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)

Both metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy but their interrelationships are poorly understood. Both aldose reductase inhibitors and vasodilators improve nerve conduction velocity, nerve blood flow, and (Na+, K+)-ATPase activity in the streptozotocin diabetic rat, implying a metabolic-vascular interaction. Nitric oxide may be the 'bridge' linking these divergent hypotheses of diabetic neuropathy. We propose a model for the pathogenesis of neuropathy invoking metabolic defects both at a vascular and neurochemical level. Early after the induction of experimental diabetes, metabolic defects may lead to a decrease in synthesis of nitric oxide in either the vascular endothelium or the sympathetic ganglia leading to decreased nerve blood flow. In addition, nitric oxide may be involved in more distal defects of somatic nerve metabolism which impair the activity of the nerve Na/K-ATPase by a mechanism involving phosphoinositide signaling and diacyl glycerol and may therefore affect nerve conduction velocity independently of ischaemia. Improved understanding of the effects of hyperglycaemia on nitric oxide metabolism, may provide important clues elucidating the mechanisms underlying the pathogenesis of diabetic neuropathy.
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PMID:Nitric oxide as a potential bridge between the metabolic and vascular hypotheses of diabetic neuropathy. 760 Jul 40

Antibodies against the holo ecto-adenosinetriphosphatase (ATPase) of rat liver and antibodies against COOH-terminal peptides of the long isoform of this enzyme reacted in Western blots with a 105-kDa band from small intestinal brush-border membranes. Indirect immunofluorescence revealed reactive proteins predominantly at the apical surface of enterocytes with some staining of basolateral membranes and of vascular endothelium. Similar results were obtained with monoclonal antibodies against HA4, a protein from rat liver closely related to the ecto-ATPase. Since these results suggested the presence of an ecto-ATPase, ATP hydrolysis was studied in intact, right-side-out brush-border membrane vesicles. Nearly half of ATP hydrolysis was caused by alkaline phosphatase (AP). Besides purine and pyrimidine trinucleotides, AP also hydrolyzed ADP, AMP, pyrophosphate, and 4-nitrophenylphosphate. Inactivation of AP by cleavage of its membrane anchor and by removal of the Zn2+ necessary for its function left the ecto-ATPase that was activated by Ca2+ and Mg2+ and hydrolyzed purine and pyrimidine trinucleotides and dinucleotides, but not AMP, pyrophosphate, and 4-nitrophenylphosphate. These features are characteristic of an ATP diphosphohydrolase (EC 3.6.1.5, also called apyrase). The physiological role of the small intestinal ecto-ATPase may be the degradation of nutrient nucleotides.
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PMID:Ecto-adenosinetriphosphatase in rat small intestinal brush-border membranes. 773 91

1. The vasoactive mechanisms of bile salts have been investigated in rat isolated portal venous and superior mesenteric arterial rings and perfused mesentery. 2. The isolated perfused mesentery was precontracted with a selective alpha 1-adrenoceptor agonist, cirazoline. Incremental doses of tauroursodeoxycholate (TUDC), taurochenodeoxycholate (TCDC) and taurodeoxycholate (TDC) caused a dose-dependent vasorelaxation. The order of potency of the vasodilator effect was TDC > TCDC > TUDC. 3. The effect of TDC (1.9 x 10(-8)-1.9 x 10(-6) mol) was examined before and after propranolol (3 microM), tetraethylammonium (5 mM), ouabain (10(-5) M), NG-nitro-L-arginine methyl ester (10(-4) M) and capsaicin (50 mg kg-1) to block, respectively, beta-adrenoceptors, K+ -channels, Na+, K+-ATPase, nitric oxide synthase, and primary sensory nerves. The vasodilator effect of TDC was not affected by any of these blocking agents or by denuding vascular endothelium with distilled water. 4. Infusion of TDC (1.9 x 10(-8)-1.9 x 10(-6) mol) with K+-free or high K+ (60 mM) physiological salt solution (PSS) did not affect the vasodilator effect of TDC. 5. Contractions induced by KCl (0.01-1.0 M), arginine vasopressin (AVP, 10(-10)-10(-7) M) or cirazoline (10(-7) x 10(-5) M) were all inhibited by TDC (300 microM). 6. TDC (10(-6) to 10(-3) M) also inhibited the basal tension and the development of spontaneous contractions in the isolated portal vein. 7. TDC (300 microM), however, did not affect noradrenaline-induced phasic contractions elicited in Ca(2+)-free PSS by Ca2+ release from intracellular stores. 8. We conclude that TDC inhibits Ca2+ entry through both voltage-operated and receptor-operated calcium channels, whereas intracellular Ca2+ release is not affected.
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PMID:Mechanism of bile salt vasoactivity: dependence on calcium channels in vascular smooth muscle. 795 83

