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)

Both atherosclerotic lesions and hypoxia alter the contractile properties of the arterial wall and, in particular, may interfere with the relaxation mechanisms dependent or not on the endothelium. The present study was designed to test the effect of severe hypoxia on the contractile behavior of the atherosclerotic rabbit aorta. Segments of aortas obtained from control, cholesterol-fed, or Watanabe hereditary hyperlipidemic rabbits were mounted in organ chambers for isometric tension recording. A change of the bath PO2 from "normoxic" conditions (95% O2-5% CO2) to "hypoxic" conditions (95% N2-5% CO2) caused relaxation in the precontracted control aortas (by approximately 85%) but a transient contraction (approximately 20% of the maximal contraction obtained with 30 mM KCl) followed by a relaxation in the precontracted atherosclerotic aortas. Both types of responses were observed in aortas contracted with aggregating platelets, 5-hydroxytryptamine (5-HT), norepinephrine, endothelin, and prostaglandin F2 alpha. The hypoxic contractions in atherosclerosis were not dependent on the presence of an intact endothelium. They could not be antagonized by blockers of alpha-adrenoceptors, 5-HT2 receptors, histamine receptors, thromboxane receptors, and muscarinic cholinoreceptors. Inhibitors of cyclooxygenase, lipoxygenase, Na+, K(+)-ATPase, and free radical scavengers or an activator of endothelium-derived relaxing factor did not significantly affect the hypoxic contraction; the absence of effect of some inhibitors of protein synthesis seems to rule out the involvement of endothelin, angiotensin II, and bradykinin. The hypoxic contraction was not influenced by omission of Ca2+ from the medium or by inhibition of Ca2+ influx but was prevented by blockade of intracellular Ca2+. The inhibitor of nitric oxide synthase (nitro-L-arginine, 100 microM) and the guanylyl cyclase inhibitor (methylene blue, 10 microM) both enhanced the initial contractile responses to 5-HT to a similar extent as hypoxia and completely prevented the hypoxic contraction in the atherosclerotic tissues. The cyclic nucleotide analogues 8-bromo-cGMP and dibutyryl cAMP also inhibited the hypoxic contraction in the atherosclerotic aorta. The cGMP levels were markedly decreased and the cAMP levels were moderately decreased in the aortas of the cholesterol-fed rabbits as compared with the control aortas. Hypoxia further decreased cGMP but not the cAMP levels in atherosclerotic aortas with and without endothelium. Our data thus demonstrate the occurrence of an unusual vasoconstrictor response in atherosclerotic arteries; this constrictor response depends on the availability of intracellular Ca2+ and seems to be due to the further inhibition of an already impaired cGMP production.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypoxia causes an abnormal contractile response in the atherosclerotic rabbit aorta. Implication of reduced nitric oxide and cGMP production. 838 23

We recently reported a novel intracellular mechanism of renal Na-K-ATPase regulation by agents that increase cell cAMP, which involves protein kinase A-phospholipase A2 and is mediated by one or more arachidonic acid metabolites (Satoh, T., H. T. Cohen, and A. I. Katz. 1992. J. Clin. Invest. 89:1496). The present studies were, therefore, designed to assess the role of eicosanoids in the modulation of Na-K-ATPase activity in the rat cortical collecting duct. The effect of various cAMP agonists (dopamine, fenoldopam, vasopressin, forskolin, and dibutyryl cAMP), which inhibited the pump to a similar extent (approximately 50%), was independent of altered Na entry as it was elicited in the presence of amiloride or nystatin, or when NaCl was replaced with choline Cl. This effect was completely blocked by SKF 525A or ethoxyresorufin, two inhibitors of the cytochrome P450-dependent monooxygenase pathway, or by pretreating the animals with CoCl2, which depletes cytochrome P450. Equimolar concentrations (10(-7) M) of the cyclooxygenase inhibitors indomethacin or meclofenamate caused only a partial inhibition of the cAMP agonists' effect on the pump, whereas nordihydroguaiaretic acid or A 63162, two inhibitors of the lipoxygenase pathway, were without effect. Furthermore, two products of this pathway, leukotriene B4 and leukotriene D4, had no effect on Na-K-ATPase activity, and ICI 198615, a leukotriene receptor antagonist, did not alter pump inhibition by cAMP agonists. Several P450 monoxygenase arachidonic acid metabolites (5,6-epoxyeicosatrienoic acid; 11,12-epoxyeicosatrienoic acid; 11,12-dihydroxyeicosatrienoic acid; and 12(R)-hydroxyeicosatetraenoic acid) as well as PGE2 inhibited the Na:K pump in dose-dependent manner, but the effect of PGE2 was blocked when Na availability was altered, whereas that of 12(R)-HETE remained unchanged. We conclude that the cytochrome P450-monooxygenase pathway of the arachidonic acid cascade plays a major role in the modulation of Na:K pump activity by eicosanoids in the rat cortical collecting duct, and that products of the cyclooxygenase pathway may contribute to pump inhibition indirectly, by decreasing intracellular Na.
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PMID:Intracellular signaling in the regulation of renal Na-K-ATPase. II. Role of eicosanoids. 838 20

