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)

The formation of palmitoylcarnitine is catalyzed by carnitine palmitoyl-transferase (CPT-I) and this catalysis is the first committed step in beta-oxidation. The malonyl-CoA-inhibited isoform appears to be distinct from latent (CPT-II) activity, which is localized to the matrix side of the mitochondrial inner membrane. Sarcoplasmic reticulum from canine cardiac muscle was fractionated on a discontinuous sucrose density gradient into three major bands, all of which contained Ca(2+)-ATPase activity. Only the fraction that banded at a concentration of 38% surcrose was slightly contaminated by mitochondria. Peroxisomal uricase was low or absent in fractionated SR. All sarcoplasmic reticulum fractions contained malonyl-CoA-sensitive medium- (COT) and long-chain (CPT) carnitine acyltransferase activities. CPT activity decreased in sarcoplasmic reticulum when Triton X-100 was present. Carnitine acyltransferase activities were inactivated by preincubating the sarcoplasmic reticulum with the sulfhydryl reagent, 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB). In contrast, mitochondrial CPT-II activity was stable in the presence of DTNB and activated by Triton X-100. Western blots of mitochondria and sarcoplasmic reticulum fractions showed that the mitochondrial fractions reacted with antibody to mitochondrial CPT-II but not with SR protein when both were added at comparable specific activities. The data suggest that cardiac SR contains a unique malonyl-CoA-sensitive isoform of CPT, and that synthesis of acylcarnitine may occur in the microenvironment of Ca2+ transport, where the extent of production of acylcarnitine is controlled by cardiac acetyl-CoA carboxylase activity.
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PMID:Evidence for malonyl-CoA-sensitive carnitine acyl-CoA transferase activity in sarcoplasmic reticulum of canine heart. 162 48

To define determinants of subcellular structures of heart, Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated for 5 wk with 15 mg.kg-1.day-1 etomoxir [reduces mitochondrial carnitine palmitoyltransferase-1 (CPT-1) activity and fatty acid synthesis]. To bypass CPT-1 inhibition, etomoxir-treated rats were fed a medium-chain fatty acid (MCFA) diet. Etomoxir induced a proportionate growth of heart, which could partially (WKY, P < 0.05) or completely (SHR, P < 0.05) be prevented by the MCFA diet. Also the etomoxir-induced increase in myosin V1 was partially prevented (P < 0.05). Etomoxir increased (P < 0.05) rate of sarcoplasmic reticulum (SR) Ca2+ uptake of WKY and SHR ventricular homogenates in the presence or absence of the SR Ca2+ release inhibitor ruthenium red. The MCFA diet resulted in SR Ca2+ uptake rates that were in between those of etomoxir-treated and untreated rats. The in vitro 32P incorporation into phospholamban and troponin I did not differ significantly in WKY. Etomoxir induced, however, an increase (P < 0.05) in the phosphorylated intermediate of the Ca2+ adenosinetriphosphatase in WKY that was prevented by the MCFA diet. In SHR, etomoxir increased the in vitro phospholamban phosphorylation, which was reduced compared with WKY. The data show that myosin and SR are affected by a chronically altered substrate utilization of heart.
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PMID:Dietary medium-chain triglycerides can prevent changes in myosin and SR due to CPT-1 inhibition by etomoxir. 757 66

The incidence of mortality from cardiovascular diseases in higher in diabetic patients. The cause of this accelerated cardiovascular disease is multifactorial and, although atherosclerotic cardiovascular disease in association with well-defined risk factors has an influence on morbidity and mortality in diabetics, myocardial cell dysfunction independent of vascular defects have also been defined. We postulate that these adverse cardiac effects could presumably result as a consequence of the following sequence of events. Major abnormalities in myocardial carbohydrate and lipid metabolism occur as a result of insulin deficiency. These changes are closely linked to the accumulation of various acylcarnitine and coenzyme derivatives. Abnormally high amounts of metabolic intermediates could cause disturbances in calcium homeostasis either directly or indirectly through structural and functional subcellular membrane alterations. Over time, chronic abnormalities such as reduced myosin ATPase activity, decreased ability of the sarcoplasmic reticulum to take up calcium as well as depression of other membrane enzymes such as Na(+)-K+ ATPase and Ca(2+)-ATPase leads to changes in calcium homeostasis and eventually to cardiac dysfunction. More importantly from the point of view of pharmacological intervention, during the initial stages, acute disturbances in both the glucose and FFA oxidative pathways may provide the initial biochemical lesion from which further events ensue. Thus therapies which target these metabolic aberrations in the heart during the early stages of diabetes, in effect, can potentially delay or impede the progression of more permanent sequelae which could ensue from otherwise uncontrolled derangements in cardiac metabolism. There is little dispute that an attempt should be made to lower raised plasma triglyceride and FFA levels. This would decrease the heart's reliance on fatty acids and, hence, overcome the fatty acid inhibition of myocardial glucose utilization. In this regard, the likely application of fatty acid oxidation inhibitors (CPT inhibitors, beta-oxidation inhibitors, sequestration of mitochondrial CoA) is also apparent.
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PMID:Myocardial substrate metabolism: implications for diabetic cardiomyopathy. 776 Mar 40