The authors tested the postulate that ouabain releases nitric oxide (NO) from the vascular endothelium of porcine carotid arteries (PCAs) with the technique of perfusion-superfusion bioassay, in which the perfused PCA with endothelium served as the source of NO and superfused left circumflex coronary artery (CMFX) rings with rubbed endothelium served as the bioassay tissue. Selective exposure of the PCA to ouabain (10 microM) enhanced the basal release of NO but did not affect bradykinin-stimulated (BK; 0.1-100 picomoles) release of NO. The effect of ouabain on basal release of NO from PCA persisted after pretreatment of either PCA or circumflex coronary artery with propranolol (1 microM); ibuprofen (1 microM); and hydrocortisone (10 microM). Finally, selective pretreatment of the PCA with L-NG-monomethylarginine (LNMMA; 100 microM) to inhibit 1-arginine-derived NO synthesis inhibited the relaxation of the circumflex coronary artery to basal, BK, and ouabain-stimulated effluent. Since a nonspecific increase in intracellular calcium ion will enhance both basal and agonist-induced release of NO, the authors conclude that a ouabain-sensitive ATPase is involved in basal release of NO from the endothelium of the PCA. Alternatively, ouabain may act on an isozyme of NO synthase in the vascular endothelium. Speculatively, ouabain-induced stimulation of NO release from vascular endothelium may contribute to the beneficial effect of ouabain in congestive heart failure.
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PMID:Ouabain enhances basal release of nitric oxide from carotid artery. 838 25

An agonist-induced Ca2+ influx pathway in vascular endothelium and other nonexcitable cells is closely aligned with the depletion of microsomal Ca2+ stores. The mechanism by which this occurs is unknown. In these studies 2',5',-di(tert-butyl-1,4-benzohydroquinone, a specific inhibitor of the microsomal Ca(2+)-adenosinetriphosphatase, and patch-clamp recordings were used to evaluate the relationship of inward Ca2+ current to the depletion of intracellular Ca2+ stores. The results demonstrate that depletion and refilling of Ca2+ stores control the amplitude of an electrogenic influx pathway in vascular endothelium. Prominent fluctuations in Ca2+ current occur when there is an imbalance between depletion and refilling of the stores. Furthermore, the studies suggest that the Ca2+ influx pathway is spatially in close association with the intracellular store.
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PMID:Depletion and refilling of intracellular Ca2+ stores induce oscillations of Ca2+ current. 838 84

Ecto-nucleotidases may have a role in the regulation of purinoceptor-mediated responses. ATP-diphosphohydrolase or apyrase has been described as an ecto-nucleotidase, which is characterized by a low specificity for its substrates and bivalent cations. The aim of this work was to demonstrate the presence of apyrase as an ecto-enzyme in the rat kidney. ATPase-ADPase activities of the renal microvillar membrane preparation, which correspond to "right side out' membranes, were characterized. The detection of ATP-diphosphohydrolase in the renal vasculature was done through perfusion of isolated rat kidney. ATPase-ADPase activities of the microvillar membrane preparation and apyrase share similar kinetic properties. These include: low substrate and bivalent metal specificities and insensitivity towards inhibitors like: oligomycin, ouabain, verapamil, levamisole and Ap5A. The M(r) or native ATPase and ADPase activities was determined by the 60Co irradiation-inactivation technique being around 65 kDa for both hydrolytic activities. Immunowestern blot analysis also supports the presence of apyrase in microvilli. Perfusion of isolated rat kidney with ATP and ADP, in the presence or absence of different inhibitors or apyrase antibodies indicated the existence of this enzyme in the vascular endothelium. The identification of ATP-diphosphohydrolase as an ecto-enzyme both in microvilli and vasculature support the proposal that the enzyme may have an important role in the extracellular metabolism of nucleotides.
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PMID:ATP-diphosphohydrolase activity in rat renal microvillar membranes and vascular tissue. 869 4

The Na pump (Na-K-ATPase) is important for regulation of membrane potential and transport in smooth muscle and heart. The alpha (catalytic)-subunit of this pump has three isoforms: alpha 1 is ubiquitous, but alpha 2 and alpha 3 are mainly localized to excitable tissue. Physiological differences between isoforms are not completely understood, but alpha 3 pumps appear to have a lower affinity for intracellular Na and a higher ouabain affinity than alpha 1 pumps. The alpha 2-and alpha 3-isoform mRNAs are expressed at high levels in the normal adult rat cardiac conduction system. Although alpha 1 and alpha 3 are both globally expressed in neonatal rat myocardia, there is a switch in the myocardial isoform pattern from alpha 3 to alpha 2 after birth. There are also important species differences in cardiac isoform patterns. Furthermore, changes in Na-K-ATPase isoforms in heart and vascular tissue have been reported in association with hypertension, but little is known about isoform expression in normal endothelia. We therefore studied the cellular distribution of Na pump protein isoforms in neonatal and adult myocardia and endothelia. Immunohistochemical analysis of rat tissues showed that the alpha 1-isoform was expressed throughout atrial and ventricular myocardium, with alpha 1 the only isoform detectable in the adult t tubule system. Although alpha 2 was also present in ventricular myocytes, the signal was markedly stronger in conduction tissue and papillary muscle. In hearts from neonatal rats, the alpha 3-isoform predominated in the cardiac conduction system, whereas alpha 2 was not detectable in any structure except vascular endothelium. In tissues and in cell lines representing a variety of species and vessel sizes, endothelia of large vessels expressed primarily alpha 1, whereas alpha 2 could be detected in endothelia of small vessels in rat heart. No evidence of alpha 3 expression in endothelium was found. Thus the complex spatial and developmental regulation of Na pump isoform expression in cardiovascular tissues may provide additional correlates to distinct physiological roles of these transporters.
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PMID:Na-K-ATPase alpha-isoform expression in heart and vascular endothelia: cellular and developmental regulation. 877 64

