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)

Studies were designed to determine the extent of the involvement of endothelium-derived relaxing factor(s) other than nitric oxide (NO) in vascular relaxation in response to acetylcholine (ACh) in the rabbit renal artery. ACh (10(-9)-10(-6) M) induced concentration-dependent relaxation of isolated endothelium-intact arterial rings preconstricted with noradrenaline. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, partly inhibited the ACh-induced endothelium-dependent relaxation, whereas it almost completely abolished the production of cyclic-3', 5'-guanosine monophosphate (cGMP) in these rings in response to ACh. Methylene blue, an inhibitor of guanylate cyclase, had an essentially similar effect to L-NAME on the relaxation. Indomethacin, an inhibitor of cyclooxygenase, had no effect. High concentrations of potassium chloride (to inhibit endothelium-dependent hyperpolarization), tetraethylammonium (TEA) or 4-aminopyridine (4-AP), a voltage-dependent or Ca(2+)-dependent K+ channel blocker, partly inhibited the relaxation while, in contrast, glibenclamide, an ATP-sensitive K+ channel blocker, had no effect. Ouabain, an inhibitor of Na+, K(+)-ATPase, also partly inhibited the ACh-induced relaxation, especially the higher concentration effect. Application of L-NAME together with ouabain, TEA, or a high concentration of potassium chloride completely abolished the relaxation. These results suggest that ACh-induced endothelium-dependent relaxation in the rabbit renal artery is mediated by NO, and by an other factor(s), which relaxes the vascular smooth muscle through opening K+ channels other than ATP-sensitive ones, and/or through the activation of a Na+, K(+)-pump.
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PMID:NG-nitro-L-arginine-resistant endothelium-dependent relaxation induced by acetylcholine in the rabbit renal artery. 804 Dec 28

In a previous work, we showed that picomolar concentrations of prostaglandin E2 (PGE2) inhibit Na-K-ATPase activity and ouabain binding in a clone of Madin-Darby canine kidney (MDCK) cells. In the present study, we demonstrate that the inhibitory effects of PGE2 on Na-K-ATPase activity, ouabain-sensitive Rb+ uptake, and ouabain binding in MDCK cells were diminished by treatment of the cells with nonsteroidal anti-inflammatory drugs. These results suggested that products of arachidonic acid synthesized through the cyclooxygenase pathway are involved in the inhibitory mechanism of PGE2. Treatment of the cells with arachidonic acid resulted in inhibition of ouabain binding, and the inhibition was eliminated by cyclooxygenase inhibitors. These observations further support the involvement of cyclooxygenase products in the PGE2-induced inhibitory process. Finally, we demonstrated that dopamine inhibits Rb+ influx and ouabain binding in MDCK cells similarly to PGE2. Cyclooxygenase inhibitors suppressed the inhibition of ouabain binding by dopamine, thus also suggesting the involvement of cyclooxygenase products in the inhibitory effect of dopamine.
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PMID:Cyclooxygenase inhibitors suppress inhibitory effect of PGE2 on Na-K-ATPase in MDCK cells. 804 70

Vasopressin (VP) stimulates adenosine 3',5'-monophosphate (cAMP) formation in an immortalized renal tubule cell line, TKC2, which is derived from transgenic mouse harboring temperature-sensitive SV40 T-antigen gene. VP (10(-8) M)-induced cAMP formation was significantly attenuated by either non-peptide vasopressin receptor V1 or V2 subtype antagonist, OPC-21268 (10(-8) and 10(-6) M) or OPC-31260 (10(-8) and 10(-6) M), respectively, and it was completely abolished by combination of both agents (10(-6) M). VP (10(-8) M) also induced an increase in cytosolic free Ca2+ and prostaglandin (PG) E2 synthesis, both of which were significantly inhibited by OPC-21268 (10(-8) M), but not by OPC-31260 (10(-6) M). Either OPC-21268 (10(-8) M), depletion of extracellular Ca2+ or inhibition of cyclooxygenase attenuated both VP-induced PGE2 synthesis and cAMP formation. In conclusion, both V1 and V2 receptors can stimulate cAMP formation. V1 receptor, however, stimulates cAMP formation via Ca(2+)-dependent PGE2 synthesis, whereas V2 receptor may stimulate it directly.
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PMID:Different cellular mechanisms of vasopressin receptor V1 and V2 subtype in vasopressin-induced adenosine 3', 5'-monophosphate formation in an immortalized renal tubule cell line, TKC2. 804 37