To define metabolic influences on cardiac myosin expression and sarcoplasmic reticulum (SR) Ca(2+)-stimulated ATPase streptozotocin-diabetic rats were treated for 9-10 wk with etomoxir, an inhibitor of carnitine palmitoyl transferase I (CPT-1) and fatty acid synthesis, or an antilipolytic drug, acipimox. Etomoxir reduced myosin V3 of diabetic rats but did not normalize it. However, the high serum triglyceride, free-fatty acid and cholesterol concentrations in diabetic animals were greatly reduced. After bypassing the CPT-1 inhibition with a medium-chain fatty acid (miglyol) diet, the V3 contents and serum lipids were still reduced in the etomoxir-treated diabetic rats; V3 was also reduced in diabetic rats fed miglyol or treated with acipimox. Since low serum insulin or triiodothyronine concentrations in diabetic rats were not improved by these interventions but changes in V3 were correlated with those in triglyceride, free-fatty acid and cholesterol concentrations, it is likely that myosin may be influenced by some metabolic factors. To assess the role of adrenergic influences, diabetic rats (7-8 wk) were treated with an antisympathotonic drug, moxonidine, a beta-adrenoceptor blocking drug, propranolol, and a bradycardic drug, tedisamil. Myosin V3 was not reduced significantly in moxonidine-treated or propranolol-treated rats in comparison to untreated diabetic rats. Serum thyroid hormones and insulin were not altered, whereas triglycerides were reduced but not significantly by these antiadrenergic agents. Lowering serum lipids in diabetic rats by treatment with etomoxir, miglyol and acipimox increased the depressed SR Ca(2+)-stimulated ATPase activity. On the other hand, in diabetic rats treated with moxonidine, propranolol or tedisamil, the ATPase activity was not increased significantly. These results suggest that normalization of blood lipids is important for improving subcellular organelle function in diabetic hearts with impaired glucose utilization.
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PMID:Modification of myosin isozymes and SR Ca(2+)-pump ATPase of the diabetic rat heart by lipid-lowering interventions. 807 10

1. The effect of the dynein inhibitor erythro-9-[3-(2-hydroxynonyl)] adenine (EHNA) on the osmotic water flow response to vasopressin or exogenous cAMP has been investigated in isolated toad urinary bladders. 2. Pretreatment with serosal EHNA had no effect on basal water flow, but inhibited the development and maintenance of the hydrosmotic response to vasopressin (20 mU ml-1) or 8-(4-parachlorophenylthio)-adenosine 3',5'-cyclic monophosphate (8 CPT-cAMP; 0.1 mM). 3. The inhibitory effect of EHNA on vasopressin-induced water flow was dose dependent. Inhibition occurred in the dose range in which EHNA inhibits the ATPase and motor activities of dynein in vitro. 4. EHNA also inhibited the maintenance of the high rate of water flow established by prior exposure to vasopressin. 5. The inhibitory effect of EHNA on the onset phase of the vasopressin response was attenuated after exposure of the tissue to the microtubule-disruptive drug nocodazole but was fully additive with that of cytochalasin B. 6. EHNA inhibited basal and vasopressin-stimulated transepithelial sodium transport. 7. The findings support the view that EHNA inhibits hormone-induced water flow through an action on a cytoplasmic dynein. The results are consistent with the hypothesis that dynein is involved in the microtubule-based delivery of water channel-containing vesicles to the apical membrane of the granular epithelial cells during both the onset and maintenance of the water permeability response to vasopressin.
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PMID:Effect of a dynein inhibitor on vasopressin action in toad urinary bladder. 868 74

