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

The rabbit cortical collecting duct absorbs Na+ by a transport system comprised of an apical membrane Na+ channel and a basolateral membrane Na(+)-K(+)-adenosinetriphosphatase. The rate of Na+ absorption across this epithelium is acutely inhibited by several hormones and autacoids including epidermal growth factor (EGF) and prostaglandin E2 (PGE2). We used electrophysiological analysis to determine which Na+ transport mechanism is primarily regulated in response to EGF and PGE2. We used concentrations of EGF and PGE2 that inhibited Na+ absorption to a comparable degree. We assessed the effects of these agents on Na+ transport primarily by the calculated equivalent current; the validity of this indicator was verified using simultaneous tracer flux measurements. EGF and PGE2 had different effects on the intracellular electrophysiological parameters. EGF (in the presence of a cyclooxygenase inhibitor) hyperpolarized the apical membrane voltage in a manner analogous to the Na(+)-channel blocker amiloride, reduced the transepithelial conductance, and increased the fractional resistance of the apical membrane. In comparison, PGE2 depolarized the apical membrane voltage in a manner analogous to the Na(+)-K+ pump inhibitor ouabain, and caused no significant changes in transepithelial conductance or apical membrane conductance. The finding that EGF hyperpolarized the apical membrane indicates that this agent attenuates Na+ absorption by reducing apical Na+ entry due to a decrease in the magnitude of the apical membrane Na+ conductance. In contrast, the electrophysiological changes produced by PGE2 indicate primary inhibition of the basolateral Na(+)-K+ pump following PGE2 treatment.
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PMID:EGF and PGE2 inhibit rabbit CCD Na+ transport by different mechanisms: PGE2 inhibits Na(+)-K+ pump. 838 71

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

When rat peritoneal macrophages were incubated in medium containing 12-O-tetradecanoylphorbol 13-acetate (TPA), a protein kinase C activator, production of cell-associated platelet-activating factor (PAF) and extracellular prostaglandin E2 (PGE2) increased. In the presence of the cyclooxygenase inhibitor indomethacin, TPA-induced PAF production was further enhanced dose-dependently in accordance with decrease of PGE2 levels. In addition, indomethacin further enhanced PAF production that was stimulated by the protein kinase C activators, aplysiatoxin and teleocidin. Other cyclooxygenase inhibitors such as naproxen and ibuprofen also enhanced TPA-stimulated PAF production in accordance with inhibition of PGE2 production. Cyclooxygenase inhibitor-induced enhancement of PAF production was markedly prevented by exogenous PGE2. Exogenous arachidonic acid also inhibited TPA-induced PAF production in parallel with increase in PGE2 levels. Inhibition of PAF production by exogenous arachidonic acid was abolished by indomethacin. Furthermore, PAF production stimulated by the endomembrane Ca+2-ATPase inhibitors thapsigargin or thapsigargicin, or by the Ca+2 ionophore A23187, was also enhanced by indomethacin in compensation for the decrease in PGE2 production. In addition, the adenylate cyclase activator forskolin, or the cyclic adenosine monophosphate (cAMP) analogues 8-bromo cAMP and dibutyryl cAMP inhibited thapsigargin-induced PAF production. TPA-induced accumulation of intracellular cAMP was inhibited by indomethacin, and indomethacin-induced decrease of cAMP level was reversed by exogenous PGE2. These results suggested that concurrently produced PGE2 in stimulated macrophages down-regulates PAF production via adenylate cyclase and cAMP pathway.
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PMID:Platelet-activating factor production in stimulated macrophages is down-regulated by concurrently produced prostaglandin E2. 866 29

