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)

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

Nitric oxide (NO) reduces the molecular activity of Na+-K+-ATPase in opossum kidney (OK) cells, a proximal tubule cell line. In the present study, we investigated the cellular mechanisms for the inhibitory effect of NO on Na+-K+-ATPase. Sodium nitroprusside (SNP), a NO donor, inhibited Na+-K+-ATPase in OK cells, but not in LLC-PK1 cells, another proximal tubule cell line. Similarly, phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator, inhibited Na+-K+-ATPase in OK, but not in LLC-PK1, cells. PKC inhibitors staurosporine or calphostin C, but not the protein kinase G inhibitor KT-5823, abolished the inhibitory effect of NO on Na+-K+-ATPase in OK cells. Immunoblotting demonstrated that treatment with NO donors caused significant translocation of PKCalpha from cytosolic to particulate fractions in OK, but not in LLC-PK1, cells. Furthermore, the translocation of PKCalpha in OK cells was attenuated by either the phospholipase C inhibitor U-73122 or the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. U-73122 also blunted the inhibitory effect of SNP on Na+-K+-ATPase in OK cells. The phospholipase A2 inhibitor AACOCF3 did not blunt the inhibitory effect of SNP on Na+-K+-ATPase in OK cells. AACOCF3 alone, however, also decreased Na+-K+-ATPase activity in OK cells. In conclusion, our results demonstrate that NO activates PKCalpha in OK, but not in LLC-PK1, cells. The activation of PKCalpha in OK cells by NO is associated with inhibition of Na+-K+-ATPase.
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PMID:Nitric oxide activates PKCalpha and inhibits Na+-K+-ATPase in opossum kidney cells. 1060 Sep 32

In this study, we show that particulate guanylate cyclase (GC) is present in rat pancreatic acinar cells and is located both on plasma membrane and membranes of endoplasmic reticulum (ER). Western blot analysis indicates that the enzyme isoform GC-A is present in the acinar cell membranes. The specific inhibitors of ER Ca(2+)-ATPase thapsigargin, 2,5-di-(t-butyl)-1,4-hydroquinone (BHQ), and cyclopiazonic acid all activated particulate GC in pancreatic acini, both in membrane fractions and intact cells. These inhibitors also induced dephosphorylation of GC. Dose dependencies of Ca(2+)-ATPase inhibition and GC activation by BHQ are very similar, and those for thapsigargin partially overlap. ER Ca(2+)-ATPase and GC are coimmunoprecipitated both by antisera against membrane GC and by antisera against ER Ca(2+)-ATPase, suggesting a physical association between the two enzymes. The results suggest that thapsigargin and the other inhibitors act through ER Ca(2+)-ATPase to activate membrane GC in pancreatic acinar cells, although their direct effect on GC cannot be excluded.
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PMID:Endoplasmic reticulum Ca(2+)-ATPase inhibitors stimulate membrane guanylate cyclase in pancreatic acinar cells. 1066 32

Bone resorption by osteoclasts is modified by agents that affect cyclic guanosine monophosphate (cGMP), but their relative physiological roles, and what components of the process are present in osteoclasts or require accessory cells such as osteoblasts, are unclear. We studied cGMP regulation in avian osteoclasts, and in particular the roles of nitric oxide and natriuretic peptides, to clarify the mechanisms involved. C-type natriuretic peptide drives a membrane guanylate cyclase, and increased cGMP production in mixed bone cells. However, C-type natriuretic peptide did not increase cGMP in purified osteoclasts. By contrast, osteoclasts did produce cGMP in response to nitric oxide (NO) generators, sodium nitroprusside or 1-hydroxy-2-oxo-3,3-bis(3-aminoethyl)-1-triazene. These findings indicate that C-type natriuretic peptide and NO modulate cGMP in different types of bone cells. The activity of the osteoclast centers on HCI secretion that dissolves bone mineral, and both NO generators and hydrolysis-resistant cGMP analogues reduced bone degradation, while cGMP antagonists increased activity. NO synthase agonists did not affect activity, arguing against autocrine NO production. Osteoclasts express NO-activated guanylate cyclase and cGMP-dependent protein kinase (G-kinase). G-kinase reduced membrane HCI transport activity in a concentration-dependent manner, and phosphorylated a 60-kD osteoclast membrane protein, which immunoprecipitation showed is not an H+-ATPase subunit. We conclude that cGMP is a negative regulator of osteoclast activity. cGMP is produced in response to NO made by other cells, but not in response to C-type natriuretic peptide. G-kinase modulates osteoclast membrane HCI transport via intermediate protein(s) and may mediate cGMP effects in osteoclasts.
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PMID:Nitric oxide regulation of cGMP production in osteoclasts. 1073 42

