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)

PGE1 has been found to improve the symptoms of diabetic neuropathy. We considered that a PGI2 derivative may also have a similar action and therefore studied its effect in diabetic rats. Iloprost was administered intraperitoneally to streptozotocin-induced diabetic rats at a dose of 10 micrograms/kg/day for a month. The changes in nerve conduction velocity (NCV) were measured in the tail. One day after the last dose of iloprost, both sciatic nerves were removed from each rat, homogenized, and extracted with 6% TCA. The sorbitol and myo-inositol concentrations were determined by a combination of HPLC and an enzymatic method. Cyclic AMP (cAMP) levels were determined by RIA, and Na+, K+ ATPase activity was assessed by the enzyme cycling method of Greene and Lattimer. Iloprost was found to improve the NCV in the diabetic rats. The sorbitol content was not affected by iloprost, but the myo-inositol content was higher in the iloprost group than in the untreated group, although the difference was not statistically significant. The Na+, K+ ATPase activity and cAMP content were significantly higher in the iloprost group than in the untreated group. These findings suggest the possibility that the cAMP-dependent protein kinase (A-kinase) system has an important influence on improvement in Na+, K+ ATPase activity.
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PMID:Effect of a prostaglandin I2 derivative (iloprost) on peripheral neuropathy of diabetic rats. 128 52

The effect of cAMP on active Ca2+ extrusion across the plasma membrane of intact human platelets was studied using quin2, a fluorimetric indicator of free Ca2+ in the cytoplasmic compartment ([Ca2+]cyt). Elevations of cAMP were achieved by incubation with dibutyryl-cAMP or by forskolin, which was found to selectively elevate cAMP without affecting cGMP levels. Progress curves of Ca2+ extrusion from quin2-overloaded platelets were measured. The rate vs. [Ca2+]cyt characteristic was calculated as previously described (Johansson, J.S. and Haynes, D.H. (1988) J. Membr. Biol. 104, 147-163). Forskolin, at a maximally effective concentration of 10 microM, was shown to stimulate Ca2+ extrusion by increasing by a factor of 1.6 +/- 0.5 the Vm of a saturable component, previously identified with a Ca(2+)-Mg(2+)-ATPase located in the plasma membrane. Neither the Km (80 nM) or Hill coefficient (1.7 +/- 0.3) of the Ca(2+)-ATPase was affected. Forskolin had no effect on the linear, non-saturable component of extrusion (previously identified with a Na+/Ca2+ exchanger) over the [Ca2+]cyt range examined (50-1500 nM). Dibutyryl-cAMP (Bt2-cAMP, 1 mM) stimulated the Ca(2+)-Mg(2+)-ATPase component of Ca2+ extrusion by a factor of 2.0 +/- 0.6. Separate experiments showed that 10 microM forskolin reduces the resting [Ca2+]cyt from 112 nM to 96 nM. Mathematical analysis showed that this can be accounted for by the above-mentioned increase in Vm of the pump, countered by a 37-74% increase in the rate constant for passive Ca2+ leakage across the plasma membrane. The results suggest two mechanisms by which prostacyclin-induced elevation of cAMP inhibits platelet aggregation: (a) lowering of resting [Ca2+]cyt and (b) increasing the rate of Ca2+ extrusion after the initial influx or triggered release event.
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PMID:Cyclic AMP stimulates Ca(2+)-ATPase-mediated Ca2+ extrusion from human platelets. 131 70

The relationship between agonist-sensitive calcium compartments and those discharged by the Ca(2+)-ATPase inhibitor thapsigargin were studied in human platelets. In this context, calcium mobilization from intracellular pools and manganese influx was investigated in relation to the effect of altered cyclic-nucleotide levels. For maximal calcium release from intracellular stores, thapsigargin, compared to a receptor agonist like thrombin, requires the platelet's self-amplification mechanism, known to generate thromboxane A2. With this lipid mediator formed, thapsigargin released calcium and stimulated manganese influx in a manner similar to thrombin. Blocking the thromboxane receptor by addition of sulotroban (BM13.177) or, alternatively, increasing platelet cAMP or cGMP using prostacyclin or sodium nitroprusside, dramatically reduced the ability of thapsigargin to release calcium from intracellular compartments. The same experimental conditions significantly reduced the rate of manganese influx initiated by thapsigargin compared to thrombin. The experiments indicate that thapsigargin-sensitive compartments play only a minor role in inducing manganese influx compared to the receptor-sensitive compartment. Cyclic nucleotides accelerate the redistribution of an agonist-elevated platelet calcium into the thapsigargin-sensitive compartment, from which calcium can be released by inhibition of the Ca(2+)-ATPase. In human platelets, thapsigargin-induced calcium increase and influx were responsible for only part the calcium release resulting from inhibition of the corresponding ATPase; another part results from the indirect effect of thapsigargin acting via thromboxane-A2-receptor activation. Cyclic nucleotides are therefore an interesting regulatory device which can modify the thapsigargin response by not allowing the self-amplification mechanism of platelets to operate.
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PMID:Cyclic nucleotides and intracellular-calcium homeostasis in human platelets. 132 18

