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)

We studied the effect of arachidonic acid on function and CPK release of normal, ischemic and reperfused isolated rat hearts. Under control conditions arachidonate (10 micrograms/ml) produced a transient inotropic effect which gradually reversed during a 90 minute perfusion. Creatinephosphokinase (CPK) release was augmented by arachidonic acid, particularly under high flow (pre-ischemia and reperfusion) conditions. Recovery of contractility following reperfusion of ischemic myocardium was significantly depressed by arachidonic acid. Vitamin E (100 ng/ml) an antioxidant and free radical scavenger, reduced the enzyme leakage and enhanced recovery of contractility of reperfused myocardium. It also prevented the depression in contractility during control perfusion. Similar protective effects were observed by perfusing the heart with reduced calcium but not by nifedipine; a calcium channel blocker, indomethacin; a prostaglandin synthesis inhibitor or nordihydroguarietic acid; a lipoxygenase inhibitor. Arachidonic acid also inhibited membrane Na+/K+-ATPase although it is unlikely that this property mediated its cardiotoxic influence since it was not prevented by vitamin E. In addition, we observed that arachidonic acid increased the coronary resistance of isolated hearts, probably through enhanced calcium influx as this constriction was reduced by low calcium as well as by nifedipine. Thus, arachidonic acid possesses distinct properties. Its cardiotoxic influence is likely mediated by free radical generation.
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PMID:Toxic properties of arachidonic acid on normal, ischemic and reperfused hearts. Indirect evidence for free radical involvement. 392 Jun 82

Lens cells can synthesize, degrade, and remodel lipids. Endogenous lipid synthesis, in conjunction with uptake of exogenous cholesterol and certain fatty acids, leads to the formation of a plasma membrane that is especially rich in sphingomyelin, cholesterol, and long-chain saturated fatty acids. As a result of this unusual lipid composition, lens membranes have very low fluidity, which is restricted even further by lipid-protein interactions. The composition and metabolism of membrane lipids may affect the formation of various types of cataracts. Diets rich in vegetable oils offer some protection against the formation of osmotic cataracts and the hereditary cataract of the RCS rat, although the mechanism of this effect is not clear. Vitamin E also protects against the formation of several types of cataract in vivo and in vitro, suggesting that lipid peroxidation may play a role in cataractogenesis. Certain drugs which inhibit lipid synthesis or degradation are cataractogenic, and a deficiency in cataractogenic, and a deficiency in phosphatidylserine is associated with a loss of Na+/K+ ATPase activity in several types of cataract. Human senile cataracts show a marked loss of protein-lipid interactions, although the overall lipid composition is normal. This loss of protein-lipid interactions may be related to oxidative damage to membrane-associated proteins. Interestingly, the decrease in the fluidity of lens membranes with age would counteract the formation of aqueous pores in the membrane, which can result from the oxidative cross-linking of membrane-associated proteins. Certain pathways of lipid metabolism seem to have regulatory functions. Among these are phosphatidylinositol turnover, phosphatidylethanolamine methylation, and arachidonic acid metabolism. All of these pathways function in the lens. Phosphatidylinositol turnover is correlated with the rate of lens epithelial cell division, while phosphatidylethanolamine methylation seems to be related to the initiation of lens fiber cell formation. Both pathways are associated with the release and metabolism of arachidonic acid in other cell types. While it is not known whether phosphatidylinositol turnover or phosphatidylethanolamine methylation result in the release of arachidonic acid in the lens, recent work has shown that lens cells from a variety of species can metabolize arachidonic acid by both the cyclooxygenase and lipoxygenase pathways. The possible physiological significance of these metabolites to the lens is yet to be determined.
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PMID:Lens lipids. 639 28