Low concentrations of angiotensin II (Ang II) increase, whereas high concentrations inhibit the apical Na/H antiporter activity in the proximal tubule, but the respective roles of the different signaling pathways in mediating these effects remains unsettled. We studied the effects of both low and high doses of Ang II in the presence of selective signaling pathway inhibitors, on the apical Na/H antiport activity of rat proximal tubule. Experiments were carried out in intact cells of freshly prepared tubule fragments obtained from the outer third of cortex, that is, devoid of basolateral Na/H antiport activity in the absence of bicarbonate transport and H(+)-ATPase activity. In tubules acid-loaded by an NH4Cl prepulse, Na/H antiport activity was assessed by the initial rate of intracellular pH recovery (dpHi/dt), measured with BCECF. When tubules were preincubated with low dose Ang II (10(-11) M for 3 min), dpHi/dt increased by 25 +/- 8%, whereas incubation with high dose Ang II (10(-7) M for 3 min) decreased dpHi/dt by 30 +/- 4%, compared to control (P < 0.01 in both cases). Both effects were abolished in the presence of 2.10(-3) M amiloride. Low dose Ang II-induced increase in dpHi/dt was not affected by preincubation with a specific PKA inhibitor, Rp-CPT-cAMP 10(-4) M, and was completely abolished by preincubation with PKC inhibitors, staurosporine 10(-7) M, sphingosine 5.10(-6) M, or calphostin 10(-6) M. In addition, pretreatment of rats with pertussis toxin led to a partial inhibition of the effect of low dose Ang II. The high dose-Ang II-induced decrease in dpHi/dt was not affected by pretreatment with a calcium-calmodulin kinase inhibitor W-7 10(-4) M. Conversely, pretreatment with the cytochrome P-450 inhibitor econazole 10(-5) M reversed the inhibitory effect of high dose Ang II to a stimulatory effect (24 +/- 8%, P < 0.01), quantitatively similar to the effect of low dose Ang II. In addition, arachidonate was found to exert an econazole-sensitive dose-dependent inhibitory effect on dpHi/dt, and 5,6-EET 10(-6) M, a cytochrome P-450 derived-arachidonic acid metabolite, induced a 38 +/- 9% inhibition, similar to that observed with high dose Ang II alone. There was no additive effect of 5,6-EET and high dose Ang II. Finally, pretreatment with two PLA2 inhibitors (BromoPhenacylBromide, 6.10(-6) M, and oleyloxyethyl phosphorylcholine, 5.10(-6) M) reversed the inhibitory effect of high dose Ang II to a stimulatory effect (32 +/- 11% and 25 +/- 11%, respectively, P < 0.05 for both inhibitors). We conclude that, in intact rat proximal cells, low dose Ang II stimulates the apical Na/H antiport through a pertussis toxin-sensitive G protein-dependent PKC pathway, whereas high dose Ang II inhibits the Na/H antiport activity through the PLA2- and cytochrome P-450-dependent metabolites of arachidonate.
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PMID:Signaling pathways in the biphasic effect of angiotensin II on apical Na/H antiport activity in proximal tubule. 891 15

Chronic salt stress in ducklings (Anas platyrhynchos) resulted in a sustained accumulation of cyclic AMP in the secretory cells of the nasal salt glands. Adaptive increases in the activity of the Na+/K+-ATPase, measured as ATP hydrolysis rates in freshly isolated tissue, were observed after 12 h of salt stress. This change in enzyme activity was associated with increases in protein abundance in the - as well as in the ss-subunit of Na+/K+-ATPase and an increase in ss-subunit glycosylation. We investigated whether the increase in the cytosolic cyclic AMP concentration and the adaptive changes in Na+/K+-ATPase activity were causally related. Using an organotypic tissue culture system for salt gland slices from unstressed (naive) ducklings, we produced similar changes in Na+/K+-ATPase activity and subunit abundance by treating cultured tissue with drugs that elevate cytosolic cyclic AMP levels (forskolin, 8-CPT-cAMP) during a 15 h culture period. Protein synthesis assays using cultured tissue revealed that elevations in cytosolic cyclic AMP level mediate increases in Na+/K+-ATPase subunit abundance by slowing down the degradation of ATPase subunits. This increase in the amount of enzyme protein was associated with a significant increase in Na+/K+-ATPase activity in tissue homogenates. The time course of these changes in cyclic-AMP-treated cultured tissue resembled that observed in salt-stressed intact animals, indicating that the elevation in cyclic AMP level in salt gland tissue may constitute a portion of the signalling events ultimately leading to the adaptive increase in Na+/K+-ATPase activity in vivo.
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PMID:Changes in Na+/K+-ATPase expression during adaptive cell differentiation in avian nasal salt gland 931 5