A regulatory role of endogenously synthesized eicosanoids on the absorption, transmural transport and metabolism of glucose in perfused, isolated loops of jejunum in vitro was investigated using the lipoxygenase/cyclooxygenase inhibitor, nordihydroguaiaretic acid (NDGA). NDGA diminished glucose absorption over the range 100-500 microM: maximal inhibition at 500 microM NDGA was 52 +/- 9 and 64 +/- 9% (mean +/- SE, P < 0.001) for jejuna from fed rats and rats maintained on glucose water for 48 hr, respectively. In each instance, transmural transport was effectively abolished. The vectorial disposition of lactate release was also changed such that the ratio of luminal to serosal production was increased from 0.19 +/- 0.02 to 1.72 +/- 0.12 (P < 0.001) in fed rats, indicating inhibition of the Na+ pump. NDGA inhibited (Na(+)+K+)-ATPase activity in whole mucosal homogenates with a concentration dependence similar to that observed for glucose absorption. However, NDGA also inhibited Mg(2+)-ATPase activity in whole homogenates and purified rabbit skeletal muscle phosphofructokinase under the same conditions. The results are discussed in terms of the dissipation of the transmembrane Na+ gradient via direct inhibition of the (Na(+)+K+)-ATPase by NDGA. Inhibition of the ATPase precludes the use of NDGA as a suitable drug with which to investigate the role of endogenously synthesized eicosanoids in the regulation of intestinal function.
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PMID:Effect of nordihydroguaiaretic acid on glucose absorption, metabolism and (Na(+)+K+)-ATPase activity in rat jejunum. 838 12

The relationship between the phospholipase-stimulating and immunosuppressive properties of cyclosporin A (CsA) has been investigated in vitro. At concentrations of 0.025 microM and upwards, CsA caused dose-related inhibition of both mitogen- and alloantigen-stimulated uptake of tritiated thymidine by human mononuclear leukocytes (MNL), which was associated with a time- and dose-related enhancement of the generation of lysophosphatidylcholine (LPC), arachidonic acid, and prostaglandin E2 from mitogen-stimulated cells. Arachidonate alone, at concentrations of up to 20 microM, did not affect lymphocyte activation, whereas cyclooxygenase and 5'-lipoxygenase inhibitors failed to protect the cells against the antiproliferative effects of CsA. However, LPC caused dose-related inhibition of MNL proliferation. Moreover, coincubation of MNL with alpha-tocopherol, a lysophospholipid-complexing agent, or with lysophospholipase protected the cells against CsA, as well as against LPC. The Na+,K(+)-ATPase activity of mitogen-activated lymphocytes was also inhibited by CsA, whereas inclusion of alpha-tocopherol or lysophospholipase protected this enzyme. Excessive production of lysophospholipids and consequent inhibition of Na+,K(+)-ATPase during CsA treatment of mitogen- or antigen-activated lymphocytes is a possible biochemical mechanism of the immunosuppressive activity of this agent.
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PMID:Lysophospholipid-mediated inhibition of Na+,K(+)-adenosine triphosphatase is a possible mechanism of immunosuppressive activity of cyclosporin A. 839 20