The aim of the present study was to determine the influence of the sodium pump on the responses elicited by 5-hydroxytryptamine (5-HT) in segments of human placental veins. 5-HT (10(-9)-3 x 10(-7) M) elicited potent concentration-dependent vasoconstrictor responses, but a fall in tone was observed at higher concentrations. In the presence of 10(-7) M ouabain, this fall in tension was abolished. A single concentration of 5-HT (10(-6) M) produced a biphasic response, consisting in a fast early contraction followed by a slow relaxation. This relaxant phase was concentration dependently inhibited by ouabain (10(-7) and 10(-6) M), and abolished by preincubating the vessels in a K(+)-free solution and reducing bath temperature to 28 degrees C, methods usually employed to inhibit the sodium pump. After adding 7.5 mM K+ or returning the temperature to 37 degrees C, marked relaxation was observed. On the other hand, the relaxant phase with the amine remained unchanged by pretreatment with phenidone, oxyhemoglobin, indomethacin (all at 10(-5) M) and endothelium removal. 5-HT (10(-7) and 10(-6) M) elicited increases in ouabain-sensitive 86Rb+ uptake. These results suggest that: (1) 5-HT activates Na+,K(+)-ATPase, likely by an indirect mechanism that involves an increase of intracellular sodium concentration; and (2) the relaxant phase of 5-HT-evoked vasoactive responses is not mediated by the release of nitric oxide or prostacyclin from the endothelium.
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PMID:Sodium pump activation by 5-hydroxytryptamine in human placental veins. 133 Jun 19

The effects of prostaglandin (PG) E2 on cell swelling were studied in isolated perfused tubules of rabbit kidney. PGE2 (1 microM) added to the bath induced cell swelling by 13.4, 7.2, and 9.6% in the connecting tubule, distal convoluted tubule, and cortical collecting duct, respectively, but it had no effect on the proximal convoluted tubule and cortical thick ascending limb. The response was dose dependent in the range of 1 nM to 1 microM. PGI2 exerted a similar effect, but PGF2 alpha had no effect. The swelling was completely blocked by basolateral Na+ removal and was attenuated by bilateral Cl- removal, suggesting that the swelling was mediated by basolateral Na+ entry in association with Cl- entry. In all segments except proximal tubule, PGE2 caused an initial transient peak followed by a sustained increase in intracellular Ca2+. Intracellular Ca2+ chelation or inhibition of Ca2+ release from intracellular stores abolished the PGE2-induced cell swelling, but extracellular Ca2+ removal did not. An inhibitor of the Na(+)-Ca2+ exchanger (3',4'-dichlorobenzamil, 100 microM) in the bath completely inhibited PGE2-induced cell swelling. Neither furosemide (1 mM) nor amiloride (1 mM) added to bath abolished the response, indicating that neither Na(+)-K(+)-2Cl- cotransport nor Na(+)-H+ exchange is involved in the action of PGE2. The swelling response to PGE2 was observed even in the presence of ouabain, indicating that the effect of PGE2 is independent of Na(+)-K(+)-adenosinetriphosphatase inhibition. Nicardipine added to bath partially inhibited the swelling response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of PGE2-induced cell swelling in distal nephron segments. 133 3

The protective effect of a stable derivative of prostacyclin (7-oxo PGI2) was studied on the model of calcium overload (Ca2+ paradox) 48 h after i.m. administration of the drug in the dose of 50 micrograms/kg. In the isolated rat heart perfused at 37 degrees C and a constant perfusion pressure of 75 Torr (Langendorff preparation) Ca2+ paradox was induced by 3 min perfusion with calcium-free Krebs-Henseleit solution and a subsequent 10 min perfusion with a normal calcium-containing solution. The late protective effect of 7-oxo PGI2 was manifested by improved recovery of heart function (increase of contractility by 50%) and by better preservation of the content of macroergic phosphates (70% sigma ADN) during the Ca2+ repletion phase and of myocardial ultrastructure (sarcolemma) already during the Ca2+ depletion phase. The protective effect of 7-oxo PGI2 can be accounted for by stimulation of Na, K-ATPase activity, otherwise decreased during calcium depletion phase, and by the consequent prevention of alterations in sodium and calcium homeostasis. (Tab. 1, Fig. 4, Ref. 41.)
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PMID:[Protective effect of 7-oxo-prostacyclin on myocardial calcium overload in the isolated rat heart]. 139 57