The effects of acetylcholine (ACh) and A23187 on ring preparations from the human umbilical artery (HUA) were investigated and compared with the rat aorta (RA). The results from the HUA demonstrate that: (1) At both high (pO2 > 600 mm Hg) and low O2 tension (pO2 < 55 mm Hg), ACh and A23187 relaxed precontracted rings in a concentration-dependent and endothelium-independent manner. Changes in pO2 did not influence the responses of the HUA to either relaxant. (2) Relaxation responses of the HUA to either ACh or A23187 were insensitive to methylene blue (50 microM), L-nitro-arginine methyl ester (100 microM), indomethacin (10 microM) and nordihydroguaiaretic acid (50 microM). Relaxations initiated by ACh were also atropine-resistant. (3) Meclofenamic acid (3 microM) suppressed the relaxations to A23187, but not ACh. (4) Regardless of pO2 superoxide dismutase (100 U/ml) potentiated the relaxant effects of ACh, whereas mannitol (60 mM) enhanced ACh-initiated relaxations at high but not low pO2. (5) Ouabain (30 nM), high potassium (HK+, 60 mM) and tetraethylammonium (20 mM) inhibited responses to ACh. (6) Na(+)-free physiological saline solution inhibited both relaxations and oscillations initiated by either ACh or A23187. (7) Both nitroglycerin and exogenous nitric oxide (NO) fully, and 8-bromoguanosine 3',5'-cyclic monophosphate partially, relaxed the HUA, and LY83583 (10 microM) reversed such relaxations. (8) In the RA, relaxation responses to ACh and A23187 were endothelium-dependent and sensitivity was reduced under high versus low pO2 conditions. We conclude that in the HUA, unlike in the RA, ACh and A23187 mediate their responses via an endothelium- and NO-independent process(es), perhaps involving the release of a muscle-derived relaxing factor. ACh-initiated relaxations are mediated by activation of Na+,K(+)-ATPase, and subsequent hyperpolarization via K+ efflux, whereas A23187-mediated relaxations result from the synthesis of an indomethacin-resistant cyclooxygenase product.
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PMID:Endothelium-independent relaxations to acetylcholine and A23187 in the human umbilical artery. 811 64

We have previously shown that parathyroid hormone (PTH)-(1-34) or its analogue PTH-(3-34) inhibits proximal tubule (PT) Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity independently of adenosine 3',5'-cyclic monophosphate generation. The present study used PT suspensions to investigate the signaling pathway responsible for this hormonal action. PTH-(1-34) and PTH-(3-34) significantly increased the release of arachidonic acid (AA) compared with control tubules, suggesting activation of phospholipase A2 (PLA2). AA, 10(-6) M, mimicked the inhibition of the pump by 10(-8) M PTH-(3-34), and together were not additive. Eicosatetraynoic acid, 3 microM, a general inhibitor of AA metabolism, blocked the PTH action. Indomethacin, 10 microM, an inhibitor of AA-dependent cyclooxygenase, did not prevent the PTH action, but 2 microM 7-ethoxyresorufin, a cytochrome P-450 inhibitor, prevented the PTH effect. 20-Hydroxyeicosatetraenoic acid (20-HETE), the main product of P-450 metabolism in PT, inhibited Na(+)-K(+)-ATPase activity to the same extent as 10(-8) M PTH-(3-34), was not additive with PTH, and was maximally inhibitory at 10(-7) M. To further investigate the signaling pathway responsible for PTH-activated PLA2, we tested the effect of PTH on cytoplasmic free Ca2+ ([Ca2+]i). PTH-(1-34), 10(-7) M, did not affect [Ca2+]i, although 10(-8) M angiotensin II promoted a Ca2+ transient. Treatment of PT with pertussis toxin (PTX) did not prevent the PTH action.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Parathyroid hormone inhibits Na(+)-K(+)-ATPase through a cytochrome P-450 pathway. 816 Aug