In this study the possible role of Na+ influx, arachidonate mediators and alpha-subunit phosphorylation in the stimulatory response of hepatic Na+/K(+)-ATPase to glucagon was examined. Glucagon stimulation of ouabain-sensitive 86Rb+ uptake in freshly isolated rat hepatocytes reached maximal levels in less than 1 min after hormone addition and was half-maximal (EC50) at a concentration of 2.4( +/- 1.3) x 10(-10) M. Analysis of the K(+)-dependence of this response indicates an effect on the apparent Vmax. for K+ with no significant change in the apparent kappa 0.5. Unlike monensin, glucagon stimulation of Na+/K(+)-ATPase-mediated transport activity was not associated with an increase in 22Na+ influx. This indicates that the stimulation of Na+/K(+)-ATPase by glucagon is not secondary to an increase in Na+ influx. A role for arachidonate mediators in this effect also appears unlikely because neither basal nor glucagon-stimulated ouabain-sensitive 86Rb+ uptake was significantly affected by supramaximal concentrations of cyclo-oxygenase, lipoxygenase, cytochrome p-450 or phospholipase A2 inhibitors. To study the possible role of protein kinase-mediated phosphorylation in the stimulation of ouabain-sensitive 86Rb uptake, hepatocytes were metabolically radiolabelled with [32P]P(i), Glucagon stimulated incorporation of 32P into a 95 kDa phosphoprotein that comigrates with Na+/K(+)-ATPase alpha-subunit immunoreactivity in two-dimensional gel electrophoresis. The alpha-subunit could be immunoprecipitated from detergent-solubilized particulate fractions of hepatocytes using an anti-(rat kidney Na+/K(+)-ATPase) serum. When hepatocytes were metabolically radiolabelled with [32P]P(i), the immunoprecipitated alpha-subunit contained 32P. Glucagon increased the incorporation of 32P into the immunoprecipitated subunit by 197 +/- 21% (n = 6). Similar results were observed with a rabbit anti-peptide serum ('anti-LEAVE' serum) prepared against an amino acid sequence in the alpha-subunit. The EC50 for glucagon-stimulated phosphorylation of the alpha-subunit (approximately 1 x 10(-10) M) was very close to that for glucagon stimulation of ouabain-sensitive 86Rb+ uptake. In conclusion, it appears that glucagon stimulation of hepatic Na+/K(+)-ATPase-mediated transport activity is not secondary to increases in Na+ influx or changes in the levels of an arachidonate mediator. The data provide support for the hypothesis that glucagon stimulation of Na(+)-pump activity in hepatocytes may be related to protein kinase-mediated changes in the phosphorylation state of the alpha-subunit.
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PMID:Glucagon stimulation of hepatic Na(+)-pump activity and alpha-subunit phosphorylation in rat hepatocytes. 861 Nov 84

To evaluate further the signal transduction mechanisms involved in the short-term modulation of Na-K-ATPase activity in the mammalian kidney, we examined the role of phospholipase C-protein kinase C (PLC-PKC) pathway and of various eicosanoids in this process, using microdissected rat proximal convoluted tubules. Dopamine (DA) and parathyroid hormone (either synthetic PTH1-34 or PTH3-34) inhibited Na-K-ATPase activity in dose-dependent manner; this effect was reproduced by PKC530-558 fragment and blocked by the specific PKC inhibitor calphostin C, as well as by the PLC inhibitors neomycin and U-73122. Pump inhibition by DA, PTH, or arachidonic acid, and by PKC activators phorbol dibutyrate (PDBu) or dioctanoyl glycerol (DiC8) was abolished by ethoxyresorufin, an inhibitor of the cytochrome P450-dependent monooxygenase pathway, but was unaffected by indomethacin or nordihydroguaiaretic acid, inhibitors of the cyclooxygenase and lipoxygenase pathways of the arachidonic acid cascade, respectively. Furthermore, each of the three monooxygenase products tested (20-HETE, 12(R)-HETE, or 11,12-DHT) caused a dose-dependent inhibition of the pump. The effect of DA, PTH, PDBu or DiC8, as well as that of 20-HETE was not altered when sodium entry was blocked with the amiloride analog ethylisopropyl amiloride or increased with nystatin. We conclude that short-term regulation of proximal tubule Na-K-ATPase activity by dopamine and parathyroid hormone occurs via the PLC-PKC signal transduction pathway and is mediated by cytochrome P450-dependent monooxygenase products of arachidonic acid metabolism, which may interact with the pump rather than alter sodium access to it.
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PMID:Regulation of Na-K-ATPase activity in the proximal tubule: role of the protein kinase C pathway and of eicosanoids. 867 85