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

The cytochrome P-450 pathway is capable of metabolizing arachidonic acid to omega- and subterminal hydroxylase metabolites, 16-, 17-, 18-, 19-, and 20-hydroxyeicosatetraenoic acids (P-450 HETEs). We have quantitated, by gas chromatography-mass spectrometry (GC/MS), endogenous HETEs exiting the rabbit isolated perfused kidney elicited by hormonal stimulation. Kidneys were perfused with Krebs-Henseleit solution containing indomethacin (2.8 microM) to prevent further metabolism of HETEs by cyclooxygenase. Phenylephrine (2-3 microM) was added to the perfusate to raise perfusion pressure to approximately 80 mmHg. Angiotensin II (ANG II), arginine vasopressin (AVP), and bradykinin (BK) were injected into the renal artery and perfusates collected throughout the vasoactive response. After addition of an internal standard, deuterated 19-HETE, perfusates were extracted and purified and P-450 HETEs were derivatized for GC/MS analysis. Under basal conditions, 16-, 18-, 19-, and 20-HETEs were released (range: 50-270 pg/ml), 19-HETE being the highest and fivefold greater than 16-HETE, the lowest. Injection of 50 ng ANG II increased by two- to sixfold P-450 HETE release associated with an increase of 40 +/- 11 mmHg in perfusion pressure. An equipressor dose of AVP (50 ng) did not release P-450 HETEs nor did a 5-micrograms dose of the vasodilator peptide BK, which decreased perfusion pressure by 22 +/- 6 mmHg. Authentic 19- and 20-HETE isomers resulted in dose-dependent dilation, as did 18(R)- and 16(R)-HETEs, whereas their enantiomers and 17-HETE isomers were without effect on perfusion pressure. The vasodilator effects of 18(R)- and 16(R)-HETEs, like 20- and 19-HETEs, were inhibited by indomethacin. Furthermore, P-450 HETEs exhibited both regio- and stereoselective inhibition of proximal tubule adenosine triphosphatase (ATPase) activity. The (S) enantiomers of 16- and 17-HETE potently inhibited activity, whereas their (R) isomers and other P-450 HETEs had negligible effects on ATPase activity. The quantity of HETEs released from the kidney, either under basal conditions or when stimulated by ANG II, and their biological profile suggest that subterminal HETEs may participate in renal mechanisms affecting vasomotion and tubular transport.
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PMID:Cytochrome P-450-dependent HETEs: profile of biological activity and stimulation by vasoactive peptides. 889 75

Phospholamban is a key regulatory protein that defines diastolic function. Proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) can depress contractility and intracellular Ca2+ currents and transients. An alteration in phospholamban expression is a possible pathway by which these cytokines modulate cardiac function. To test this hypothesis, primary cultures of neonatal rat cardiomyocytes were incubated with IL-1 beta, TNF-alpha, or both, and the level of phospholamban transcripts was examined by Northern blot analyses. Phospholamban transcript levels were decreased approximately equal to 50% (P < .0001) in cells exposed to 2 ng/mL IL-1 beta (20 hours), whereas TNF-alpha had no effect. Western blot analyses showed that IL-1 beta also reduced phospholamban protein levels (60% of control, P < .0001). The effects on transcript levels were gene specific; IL-1 beta induced transcripts for inducible NO synthase (iNOS), did not alter GAPDH transcripts, and reduced sarcoplasmic reticulum Ca(2+)-ATPase (65% of control, P < .001) transcripts. Cardiomyocytes treated with IL-1 beta showed no alterations in basal contractile parameters (maximum velocity of contraction and relaxation and maximal amplitude of contraction) but were unresponsive to beta-adrenergic stimulation. Studies performed in the presence of second-messenger inhibitors showed that the effect of IL-1 beta on phospholamban transcript levels was blocked by dexamethasone, was insensitive to inhibitors of iNOS, cyclooxygenase, or tyrosine kinases, but was enhanced by the addition of the protein kinase inhibitor staurosporine. These data demonstrate that IL-1 beta alters the expression of phospholamban, a key regulator of cardiac contractility, at both the transcript and protein levels. The results suggest novel mechanisms by which IL-1 beta may modify cardiac function.
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PMID:Interleukin-1 beta inhibits phospholamban gene expression in cultured cardiomyocytes. 931 30

The prostaglandin G2/H2 synthase (cyclooxygenase, COX) is a key regulatory enzyme of prostanoid synthesis pathway. The message-encoding COX isoenzymes (constitutive COX-1 and inducible COX-2) have been described in the rat kidney. However, there is scarce information on the localization of COX-2 in the kidney, although it has been recently reported to be localized in the macula densa. The present study was designed to evaluate the localization of COX-2 in adult rat kidneys. Normal rat kidneys (n=10) were fixed in Bouin and were immunostained with specific antibodies against COX-2 by the peroxidase method. The cellular origin of COX-2 was assessed by the immunostaining of serial consecutive sections with antibodies against Na-K-ATPase, Tamm-Horsfall glycoprotein, H-K-ATPase, kallikrein, and macrophages. COX-2 was consistently observed in a subset of tubular cells located in the cortex and in the outer medulla. The staining of serial sections showed that the COX-2+ cells contained both Na-K-ATPase and Tamm-Horsfall, indicating that they corresponded to thick ascending limb (TAL) cells. They were observed at a considerable distance from the corresponding macula densa, although occasionally they were observed close to glomeruli. The COX-2 staining in the TAL cells was not abolished by dexamethasone treatment (1 to 20 mg/kg), suggesting its constitutive expression in normal kidneys. The presence of COX-2 in TAL (a tubular segment postulated to be devoid of COX-1) may contribute to the handling of ions through local production of prostaglandins.
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PMID:Renal identification of cyclooxygenase-2 in a subset of thick ascending limb cells. 932 6


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