The microsomal Ca(2+)-ATPase inhibitor 2,5-di-(tert-butyl)-1,4-benzohydroquinone (tBuBHQ) induced bronchoconstriction and vasoconstriction in the isolated perfused and ventilated rat lung. These effects were accompanied by increased levels of thromboxane and prostacyclin in the effluent perfusate. The effect of tBuBHQ was inhibited by L-655,240, a thromboxane receptor antagonist, indicating thromboxane-A2-mediated bronchoconstriction and vasoconstriction. Accordingly, the cyclooxygenase inhibitor indomethacin largely blocked the effects of tBuBHQ. The involvement of a phospholipase in the generation of thromboxane A2(TXA2) was supported by dibucaine protection on tBuBHQ effects. The results from this study indicate that tBuBHQ, probably by inhibiting the microsomal Ca(2+)-ATPase, can trigger the arachidonic acid cascade leading to the formation of TXA2, which in turn causes bronchoconstriction and vasoconstriction in rat lung.
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PMID:Vasoconstriction and bronchoconstriction induced by 2,5-di-(tert-butyl)1,4-benzohydroquinone, an endoplasmic reticular Ca2+-ATPase inhibitor, in isolated and perfused rat lung. 141 86

The delayed effects of 7-oxo-prostacyclin, protecting the heart against extrasystoles, ventricular fibrillation, and cardiac arrest induced by high doses of ouabain or in ischemia and postischemic reperfusion, have already been described; but little is known about the molecular mechanisms involved. In this study, 50 micrograms.kg-1 7-oxo-prostacyclin administered intramuscularly significantly stimulated the activity of (Na+K+)-ATPase in rat heart sarcolemma 24 and 48 hours after application (p less than 0.01 and p less than 0.001, respectively). Kinetic analysis revealed a mixed type of stimulation of ATPase activity, with increased Vmax and decreased Km values. Cycloheximide (1 mg.kg-1) applied together with 7-oxo-prostacyclin, significantly antagonized the stimulatory effect of 7-oxo-prostacyclin, and had a modulatory effect on the kinetics of the (Na+K+)-ATPase both 24 and 48 hours after administration. The results show that protein synthesis is involved in the mechanism of the increase in enzyme activity.
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PMID:Increased activity of sarcolemmal (Na+K+)-ATPase is involved in the late cardioprotective action of 7-oxo-prostacyclin. 165 98

Ras-GAP (GTPase activating protein) is a regulatory protein that stimulates the intrinsic guanosine triphosphatase (GTPase) activity of the proto-oncogene product p21ras. A domain of the neurofibromatosis gene product (NF1) that has sequence similarity to the catalytic domain of Ras-GAP and to yeast IRA gene products also has a specific stimulatory activity toward p21ras GTPase. Arachidonic acid and phosphatidic acid inactivate GAP, but no agents have been identified that stimulate GAP and thereby switch p21ras off. With the use of recombinant Ha-c-Ras and Ras-GAP, NF1, and GAP catalytic domains, it was found that prostaglandins PGF2 alpha and PGA2 stimulated Ras-GAP and that prostacyclin PGI2 inhibited Ras-GAP. The stimulatory effect of PGF2 alpha was saturable and structure-specific and competed with the inhibitory effect of arachidonic acid. Arachidonic acid also inhibited the catalytic activity of NF1, but prostaglandins were not stimulatory. These results suggest a mechanism for the allosteric control of Ras function through the modulation of arachidonate metabolism.
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PMID:Regulation of Ras-GAP and the neurofibromatosis-1 gene product by eicosanoids. 190 23

Prostacyclin (PGI2) did not alter the basal perfusion pressure in the isolated rat mesenteric arteries perfused with Krebs' solution, but produced a biphasic effect in arteries preconstricted with norepinephrine or arginine vasopressin: constriction, then prolonged dilation. Both these components of PGI2 effect were diminished in arteries denuded of their endothelia by a 10 min perfusion with distilled water or p-bromophenacyl bromide (10 microM). The present study elucidates the mechanism of these PGI2 actions. Indomethacin (0.28 microM) SQ 29548 (1 microM, thromboxane A2 receptor antagonist), saralasin (1 microM, angiotensin II receptor antagonist) or the free radical scavengers, superoxide dismutase (60 U/ml) and catalase (40 U/ml) did not inhibit the initial vasoconstriction, suggesting it was not mediated through endothelially generated thromboxane A2, angiotensin II or oxygen-derived free radicals. However, ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (50 microM; Ca++ chelating agent), 8-(diethyl-amino)octyl 3,4,5-trimethoxy benzoate (10 microM; intracellular Ca++ antagonist), or neomycin (5 mM; phospholipase-C inhibitor) abolished the vasoconstriction. Ouabain (0.5 mM) did not affect the vasodilation, but perfusion with excess (50 mM) or 0 K+ Krebs' solution abolished it, suggesting this PGI2 action involves changes in membrane K+ conductance via a mechanism independent of Na+/K+ adenosine triphosphatase. Vasodilation evoked by BRL 34915 (K+ channel activator) was similarly attenuated under these conditions, but not by ouabain. Furthermore, procaine (1 mM; nonspecific K+ channel inhibitor), but not apamin (0.5 microM) or tetraethylammonium (10 mM) blocked PGI2- and BRL 34915-induced vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of vascular actions of prostacyclin in the rat isolated perfused mesenteric arteries. 210 93


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