Linoleic acid, a polyunsaturated C18 fatty acid, is one of the major fatty acids in the coronary arterial wall. Although diets rich in linoleic acid reduce blood pressure and prevent coronary artery disease in both humans and animals, very little is known about its mechanism of action. We believed that its beneficial effects might be mediated by changes in vascular tone. We investigated whether linoleic acid induces relaxation of porcine coronary artery rings and the mechanism involved in this process. Linoleic acid and two of its metabolites, 13-hydroxyoctadecadienoic acid (13-HODE) and 13-hydroperoxyoctadecadienoic acid (13-HPODE), induced dose-dependent relaxation of prostaglandin (PG) F2alpha-precontracted rings that was not affected by indomethacin (10[-5] mol/L), a cyclooxygenase inhibitor, or cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC; 10[-5] mol/L), a lipoxygenase inhibitor. Removal of endothelial cells had no effect on vasorelaxation, suggesting a direct effect on the vascular smooth muscle cells (VSMC). When rings were contracted with KCl, linoleic acid failed to induce relaxation. Although tetrabutylammonium (5 x 10[-3] mol/L), a nonselective K+ channel blocker, slightly inhibited the relaxation caused by linoleic acid, glibenclamide (10[-6] mol/L), an ATP-sensitive K+ channel blocker, and charybdotoxin (7.5x10[-8] mol/L) or tetraethylammonium (5x10[-3] mol/L), two different Ca2+-activated K+ channel blockers, had no effect. However, relaxation was completely blocked by ouabain (5x10[-7] mol/L), a Na+/K+-ATPase inhibitor, or by a K+-free solution. In addition, linoleic acid (10[-6] mol/L) caused sustained hyperpolarization of porcine coronary VSMC (from -49.5+/-2.0 to -60.7+/-4.2 mV), which was also abolished by ouabain. We concluded that linoleic acid induces relaxation and hyperpolarization of porcine coronary VSMC via a mechanism that involves activation of the Na+/K+-ATPase pump.
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PMID:Linoleic acid induces relaxation and hyperpolarization of the pig coronary artery. 946 Dec 30

The susceptibility of the developing brain to hypoxia should depend on the lipid composition of the brain cell membrane; the rate of lipid peroxidation; the presence of antioxidant defenses; and the development and modulation of the excitatory neurotransmitter receptors such as the N-methyl-D-aspartate (NMDA) receptor, the intracellular Ca++ and intranuclear Ca++-dependent mechanisms. In addition to the developmental status of these cellular components, the response of these potential mechanisms to hypoxia determines the fate of the hypoxic brain cell in the developing brain. In the fetal guinea pig and newborn piglet models, studies have demonstrated that brain tissue hypoxia results in brain cell membrane damage as evidenced by increased membrane lipid peroxidation and decreased Na+,K+-ATPase activity. Using electron spin resonance spectroscopy of alpha-phenyl-N-tert-butyl-nitrone spin-adducts, studies from our laboratory have demonstrated that tissue hypoxia results in increased free radical generation in the cortex of fetal guinea pigs and newborn piglets. We have also shown that brain tissue hypoxia modifies the N-methyl-D-aspartate receptor-ion channel, recognition and modulatory sites. Furthermore, a higher increase in NMDA receptor agonist-dependent Ca++ in synaptosomes of hypoxic as compared to normoxic fetuses was demonstrated. The increase in intracellular Ca++ may activate several enzymatic pathways such as phospholipase A2 and metabolism of arachidonic acid by cyclooxygenase and lipoxygenase, conversion of xanthine dehydrogenase to xanthine oxidase by proteases and activation of nitric oxide synthase. Using specific inhibitors of each of these enzymes such as cyclooxygenase (indomethacin), lipoxygenase (nordihydroguaiaretic acid), xanthine oxidase (allopurinol) and nitric oxide synthase (N-nitro-L-arginine), studies have shown that these enzyme reactions result in oxygen free radical generation, membrane lipid peroxidation and cell membrane dysfunction in the hypoxic brain. We suggest that, during hypoxia, the increased intracellular Ca++ may lead to an increased intranuclear Ca++ concentration and alter nuclear events including transcription of specific genes responsible for programmed cell death. In view of the developmental studies presented, the susceptibility of the fetal brain to hypoxia appears to increase with brain development as gestation approaches term.
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PMID:Cellular mechanisms of hypoxic injury in the developing brain. 1022 30