The mechanism(s) by which dopamine inhibits Na+-K+-ATPase activity in the renal proximal tubule is still controversial. We studied the short-term effects of dopamine on the sodium pump in rat renal proximal tubule suspensions with the 86Rb uptake method. Dopamine and the D1-like agonist, SKF81297, initially stimulated Na+-K+-ATPase activity at 5 min and subsequently inhibited it at 10 min and 20 min; the inhibition by 10 microM dopamine at 20 min was 21.3 +/- 4.5%. The inhibitory effect of dopamine on Na+-K+-ATPase activity was mimicked by thymeleatoxin (a classical protein kinase C [PKC] agonist) while Sp-8-CPT-cAMPS (a protein kinase A [PKA] agonist) had no effect. However, the combination of the PKC and PKA agonists mimicked the biphasic effects of dopamine and SKF81297. Rp-8-CPT-cAMPS (a PKA inhibitor), U-73122 (a phospholipase C inhibitor), or calphostin C (a PKC inhibitor), blocked the dopamine-mediated biphasic effects on Na+-K+-ATPase activity. It is suggested that the biphasic effects of dopamine on Na+-K+-ATPase activity (an initial stimulation and a subsequent inhibition) are transduced by activating both PKA and PKC through a D1-like receptor.
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PMID:Biphasic effects of dopamine on 86rubidium uptake in rat renal proximal tubules. 1080 34

The antisecretory effects of flufenamate in the rat distal colon were investigated with the Ussing-chamber and the patch-clamp method as well as by measurements of the intracellular Ca(2+) concentration using fura-2-loaded isolated crypts. Flufenamate (5.10(-4) mol l(-1)) suppressed the short-circuit current (Isc) induced by carbachol (5.10(-5) mol l(-1)), forskolin (5.10(-6) mol l(-1)) and the Isc induced by the membrane-permeable analogue of cyclic AMP, CPT - cyclic AMP (10(-4) mol l(-1)). Indomethacin (10(-6) - 10(-4) mol l(-1)) did not mimic the effect of flufenamate, indicating that the antisecretory effect of flufenamate is not related to the inhibition of the cyclo-oxygenase. When the basolateral membrane was depolarized by a high K(+) concentration and a Cl(-) current was induced by a mucosally directed Cl(-) gradient, the forskolin-stimulated Cl(-) current was blocked by flufenamate, indicating an inhibition of the cyclic AMP-stimulated apical Cl(-) conductance. When the apical membrane was permeabilized by the ionophore, nystatin, flufenamate decreased the basolateral K(+) conductance and inhibited the Na(+) - K(+)-ATPase. Patch-clamp experiments revealed a variable effect of flufenamate on membrane currents. In seven out of 11 crypt cells the drug induced an increase of the K(+) current, whereas in the remaining four cells an inhibition was observed. Experiments with fura-2-loaded isolated crypts indicated that flufenamate increased the basal as well as the carbachol-stimulated intracellular Ca(2+) concentration. These results demonstrate that flufenamate possesses multiple action sites in the rat colon: The apical Cl(-) conductance, basolateral K(+) conductances and the Na(+) - K(+)-ATPase.
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PMID:Multiple action sites of flufenamate on ion transport across the rat distal colon. 1086 95

Previous studies have demonstrated that functional interaction between endothelin (ET)-1 and nitric oxide (NO) involves changes in Ca(2+) mobilization and cytoskeleton in human brain microvascular endothelial cells. The focus of this investigation was to examine the possible existence of analogous interplay between these vasoactive substances and elucidate their signal transduction pathways in human brain capillary endothelial cells. The results indicate that ET-1-stimulated Ca(2+) mobilization in these cells is dose-dependently inhibited by NOR-1 (an NO donor). This inhibition was prevented by ODQ (an inhibitor of guanylyl cyclase) or Rp-8-CPT-cGMPS (an inhibitor of protein kinase G). Treatment of endothelial cells with 8-bromo-cGMP reduced ET-1-induced Ca(2+) mobilization in a manner similar to that observed with NOR-1 treatment. In addition, NOR-1 or cGMP reduced Ca(2+) mobilization induced by mastoparan (an activator of G protein), inositol 1,4,5-trisphosphate, or thapsigargin (an inhibitor of Ca(2+)-ATPase). Interestingly, alterations in endothelial cytoskeleton (actin and vimentin) were associated with these effects. The data indicate for the first time that the cGMP-dependent protein kinase colocalizes with actin. These changes were accompanied by altered levels of phosphorylated vasodilator-stimulated phosphoprotein, which were elevated in endothelial cells incubated with NOR-1 and significantly reduced by ODQ or Rp-8-CPT-cGMPS. The findings indicate a potential mechanism by which the functional interrelationship between ET-1 and NO plays a role in regulating capillary tone, microcirculation, and blood-brain barrier function.
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PMID:ET-1- and NO-mediated signal transduction pathway in human brain capillary endothelial cells. 1252 47


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