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 effects of polyunsaturated fatty acids on brain edema formation have been studied in rats. Intracerebral injection of polyunsaturated fatty acids (PUFAs), including linolenic acid (18:3) and arachidonic acid (20:4), caused significant increases in cerebral water and sodium content concomitant with decreases in potassium content and Na+- and K+- dependent adenosine triphosphatase activity. There was gross and microscopic evidence of edema. Saturated fatty acids and monounsaturated fatty acid were not effective in inducing brain edema. The [125I]-bovine serum albumin spaces increased twofold and threefold at 24 hours with 18:3 and 20:4, respectively, indicating vasogenic edema with increased permeability of brain endothelial cells. Staining of the brain was observed five minutes after injection of Evans blue dye followed by arachidonic acid perfusion. A major decrease in brain potassium content was evidence of concurrent cellular (cytotoxic) edema as well. The induction of brain edema by arachidonic acid was dose dependent and maximal between 24 and 48 hours after perfusion. Dexamethasone (10 mg/kg) was effective in ameliorating the brain edema, whereas a cyclooxygenase inhibitor, indomethacin (10 mg/kg), was not. These data indicate that arachidonic acid and other PUFAs have the ability to induce vasogenic and cellular brain edema and further support the hypothesis that the degradation of phospholipids and accumulation of PUFAs, particularly arachidonic acid, initiate the development of brain edema in various disease states.
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PMID:Induction of brain edema following intracerebral injection of arachidonic acid. 630 72

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

We have concluded that Ibuprofen, a cyclooxygenase inhibitor with high specificity for the preferential blockage of thromboxane synthetase, significantly improves arterial blood pressure, cardiac index, and arterial pH during endotoxin shock in dogs (J. Clin. Invest. 70:536, 1982). This study was undertaken to determine whether Ibuprofen (25 mg/kg i.v.) administered 20 min prior to endotoxin (2 mg/kg i.v.) is able to overcome the depressed ability of cardiac microsomes to actively sequester calcium after 2 hrs of endotoxin shock. Results indicate that microsomes isolated from hearts of animals pretreated with Ibuprofen and then given endotoxin are able to sequester calcium at rates similar to microsomes isolated from control hearts. Microsomes isolated from hearts of animals in endotoxin shock without Ibuprofen show the anticipated depression of calcium sequestering ability. The improved ability of microsomes from the hearts of animals pretreated with Ibuprofen to sequester calcium is the result of normal Ca+2-Mg+2 ATPase activity in the microsomal membrane. We conclude that Ibuprofen protects against the detrimental hemodynamic derangements of endotoxin induced shock in the dog, and thereby also improves cardiac subcellular calcium transport; the factor regulating contractility. Ibuprofen may warrant evaluation as a protective agent to be used prophylactically in high risk cases of endotoxemia.
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PMID:Protection of myocardial function during endotoxin shock by ibuprofen. 658 48

In porcine coronary artery endothelium-dependent relaxation to bradykinin is in part attributed to a chemically unidentified factor, termed endothelium-derived hyperpolarizing factor (EDHF). We hypothesize that arachidonic acid, acting through a cyclooxygenase-independent mechanism, is responsible for EDHF production. To define the relationship between EDHF production and arachidonic acid release, we investigated the role of phospholipase C in bradykinin-induced relaxation and prostaglandin I2 production (an index of arachidonic acid release) in porcine coronary artery. The phospholipase C inhibitor U73122 (1 mumol/L) abolished bradykinin-induced, nitric oxide-mediated relaxation but did not inhibit either bradykinin-induced, EDHF-mediated relaxation or prostaglandin I2 production. However, when given at a larger dose (20 mumol/L) U73122 abolished both bradykinin-induced, EDHF-mediated relaxation and prostaglandin I2 production. Similarly, the calcium-ATPase inhibitor thapsigargin, given at a dose (1 mumol/L) that abolished bradykinin-induced increases in intracellular calcium concentration in cultured porcine coronary artery endothelial cells, eliminated both bradykinin-induced. EDHF-mediated relaxation and prostaglandin I2 production. Although thapsigargin abolished bradykinin-induced prostaglandin I2 production, the basal production of prostaglandin I2 was enhanced and contraction of endothelium-intact rings was attenuated. These latter responses are most likely related to enhanced basal arachidonic acid release and associated EDHF production. These observations suggest that phospholipase C activation and increased intracellular calcium concentration are required for both bradykinin-induced arachidonic acid release and EDHF production in porcine coronary artery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relationship of arachidonic acid release to porcine coronary artery relaxation. 755 31

The present work was designed to study the mechanism of inhibitory action of flufenamic and tolfenamic acids on the degranulation response of human polymorphonuclear leukocytes (PMNs). We have recently shown that fenamates inhibit PMN degranulation as well as other PMN functions at micromolar drug concentrations. However, the mechanism of their action remains unknown. To clarify this mechanism, the degranulation response was induced by agents known to activate different steps in the activation cascade in PMNs: the receptor-mediated activator fMLP (N-formyl-L-methionyl-L-leucyl-L-phenylalanine); a calcium ionophore (A23187); an inhibitor of calcium-ATPase (thapsigargin); and an activator of protein kinase C (phorbol myristate acetate, PMA). For comparison, SK&F 96365 (an inhibitor of receptor-mediated calcium entry), Ro 31-8220 (an inhibitor of protein kinase C) and ketoprofen (another cyclooxygenase inhibitor) were used. Flufenamic and tolfenamic acids inhibited A23187- and fMLP-induced degranulation in a dose-dependent manner. The thapsigargin-triggered response was reduced only slightly and that induced by PMA remained unaltered. The pattern of the inhibitory action of fenamates differed from those of Ro 31-8220 and ketoprofen. The action of fenamates resembled that of the inhibitor of receptor-mediated calcium entry, SK&F 96365, especially when A23187, fMLP or PMA were used to stimulate the cells. This prompted us to measure the effects of flufenamic and tolfenamic acids on receptor-mediated calcium entry. The two fenamates inhibited the fMLP-induced increase in intracellular free calcium in fura-2 loaded PMNs in the presence but not in the absence of extracellular calcium. The results suggest that the suppressive actions of fenamates on PMN degranulation are neither related to the activity of cyclooxygenase nor PMA-activated protein kinase C. In contrast, fenamates resemble the antagonist of receptor-mediated calcium entry, SK&F 96365, in their antagonistic action on PMN degranulation.
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PMID:Pharmacological control of human polymorphonuclear leukocyte degranulation by fenamates and inhibitors of receptor-mediated calcium entry and protein kinase C. 763 63