Although endothelium-derived hyperpolarizing factor (EDHF) is thought to be a cytochrome P-450 product (arachidonic acid metabolite) in some tissues, in porcine coronary arteries (PCAs) its nature remains unclear. Because phospholipase A2 and C are involved in the synthesis and/or release of EDHF in the PCA, the arachidonic acid (AA) pathway may be involved. In the presence of the cyclooxygenase inhibitor indomethacin (10(-5) M) and the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 10(-4) M), both bradykinin (BK; 10(-9)-10(-6) M) and AA (10(-7)-10(-4) M) induced dose-dependent relaxation of PGF2alpha-contracted PCA rings, which was blocked by a high extracellular concentration of KCl (30 mM) or pretreatment with ouabain, a Na+/K+-adenosine triphosphatase (ATPase) inhibitor (5 x 10(-7) M). Eicosatetraynoic acid (ETYA; 20 microM), which inhibits all AA pathways, slightly affected the response to BK and AA; however, lipoxygenase or cytochrome P-450 inhibitors had no effect, suggesting that relaxation is independent of these enzymatic pathways. Because endothelial cells can generate reactive oxygen species (ROS) via metabolism of AA and independent of cyclooxygenase activity, we also studied (a) whether ROS can relax the PCA, as well as the mechanism(s) involved, and (b) the role of ROS in BK- and AA-induced relaxation. Xanthine (X; 100 microM) plus xanthine oxidase (XO; 0.02 U/ml) induced time-dependent relaxation of PGF2alpha-contracted PCA rings in the presence of indomethacin and L-NAME. Dilatation was not affected by superoxide dismutase (SOD; 500 U/ml) but was abolished by catalase (300 U/ml), suggesting that hydrogen peroxide (H2O2) is involved. When rings were contracted by depolarizing them with 30 mM KCl, X/XO failed to elicit relaxation. Ouabain abolished the response to X/XO, suggesting that X/XO may induce relaxation by hyperpolarizing vascular smooth muscle cells via stimulation of the Na+/K+-ATPase pump. We therefore questioned whether ROS might be involved in BK- and AA-induced relaxation. Because catalase combined with SOD had little or no effect, we concluded that in the PCA, the relaxation induced by BK via EDHF involves some mechanism independent of NO, AA metabolism, or ROS.
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PMID:Reactive oxygen species: role in the relaxation induced by bradykinin or arachidonic acid via EDHF in isolated porcine coronary arteries. 1051 Nov 33

Locally formed arachidonic acid (AA) metabolites are important as modulators of many aspects of renal tubular function, including regulation of the activity of tubular Na(+)-K(+)-ATPase. Here we examined the ontogeny of the AA metabolic pathways regulating proximal convoluted tubular (PCT) Na(+)-K(+)-ATPase activity in infant and adult rats. Eicosatetraynoic acid, an inhibitor of all AA-metabolizing pathways, abolished this effect. AA inhibition of PCT Na(+)-K(+)-ATPase was blocked by the 12-lipoxygenase inhibitor baicalein in infant but not in adult rats and by the specific cytochrome P-450 fatty acid omega-hydroxylase inhibitor 17-octadecynoic acid in adult but not in infant rats. The lipoxygenase metabolite 12(S)-hydroxyeicosatetraenoic acid (HETE) and the cytochrome P-450 metabolite 20-HETE both inhibited PCT Na(+)-K(+)-ATPase in a protein kinase C-dependent manner, but the effect was significantly more pronounced in infant PCT. Lipoxygenase mRNA was only detected in infant cortex. Expression of renal isoforms of cytochrome P-450 mRNA was more prominent in adult cortex. In summary, the AA metabolic pathways that modulated the activity of rat renal proximal tubular Na(+)-K(+)-ATPase are age dependent.
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PMID:Arachidonic acid metabolic pathways regulating activity of renal Na(+)-K(+)-ATPase are age dependent. 1080 95


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