose-response curves were significantly reduced and the same happened in the presence of the inhibitor of sarcoplasmic reticulum Ca-2+-ATPase, cyclopiazonic acid (CPA) (3 x 10(-6) M). The results suggest that simvastatin might increase intracellular calcium concentration. This effect could lead to an activation of NO synthase and cyclooxygenase pathways in endothelial cells and to contraction in vascular smooth muscle cells. This rise in Ca2+ concentration could be due to an inhibition of isoprenoid synthesis prevented by mevalonate.
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PMID:Endothelium modulates contractile response to simvastatin in rat aorta. 1073 11

The purpose of this study was to examine the mechanisms of thapsigargin-induced apoptosis in rat glomerular mesangial cells and the possible involvement of nitric oxide (NO) in this process. In mesangial cell monolayers incubated for 12 h in a medium without growth factors and with 10(-6) M thapsigargin, a known specific inhibitor of endoplasmic reticulum Ca(2+)-ATPase, a high percentage of cells showed typical nuclear features of apoptosis, assessed either by staining with propidium iodide (23 vs. 9% in control conditions) or by terminal desoxynucleotidyl transferase-mediated dUTP biotin nick end labelling (TUNEL; 17 vs. 5% in control conditions). When cells were maintained in a medium containing 10% fetal calf serum (FCS) or in a free-calcium medium, the thapsigargin-induced apoptosis rate was very low. In rat mesangial cells treatment with thapsigargin decreased the expression of BCL-2 protein and bcl-2 mRNA, whereas it did not alter the levels of BAX protein or bax mRNA. When mesangial cells were incubated with thapsigargin in the absence of FCS, we detected a significant increase in nitrite production (3.78 +/- 0.96 vs. 1.76 +/- 0.44 micromol/well). Furthermore, the treatment with the NO synthesis inhibitor L-NAME (10(-4) M) induced a significant decrease in the number of apoptotic cells (9%), whereas incubation with the NO donor SIN-1 (10(-5) M) induced a marked increase in the rate of apoptosis (29%). Western and Northern blot analysis of macrophage-type inducible NO synthase (iNOS) demonstrated that thapsigargin treatment induces the expression of the iNOS protein and iNOS mRNA. Treatment with L-NAME prevented the thapsigargin-induced BCL-2 decrease, whereas incubation with SIN-1 potentiated the effect of thapsigargin on BCL-2. Double labelling by immunohistochemistry for iNOS and TUNEL revealed that the same cells that suffered apoptosis were positive for iNOS. In summary, our results indicate that thapsigargin is able to enhance the apoptosis rate of rat mesangial cells by a mechanism that is mediated by an increase in cytosolic free calcium. Increased iNOS expression, and hence increased NO production, seems to be involved in this effect.
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PMID:Nitric oxide is involved in apoptosis induced by thapsigargin in rat mesangial cells. 1074 95

A significant role for nitric oxide (NO) in proximal tubule physiology and pathophysiology has been revealed by a series of in vivo and in vitro studies. Whether the proximal tubule produces NO under basal conditions is still controversial; however, evidence suggests that the proximal tubule is constantly exposed to NO that might include NO from nonproximal tubule sources. When challenged with a variety of stimuli, including hypoxia, the proximal tubule is able to produce large quantities of NO. In vivo studies generally indicate that NO inhibits fluid and sodium reabsorption by the proximal tubule. However, the final effect of NO on proximal tubular reabsorption appears to depend on the concentration of NO and involve interaction with other regulatory mechanisms. NO regulates Na(+)-K(+)-ATPase, Na(+)/H(+) exchangers, and paracellular permeability of proximal tubular cells, which may contribute to its effect on proximal tubular transport. Enhanced production of NO, perhaps depending on macrophage type inducible NO synthase, participates in hypoxic/ischemic proximal tubular injury. In conclusion, NO plays a fundamental role in both physiology and pathophysiology of the proximal tubule.
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PMID:Production and functional roles of nitric oxide in the proximal tubule. 1080 Dec 77