The regulation of gene expression by nutrients plays an important role in the overall manifestations of nutritional deficiencies. Insufficient intakes of dietary micronutrients, such as zinc, produce profound effects in multiple organs and tissues. One of the major challenges, however, is to identify genes affected by changes in nutritional status. Differential display of mRNA has proved to be a valuable technique in meeting this challenge. In our ongoing search for genes responsive to dietary zinc, we compared small intestinal mRNA from rats that were fed zinc-deficient or -adequate diets using differential display to generate 3' anchored expressed sequence tags (EST). EST for intestinal mRNAs with altered expression due to zinc deficiency include two peptide hormones, intestinal fatty acid binding protein, intestinal alkaline phosphatase II, a proteasomal ATPase, cis-Golgi p28 and two subunits of the ubiquinone oxidoreductase. The EST for one of the hormones yielded the sequence for the 3' end of an mRNA encoding preprouroguanylin and was used to clone the remaining portion of the rat cDNA via 5' rapid amplification of cDNA ends. Northern blot analysis of RNA from rat intestine demonstrated that preprouroguanylin mRNA was 2.5-fold more abundant during zinc deficiency. Uroguanylin, a natriuretic peptide hormone, is an endogenous ligand for the same guanylate cyclase C that the Escherichia coli heat-stable enterotoxin (STa) binds when it causes secretory diarrhea by activating the cystic fibrosis transmembrane conductance regulator, thus altering fluid balance in the intestine. This suggests a mechanism whereby zinc deficiency could induce uroguanylin levels in the intestine and cause or potentiate diarrhea.
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PMID:Regulation of intestinal gene expression by dietary zinc: induction of uroguanylin mRNA by zinc deficiency. 1080 50

In rat pulmonary artery pre-contracted with phenylephrine, the mechanisms of relaxation to the nitric oxide (NO) donor, spermine NONOate, were investigated. Responses to spermine NONOate were only partially blocked by the soluble guanylate cyclase inhibitor, ODQ (1H:-[1,2,4]Oxadiazolo-[4,3,-a]quinoxalin-1-one) at concentrations up to 30 microM. Ten microM ODQ gave maximal inhibition. Endothelium removal had no effect on the potency of spermine NONOate or its inhibition by ODQ. The protein kinase G inhibitor, Rp-8-Br-cGMPS (100 microM), caused minimal inhibition of spermine NONOate despite causing marked inhibition of glyceryl trinitrate and isosorbide dinitrate. Spermine NONOate (100 microM) caused a 35 fold increase in guanosine 3'5' cyclic monophosphate (cyclic GMP) above basal levels in pulmonary artery rings. ODQ (3 microM) abolished this cyclic GMP production but did not inhibit corresponding relaxant responses. Similar results were seen with another NONOate (MAHMA NONOate; 10 microM). ODQ-resistant relaxation to spermine NONOate (i. e. relaxation seen in the presence of 10 microM ODQ) was inhibited by potassium (80 mM), charybdotoxin (300 nM), iberiotoxin (300 nM), apamin (100 nM), ouabain (1 mM) or thapsigargin (100 nM) but not by 4-aminopyridine (3 mM), glybenclamide (10 microM) or diltiazem (10 microM). Potassium, charybdotoxin, ouabain and thapsigargin also inhibited ODQ-resistant relaxation to FK409 ((+/-)-E:-4-ethyl-2-[E:-hydroxyimino]-5-nitro-3-hexenamide). We conclude that, on rat pulmonary artery, spermine NONOate can produce cyclic GMP-independent relaxation that involves, at least in part, activation of Na(+)/K(+)-ATPase, sarco-endoplasmic reticulum Ca(2+)-ATPase and calcium-activated potassium channels.
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PMID:Cyclic GMP-independent relaxation of rat pulmonary artery by spermine NONOate, a diazeniumdiolate nitric oxide donor. 1103 Jul 15