Vascular endothelial cells regulate vascular smooth muscle tone through Ca2+-dependent production and release of vasoactive molecules. Phospholamban (PLB) is a 24- to 27-kDa phosphoprotein that modulates activity of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA). Expression of PLB is reportedly limited to cardiac, slow-twitch skeletal and smooth muscle in which PLB is an important regulator of [Ca2+]i and contractility in these muscles. In the present study, we report the existence of PLB in the vascular endothelium, a nonmuscle tissue, and provide functional data on PLB regulation of vascular contractility through its actions in the endothelium. Endothelium-dependent relaxation to acetylcholine was attenuated in aorta of PLB-deficient (PLB-KO) mice compared with wild-type (WT) controls. This effect was not due to actions of nitric oxide on the smooth muscle, because sodium nitroprusside-mediated relaxation in either denuded or endothelium-intact aortas was unaffected by PLB ablation. Relative to denuded vessels, relaxation to forskolin was enhanced in WT endothelium-intact aortas. The endothelium-dependent component of this relaxation was attenuated in PLB-KO aortas. To investigate whether these changes were due to PLB, WT mouse aorta endothelial cells were isolated. Both reverse transcriptase-polymerase chain reaction and Western blot analyses revealed the presence of PLB in endothelial cells, which were shown to be >98% pure by diI-acetylated LDL uptake and nuclear counterstaining. These data indicate that PLB is present and modulates vascular function as a result of its actions in endothelial cells. The presence of PLB in endothelial cells opens new fields for investigation of Ca2+ regulatory pathways in nonmuscle cells and for modulation of endothelial-vascular interactions.
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PMID:Phospholamban is present in endothelial cells and modulates endothelium-dependent relaxation. Evidence from phospholamban gene-ablated mice. 1002 11

Metamizol produced a dose- and time-dependent relaxation in rabbit thoracic aorta smooth muscle that was precontracted by phenylephrine. Such a relaxation was not observed with indomethacin, which is also a nonsteroidal anti-inflammatory drug. The relaxing effect of metamizol was independent of the presence of vascular endothelium. Tetraethylammonium (a calcium-activated potassium channel inhibitor), glybenclamide (an ATP-dependent potassium channel inhibitor), indomethacin (a cyclooxygenase inhibitor), and methylene blue (a soluble guanylate cyclase inhibitor) did not have any effect on metamizol-induced relaxation response. Metamizol did not produce any relaxation effect on aortic smooth muscle when KCl (30, 60, and 117 mM KCl) was used instead of phenylephrine to precontract the preparation. Ouabain (a Na-K ATPase pump inhibitor) showed a dose-dependent inhibition on metamizol's relaxation response. However, in potassium-free medium, which is an alternative way to block the Na-K ATPase pump, no inhibition in metamizol-induced relaxation response was observed. When metamizol was incubated for 2 h in organ-bath conditions before evaluating its relaxing effect, it produced a relatively faster relaxation, indicating that the relaxing effect of metamizol is produced by one of its (active) spontaneous degradation products (possibly 4-methylaminoantipyrine).
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PMID:Pharmacological characterization of metamizol-induced relaxation in phenylephrine-precontracted rabbit thoracic aorta smooth muscle. 1048 Jun 56

There is recent evidence that the membrane potential of vascular endothelium regulates not only nitric oxide (NO) synthesis, but also superoxide generation, such that hyperpolarization stimulates NO production while suppressing that of superoxide. Given that NO works in a variety of ways to inhibit atherothrombotic disease and hypertension, whereas superoxide not only vetoes the benefits of NO but also disrupts endothelial metabolism and promotes LDL oxidation through its oxidant activity, it is thus evident that endothelium membrane potential is a crucial determinant of cardiovascular risk. Membrane polarization can be enhanced by measures which increase the synthesis or availability of the Na+-K+-ATPase, moderately enhance serum K+ and increase the conductance of membrane K+ channels. Such measures may include high-K+/low-Na+ natural diets, insulin sensitizing modalities, 'euthyroid replacement therapy' and ACE inhibitors. Epidemiological correlations of insulin resistance with hypertension and cardiovascular risk may reflect the low membrane potential of insulin-resistant vascular endothelium. Adjunctive measures for suppressing the generation or half-life of endothelial superoxide are suggested.
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PMID:Endothelial membrane potential regulates production of both nitric oxide and superoxide--a fundamental determinant of vascular health. 1060 62


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