It is known that hypertension is accompanied by increased [Na+]i. The functional properties of Na,K-ATPase, which transports the Na+ out and K+ into myocardial cells during the relaxation phase, were investigated in the left ventricle (LV), septum (SV) and the right ventricle (RV) of anesthetized dogs with moderate acute blood pressure elevation elicited by short-term (4-hour) NO synthase inhibition. The NO-insufficiency was induced by administration of an L-arginine analogue, the N(G)-nitro-L-arginine methyl ester (L-NAME). Concerning the function of Na,K-ATPase under the conditions of lowered NO synthesis, we focused our attention to the binding of Na+ to the enzyme molecule. Activation of the enzyme by increasing Na+ concentrations revealed significant changes in both the maximal velocity (Vmax) and the affinity for Na+ (K(Na)) in all investigated heart sections. The Vmax increased by 27% in LV, by 87% in SV and by 58% in RV. The K(Na) value increased by 86% in LV, by 105% in SV and by 93% in RV, indicating an apparent decrease in the sensitivity of the Na+-binding site in the Na,K-ATPase molecule. This apparently decreased pump affinity for Na+ together with the increase of Vmax suggest that, during the short-term inhibition of NO synthesis, the Na,K-ATPase is capable of extruding the excessive Na+ from the myocardial cells more effectively at higher [Na+]i, as compared to the Na,K-ATPase of control animals.
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PMID:Short-term NO synthase inhibition and the Na+-binding properties of cardiac Na,K-ATPase. 1080 6

1. In rat isolated renal artery segments contracted with 0.1 microM phenylephrine and in the presence of the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), carbachol and acetylcholine produced endothelium-dependent relaxations. The mechanisms underlying these relaxations were studied. 2. These relaxations were not affected by ODQ (1H-[1,2,4]oxadiazolo[4,3, -a]quinoxalin-1-one) or indomethacin. In arteries contracted with 20 - 30 mM K(+), L-NAME-resistant relaxations induced by carbachol and acetylcholine were virtually absent. 3. The Na(+)-K(+) ATPase inhibitor ouabain reduced these relaxations in a concentration-dependent manner. 4. In K(+)-free media, addition of K(+) (5 mM) produced 90. 5+/-3.9% (n=3) relaxation of phenylephrine-induced tone. This relaxation was endothelium-independent and ouabain-sensitive. 5. Tetraethylammonium (TEA), charybdotoxin (ChTX) and iberiotoxin (IbTX) reduced the sensitivity of carbachol-induced relaxations, but did not change the maximal response. These relaxations were not altered by 4-aminopyridine (4-AP), glibenclamide or apamin. Acetylcholine (1 microM)-induced relaxation was reduced by ChTX, but not by TEA or IbTX. 6. The cytochrome P450 inhibitor miconazole, but not 17-octadecynoic acid, reduced the sensitivity of carbachol-induced relaxations, without changing the maximal response. 7. In conclusion, in rat isolated renal arteries, acetylcholine and carbachol produced a non-NO/non-PGI(2) relaxation which is mediated by an endothelium-derived hyperpolarizing factor (EDHF). This factor does not appear to be a cytochrome P450 metabolite. The inhibition by ouabain of these relaxations suggests the possible involvement of Na(+)-K(+) ATPase activation in EDHF responses, although other mechanisms cannot be totally ruled out.
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PMID:Mechanisms of nitric oxide-independent relaxations induced by carbachol and acetylcholine in rat isolated renal arteries. 1090 55

Secretion of cerebrospinal fluid by the choroid plexus can be inhibited by its cholinergic innervation. We demonstrated that carbachol inhibits the Na(+)-K(+)-ATPase in bovine choroid tissue slices and investigated the mechanism. Many of the actions of cholinergic agents are mediated by nitric oxide (NO), which plays important roles in fluid homeostasis. The inhibition of Na(+)-K(+)-ATPase was blocked by the NO synthase inhibitor [N(omega)-nitro-L-arginine methyl ester] and was quantitatively mimicked by the NO agonists sodium nitroprusside (SNP) and diethylenetriamine NO. Inhibition by SNP correlated with an increase in tissue cGMP and was abolished by 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. Inhibition was mimicked by the protein kinase G activator 8-bromo-cGMP and by okadaic acid, an inhibitor of protein phosphatases 1 and 2A. cGMP-dependent protein kinase inhibitors Rp-8-pCPT-cGMP (0.5-5 microM) and KT-5823 (2.0 microM) did not block the effects of SNP, but higher concentrations of the more selective inhibitor (Rp-8-pCPT-cGMP) had a pharmacological inhibitory effect on Na(+)-K(+)-ATPase. The data suggest that cholinergic regulation of the Na(+)-K(+)-ATPase is mediated by NO and involves activation of guanylate cyclase and elevation of cGMP.
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PMID:Carbachol inhibits Na(+)-K(+)-ATPase activity in choroid plexus via stimulation of the NO/cGMP pathway. 1107 82


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