At concentrations of 0.5 microM and upward, cyclosporin A (CsA) caused dose-related inhibition of the growth of a hamster renal tubular cell line (HAK ATCC; CCL15) in vitro. Inhibition of cell growth was due to the cytotoxic properties of CsA which were associated with enhancement of activity of phospholipase A2 (PLA2) according to the increased generation of arachidonic acid and lysophosphatidylcholine (LPC). Arachidonate per se, at concentrations of up to 20 microM, did not affect the growth of HAK cells, while cyclooxygenase and 5-lipoxygenase inhibitors failed to protect the cells against the antiproliferative effects of CsA. However, LPC caused dose-related inhibition of the growth of HAK cells. Moreover, coincubation with lysophospholipase or alpha-tocopherol (AT, vitamin E), a PLA2 inhibitory and lysophospholipid-complexing agent, protected the HAK cells against both CsA and LPC. The Na+, K(+)-ATPase activity of HAK cells was also inhibited by CsA, with the enzyme being protected by inclusion of AT or lysophospholipase. Increased activity of PLA2 and inhibition of Na+, K(+)-ATPase preceded cytotoxicity and cytolysis. Excessive production of lysophospholipids and consequent inhibition of Na+, K(+)-ATPase in renal tubular cells is a possible mechanism of CsA-induced nephrotoxicity. The protective effects of AT suggest that this agent may be clinically useful in preventing the renal side effects of CsA.
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PMID:Alpha-tocopherol prevents cyclosporin A-mediated activation of phospholipase A2 and inhibition of Na+, K(+)-adenosine triphosphatase activity in cultured hamster renal tubular cells. 817 26

The effects of one of the main components of fish oil, docosahexaenoic acid (DHA), on prostaglandin (PG) and Ca2+ signaling pathways were examined in intact mucosa and freshly isolated crypt cells of rabbit descending colon. Preincubation of serosal mucosa for 20 min with 1 microM DHA fully suppressed the short-circuit and transepithelial conductance increase induced by serosal addition of 10 microM arachidonic acid (AA). DHA at 1 microM also prevented the Cl- secretion promoted by 10 microM AA, as estimated by unidirectional 36Cl flux measurements (net flux = 0.68 +/- 0.30 versus -1.91 +/- 0.20 microEq/hr/cm2, four experiments, p < 0.001), whereas it did not affect the electrophysiological and ion flux responses to PGE2. Addition of 1 microM DHA to the serosal side of the mucosa also inhibited the PG cascade activation elicited by AA (PG synthesis and second messenger cAMP increase). In vitro assays of colonic cyclooxygenase activity showed that 1 microM DHA inhibited (with a 20-min lag) cyclooxygenase activity to the same extent as 5 microM indomethacin (approximately 82% and 80%, respectively). DHA also affected the Ca2+ signaling pathway; in isolated crypt cells, the cytosolic free Ca2+ concentration ([Ca2+]i) dropped by 49 +/- 7.6% (mean +/- standard error, six experiments) after incubation with 1 microM DHA. The sustained phase of the [Ca2+]i response to 500 nM concentrations of the intracellular Ca(2+)-ATPase inhibitor thapsigargin was also inhibited within 150 sec upon 1 microM DHA addition (141 +/- 5.8 versus 243 +/- 8.2 nM [Ca2+]i mean +/- standard error, eight experiments, p < 0.01). The [Ca2+]i-lowering effect of DHA, which was not achieved by incubation with other free fatty acids, was not prevented by removal of Na+ from the incubation medium (-46 +/- 4.3% versus -47 +/- 3.8%, mean +/- standard error, four experiments), nor it was mediated by cAMP-, protein kinase C-, or calmodulin-dependent mechanisms. The incubation of highly purified basolateral membranes of crypt cells with 1 microM DHA for 1 min produced a 5-fold increase (IC50 = 0.25 microM) in the plasma membrane Ca(2+)-ATPase activity (34.3 +/- 2.73 versus 6.02 +/- 0.50 nmol/mg of protein/min, mean +/- standard error, four experiments, p < 0.0001), thus indicating that the DHA effects on the Ca2+ pathway were mediated mainly by an increase in plasma membrane Ca2+ pump activity. These findings suggest that DHA is a powerful modulator of the cellular response to activation of PG and Ca2+ signaling pathways.
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PMID:Docosahexaenoic acid and signaling pathways in rabbit colon. 818 54