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

To test the hypothesis that indomethacin, an inhibitor of cyclooxygenase, reduces free radical-induced brain cell membrane changes during cerebral hypoxia, we determined levels of brain cell membrane lipid peroxidation products and Na+,K(+)-ATPase activity as indicators of free radical production and membrane function, respectively, in 29 newborn piglets divided into 4 groups. Eight saline- and 4 indomethacin-treated normoxic animals served as controls; 8 saline-pretreated piglets and 9 piglets pretreated with indomethacin were exposed to hypoxic hypoxia for 60 min. Cerebral hypoxia was documented using 31P-NMR spectroscopy. In saline-pretreated hypoxic animals Na+,K(+)-ATPase activity decreased significantly and levels of membrane lipid peroxidation products increased significantly compared to normoxic controls. Indomethacin pretreatment prevented the hypoxia-induced increase in membrane lipid peroxidation products but had no effect on the decrease in Na+,K(+)-ATPase activity. Thus the apparent reduction in free radical production by indomethacin pretreatment did not prevent the hypoxia-induced change in Na+,K(+)-ATPase activity.
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PMID:Effect of cyclooxygenase inhibition on brain cell membrane lipid peroxidation during hypoxia in newborn piglets. 772 19

Previously, it has been shown that the addition of bradykinin (Bk) to M-1 cortical collecting duct cells in the presence of endothelial cells decreased short-circuit current (Isc), a measure of net active transport. This effect is presumably due to the release of endothelium-derived nitric oxide (EDNO), because the decrease in Isc could be blocked with Nw-nitro-L-arginine. To show that the inhibition of Isc was due to EDNO rather than prostaglandins, the ability of a cyclooxygenase inhibitor to block the inhibition was examined. When Bk was added to cocultures in the presence of meclofenamate (10(-5) M), Isc decreased from 62 +/- 12 to 44.5 +/- 7 muA/cm2, not significantly different from that in the absence of meclofenamate. To determine if the effect was due to an alteration of sodium absorption, Bk (10(-9) M) was added to cocultures, resulting in a decrease in Na flux from 28 +/- 3.1 to 20 +/- 2.2 nEq/min (P < 0.05), with Isc decreasing from 25 +/- 2.4 to 20 +/- 3.6 nEq/min (P < 0.05). To examine if the inhibition was due to blockade at the apical membrane sodium channel or the basolateral Na+/K+ ATPase, the cation-selective ionophore nystatin was used. Nystatin reversed the effect of EDNO on Isc. The effects of EDNO on Na+/K+ ATPase were also measured directly. Under maximum rate conditions, the Na+/K+ ATPase activity of control and Bk-treated cocultures was 5.2 +/- 0.3 and 6.8 +/- 1.0 nmol/min per square centimeter, respectively (not significantly different).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelial-derived nitric oxide inhibits sodium transport by affecting apical membrane channels in cultured collecting duct cells. 791 34

The present study was conducted to investigate the influence of arachidonic acid, which is known to be an important unsaturated fatty acid component of membrane phospholipids and to be liberated by phospholipase A2 action, on secretion of catecholamines (CA) from the isolated perfused rat adrenal glands and to clarify the mechanism of its action. Arachidonic acid (10 uM) perfused into an adrenal gland of the rat for 20 min caused a significant inhibition of CA secretion evoked by ACh (5.32 x 10(-3) M), DMPP (10(-4) M) and muscarine (10(-4) M) while it did not affect that induced by excess K+ (5.6 x 10(-2) M). Arachidonic acid, in the presence of ouabain (100 uM), an inhibitor of Na+, K(+) -ATPase, also produced a marked inhibitory effect of CA secretion evoked by ACh, DMPP and muscarine but did not modify the secretory effect of excess K+. The perfusion of arachidonic acid along with indomethacin (30 uM), which is an inhibitor of cyclooxygenase, for 20 min attenuated markedly CA secretory effect evoked by ACh, DMPP and muscarine while it did not influence that by excess K+. Prostaglandin F2 alpha perfused in a retrograde direction for 20 min inhibited greatly the CA secretion evoked by DMPP but did not affect the effect evoked by excess K+. All of arachidonic acid, ouabain, indomethacin and prostaglandin F2 alpha used in the present study did not affect the spontaneous basal release of CA in the perfused rat adrenal glands. Taken together, these experimental results suggest that arachidonic acid, as well as prostaglandin F2 alpha, cause the inhibitory action of CA secretion evoked by cholinergic receptor-mediated stimulation, but not by membrane depolarization, and also play a modulatory role in regulating CA secretion from the rat adrenal medulla.
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PMID:Influence of arachidonic acid on catecholamine secretion in the perfused rat adrenal medulla. 803 23


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