We studied arachidonic acid (AA) metabolism by a cell suspension containing principally cells of the thick ascending limb of the loop of Henle (TALH) obtained from the inner stripe of the outer medulla of the rabbit kidney. Based on comparison of specific activities of enzymes before and after separation, alkaline phosphatase, Na+-K+-adenosine triphosphatase, as well as Tamm-Horsfall glycoprotein and electron microscopic appearance, 80% of these cells were estimated to be TALH in origin. TALH cells had low activity of cyclooxygenase and did not show evidence of lipoxygenase activity. However, they selectively converted exogenous AA to oxygenated metabolites by a cytochrome P-450 related mechanism. AA metabolites were produced in large amounts (30-40% conversion of [14C]AA, 1 to 5 micrograms/mg of protein/30 min) and were increased 5-fold after separation of TALH cells from a suspension of outer medullary cells, suggesting that TALH cells synthesized these metabolites. Induction of cytochrome P-450 by pretreatment of rabbits with beta-naphthoflavone and 3-methylcholanthrene increased formation of the AA metabolites by almost 2-fold in the separated cells and correlated with cytochrome P-450 content of the renal outer medulla. Additionally, SKF 525A and carbon monoxide inhibited product formation in these renomedullary cells, supporting a role for a cytochrome P-450-like monooxygenase in TALH cell function.
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PMID:Arachidonic acid metabolism in a cell suspension isolated from rabbit renal outer medulla. 643 72

Arachidonic acid has been shown to release Ca2+ from isolated skeletal and cardiac sarcoplasmic reticulum (SR) vesicles. The release took place nearly equally well from all fractions of the SR and was only partially inhibited by ruthenium red, suggesting that some other pathway is involved in addition to the SR Ca2+ release channel. Arachidonic acid increased SR Ca2+ efflux even in the presence of several different SR Ca2+ pump inhibitors. It also had considerably less effect on uptake measured in the presence of oxalate and did not appear to inhibit Ca(2+)-dependent ATPase activity. Thus, the SR Ca2+ pump also appears to be minimally perturbed by arachidonic acid. Arachidonyl CoA was more effective at releasing Ca2+ than the parent compound. Arachidonic acid effects were not inhibited by lipoxygenase or cyclooxygenase inhibitors, suggesting that no eicosanoids are involved in the effects under study here. Flunarizine, cinnarizine and propyl-methylenedioxyindene inhibited the Ca2+ release induced by arachidonic acid. The effects of arachidonic acid appear to depend on the ratio of arachidonic acid to membrane vesicles.
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PMID:Arachidonic acid-induced Ca2+ release from isolated sarcoplasmic reticulum. 768 75

Microsomal fractions from porcine ocular tissues synthesized 12(S)-5,8,10,14-hydroxyeicosatetraenoic acid [12(S)-HETE] from arachidonic acid by a membrane-bound lipoxygenase and 12(R)-HETE by the cytochrome P450-dependent monooxygenase system. Both activities were the highest in corneal microsomes. The 12(R)-HETE synthesizing activity of corneal microsomes was dependent on NADPH and inhibited by 0.1 mM SKF-525A, an inhibitor of P450 enzymes. The activity to form 12(R)-enantiomer was significantly enhanced by treatment of corneal epithelium with 3-methylcholanthrene or clofibrate. The induced activity was suppressed by cycloheximide, indicating that the induction of enzyme activities involved a translational process. The effect of these inducers on 12(R)-HETE synthesizing activity appeared to be additive. The activity to form 12(S)-enantiomer was markedly stimulated by 3 mM CaCl2. The 12-lipoxygenase of corneal microsomes was capable of oxygenating linoleic acid in addition to arachidonic acid, a characteristic of 12-lipoxygenases of the leukocyte type. 12(R)-HETE at 10(-6) M inhibited almost completely the Na,K-ATPase of corneal epithelium but had little or no effect on ciliary epithelial enzymic activity. 12(S)-HETE at 10(-6) M also inhibited corneal enzymic activity but to a lesser extent, and had no significant effect on ciliary epithelial Na,K-ATPase activity.
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PMID:Synthesis of 12(R)- and 12(S)-hydroxyeicosatetraenoic acid by porcine ocular tissues. 783 61