The corneal epithelium of several species, has the capacity to metabolize arachidonic acid (arachidonic acid) via an NADPH-dependent cytochrome P450 mechanism. The major metabolites are 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) and 12-hydroxy-5,8,14-eicosatrienoic acid (12-HETrE), both of which exist in stereoisomeric configurations. However, the R enantiomers are predominantly produced by this enzyme system and exhibit potent biological activities. 12(R)-HETE inhibits Na-K-ATPase, increases corneal thickness and reduces intraocular pressure. 12(R)-HETrE causes vasodilation, neutrophil chemoattraction and angiogenesis. The formation of these metabolites is unaffected by cyclooxygenase and lipoxygenase inhibitors (indomethacin, diclofenac and BW755C) but inhibited by cytochrome P450 enzyme inhibitors such as carbon monoxide, SKF-525A and clotrimazole. The capacity of the normal corneal epithelium to metabolize arachidonic acid via cytochrome P450 is very low although under certain conditions this enzymatic pathway may become greatly induced. Corneal epithelial hypoxia in response to contact lens wear results in the time-dependent formation of NADPH-cytochrome P450-dependent arachidonate metabolites, 12(R)-HETE and 12(R)-HETrE. Under this condition, metabolite production correlates strongly with the in situ inflammatory response and inhibition of their formation significantly attenuates inflammation. It is evident that the cytochrome P450 arachidonate metabolites should be added to the realm of cyclooxygenase and lipoxygenase-derived eicosanoids as possible inflammatory mediators. Therefore, studies to evaluate eicosanoid involvement in inflammation should examine inhibitors of this pathway in addition to the classically studied non-steroidal antiinflammatory drugs (NSAIDs).
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PMID:Effect of metabolic inhibitors on arachidonic acid metabolism in the corneal epithelium: evidence for cytochrome P450-mediated reactions. 820 35

The biochemical effects of the non-12-0-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoter thapsigargin (TG), which does not bind to the phorbol-ester receptor, or activate protein kinase C (PKC) or increase inositol polyphosphates, were characterized in mouse epidermis in vivo. The cold scraping method is required to detect the induction of ornithine decarboxylase (ODC) activity by TG, a response much smaller than that caused by TPA and with a different time course. TG pre-treatments do not alter or cause a refractory state against ODC induction by TPA. But TG stimulates hydroperoxide (HPx) production and RNA, protein, and DNA synthesis almost as much as TPA. Moreover, the sequential effects of TG and TPA on DNA synthesis are identical: early inhibition at 8 hr followed by maximal stimulation at 16-32 hr. TG-stimulated HPx production requires protein synthesis and xanthine oxidase, phospholipase A2, and lipoxygenase activities but not RNA and DNA synthesis, and cyclooxygenase and protease activities. The HPx response to TG is not mimicked by the PKC activator prostratin or inhibited by pre-treatments with prostratin or specific PKC inhibitors. However, the Ca(2+)-ATPase inhibitor cyclopiazonic acid and the Ca2+ ionophore and weak ODC inducer A23187 mimic remarkably the HPx responses to TG and TPA. Since TG and A23187 are known to be, respectively, weak and incomplete tumor promoters as compared with TPA, the present results suggest that the HPx responses common to Ca(2+)-mobilizing and TPA- or non-TPA-type agents are insufficient to achieve tumor promotion in the absence of major ODC induction.
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PMID:Ability of the non-phorbol ester-type tumor-promoter thapsigargin to mimic the stimulatory effects of 12-0-tetradecanoylphorbol-13-acetate on ornithine decarboxylase activity, hydroperoxide production, and macromolecule synthesis in mouse epidermis in vivo. 825 22

The relationship between the phospholipase-stimulating and immunosuppressive properties of the riminophenazine anti-mycobacterial agent clofazimine and its experimental analogue, B669, has been investigated in vitro. At concentrations of 0.6 microM and upwards, both riminophenazines, particularly B669, caused dose-related inhibition of mitogen- and alloantigen-stimulated uptake of tritiated thymidine by human mononuclear leucocytes (MNL), while in short-term assays both agents increased the release of lysophosphatidylcholine (LPC) and arachidonic acid from these cells. Arachidonate per se at a concentration of 20 microM did not affect mitogen-activated lymphocyte proliferation, while cyclooxygenase and 5'-lipoxygenase inhibitors, as well as water- and lipid-soluble oxidant-scavengers and anti-oxidant enzymes, failed to protect the cells against the anti-proliferative effects of clofazimine and B669. However, LPC caused dose-related inhibition of lymphocyte proliferation. Moreover, co-incubation of NML with alpha-tocopherol (vitamin E), a lysophospholipid complex-forming agent, or with lysophospholipase, protected the cells against clofazimine and B669, as well as against LPC. Na+, K(+)-adenosine triphosphatase was identified as the primary target of riminophenazine/LPC-mediated inhibition of lymphocyte proliferation. Excessive release of anti-proliferative lysophospholipids during clofazimine or B669 treatment of mitogen- or antigen-activated lymphocytes is the probable biochemical mechanism of the immunosuppressive activity of these agents.
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PMID:Clofazimine and B669 inhibit the proliferative responses and Na+, K(+)-adenosine triphosphatase activity of human lymphocytes by a lysophospholipid-dependent mechanism. 826 51


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