1. It has been shown previously that nordihydroguaiaretic acid (NDGA) inhibits endothelin-1 (ET-1)-induced contractions in rat isolated tracheal smooth muscle. To investigate the underlying mechanisms, this study examined the effects of NDGA on various aspects of the ETA and ETB receptor-effector systems which mediate ET-1-induced contractions in this preparation. 2. NDGA inhibited contractions induced by each of the isoforms of ET (ET-1, ET-2 and ET-3) but not those induced by the ETB receptor-selective agonist, sarafotoxin S6c, the cholinoceptor agonist, carbachol or the depolarizing spasmogen, KCl. 3. Quantitative autoradiographic studies of [125I]-ET-1 binding to rat tracheal smooth muscle indicated that NDGA was not an ET receptor antagonist. 4. NDGA inhibited the ETA receptor-mediated, intracellular Ca(2+)-dependent contractions induced by 100 nM ET-1 in Ca(2+)-free solution (by 75%, P < 0.01). Furthermore, NDGA markedly inhibited the contractions induced by ryanodine and cyclopiazonic acid; contractions purportedly due to Ca2+ release from intracellular stores. 5. Like NDGA, the sarcoplasmic reticulum Ca(2+)-ATPase inhibitors cyclopiazonic acid and thapsigargin inhibited contractions to ET-1, but not carbachol or KCl. However, cyclopiazonic acid, but not NDGA, also (a) induced transient contractions in rat trachea, (b) potentiated contractions induced by KCl, and (c) potentiated the extracellular Ca(2+)-dependent phase of ET-1-induced contractions, indicating that NDGA did not inhibit ET-1-induced contractions through Ca(2+)-ATPase inhibition and depletion of sarcoplasmic reticular Ca2+. 6. In control preparations, ET-1 induced a slowly developing, sustained contraction. However, in the presence of NDGA or the ETA receptor antagonist, BQ123, ET-1-induced contractions resembled the transient contractions induced by sarafotoxin S6c. In nominally Ca2+-free solution, ETA receptor mediated contractions induced by ET-1 developed very slowly and were inhibited by NDGA.7. Additional studies indicated that the inhibitory effects of NDGA on endothelin-1-induced contractions were not the result of any significant actions of NDGA on lipoxygenase, cytochrome P450, L- orT-type Ca2+-channels, Na+-channels or protein kinase C.8. In summary, NDGA selectively inhibited ET-1-induced contractions in rat tracheal smooth muscle via a lipoxygenase-independent mechanism involving inhibition of the ETA but not the ETB, receptor effector system. NDGA did not appear to inhibit the initial events in the ETA signal transduction pathway, such as receptor binding and protein kinase C activation. However, NDGA inhibited the intracellular Ca2+-dependent component of ET-1-induced contraction, possibly by inhibiting mobilisation of intracellular Ca2+. As an apparent direct consequence of inhibiting the ETA receptor-effector system, NDGA markedly changed the time course of ET-1-induced contractions; from a slowly developing and sustained contraction into a transient contraction resembling that induced by sarafotoxin S6c.
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PMID:Inhibitory effects of nordihydroguaiaretic acid on ETA-receptor-mediated contractions to endothelin-1 in rat trachea. 800 99

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

In T cells CD3 monoclonal antibodies mediate an elevation of cytosolic Ca2+ concentration due to a release from internal stores and also due to an entry from extracellular medium, the mechanism of which is not clearly elucidated. Previous studies on several cell types have reported that depleting intracellular Ca2+ stores with inhibitors of the reticulum Ca(2+)-ATPase resulted in an increased plasma membrane permeability to calcium ions. It has been suggested that emptying the reticulum triggers a Ca2+ influx from extracellular medium, independent of phosphoinositide hydrolysis. To document the physiological relevance of such a mechanism, we compared CD3- and thapsigargin-induced sustained increase of cytosolic Ca2+ concentration in Jurkat T cells with regard to their sensitivity to internal and external Ca2+ level and to several inhibitors which do not affect the release of internal stores. We show that (1) there was no additivity of the two effects; (2) both CD3- and thapsigargin-evoked Ca2+ influx were inhibited when membrane was depolarized by either gramicidin or a high potassium concentration; and (3) Ca2+ influx was abrogated by cytochrome P450 inhibitors such as lipoxygenase inhibitors or imidazole antimicotic drugs. CD3 mAb and thapsigargin thus triggered the same signaling events, probably involving a cytochrome P450, to transmit information from depleted endoplasmic reticulum to the plasma membrane.
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PMID:CD3 monoclonal antibodies evoke the same cytochrome P450-regulated capacitative entry of calcium as thapsigargin in Jurkat T cells. 824 57

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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