Secretion of cerebrospinal fluid by the choroid plexus can be inhibited by its cholinergic innervation. We demonstrated that carbachol inhibits the Na(+)-K(+)-ATPase in bovine choroid tissue slices and investigated the mechanism. Many of the actions of cholinergic agents are mediated by nitric oxide (NO), which plays important roles in fluid homeostasis. The inhibition of Na(+)-K(+)-ATPase was blocked by the NO synthase inhibitor [N(omega)-nitro-L-arginine methyl ester] and was quantitatively mimicked by the NO agonists sodium nitroprusside (SNP) and diethylenetriamine NO. Inhibition by SNP correlated with an increase in tissue cGMP and was abolished by 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. Inhibition was mimicked by the protein kinase G activator 8-bromo-cGMP and by okadaic acid, an inhibitor of protein phosphatases 1 and 2A. cGMP-dependent protein kinase inhibitors Rp-8-pCPT-cGMP (0.5-5 microM) and KT-5823 (2.0 microM) did not block the effects of SNP, but higher concentrations of the more selective inhibitor (Rp-8-pCPT-cGMP) had a pharmacological inhibitory effect on Na(+)-K(+)-ATPase. The data suggest that cholinergic regulation of the Na(+)-K(+)-ATPase is mediated by NO and involves activation of guanylate cyclase and elevation of cGMP.
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PMID:Carbachol inhibits Na(+)-K(+)-ATPase activity in choroid plexus via stimulation of the NO/cGMP pathway. 1107 82

1. We have compared the mechanisms involved in sodium nitroprusside (SNP)-induced relaxation and [Ca2+]i reduction in isolated piglet pulmonary (PA) and mesenteric (MA) arteries. 2. SNP (10(-8) M-3x10(-5) M) evoked a concentration-dependent relaxation of PA and MA (pD2=6.66+/-0.06 and 6.74+/-0.14, respectively) stimulated by noradrenaline, which was markedly reduced by the guanylate cyclase inhibitor ODQ. In fura 2-incubated PA and MA, SNP produced a parallel reduction in contractile force and in [Ca2+]i, expressed as the ratio of emitted fluorescence at 340 and 380 nm (F340/F380). 3. The inhibition of the Na+/K+-ATPase after the incubation in a K+-free medium or the exposure to ouabain (10(-6) M) inhibited SNP-induced relaxation in MA but not in PA. SNP-induced relaxation was not attenuated by 80 mM KCl plus nifedipine (10(-6) M) but was inhibited by thapsigargin (2x10(-6) M; pD2=5.69+/-0.19 and 5.89+/-0.19 for PA and MA, respectively). 4. Pretreatment of PA with thapsigargin and MA with thapsigargin plus ouabain induced a stronger inhibition on the reduction in [Ca2+]i than on the relaxation induced by SNP, indicating the existence of Ca2+-independent mechanisms. 5. The activation of the Na+/K+-ATPase by the addition of KCl after the incubation in a K+-free medium similarly reduced [Ca2+]i in PA and MA, whereas it relaxed with much less efficacy PA than MA. 6. We conclude that SNP reduces [Ca2+]i and causes relaxation through the activation of SERCA in PA and SERCA and Na+/K+-ATPase in MA. However, Ca2+-independent mechanisms also contribute to SNP-induced effects.
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PMID:Mechanisms involved in SNP-induced relaxation and [Ca+]i reduction in piglet pulmonary and systemic arteries. 1118 38

Nitric oxide is a ubiquitous cell-signaling molecule involved in regulation of numerous homeostatic mechanisms and in mediation of tissue injury. Nitric oxide influences contraction, blood flow, and metabolism, as well as myogenesis. Nitric oxide exerts its influence by activation of guanylate cyclase and nitrosylation of proteins, which include glyceraldehyde-3-phosphate dehydrogenase, the ryanodine receptor and actomyosin ATPase. Skeletal muscle expresses all three isoforms of the nitric oxide synthase, including a muscle-specific splice variant; expression of the isoforms is fiber-type specific and influenced by age and disease. Nitric oxide produced with certain systemic conditions and local inflammation is likely toxic to skeletal muscle, either directly or in reactions with oxygen-derived radicals. Although nitric oxide impacts on many functions in muscle, its effects are subtle, and much work remains to be done to determine its importance in the pathogenesis of muscle diseases.
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PMID:Nitric oxide: biologic effects on muscle and role in muscle diseases. 1152 79

Snake envenomation employs three well integrated strategies: prey immobilization via hypotension, prey immobilization via paralysis, and prey digestion. Purines (adenosine, guanosine and inosine) evidently play a central role in the envenomation strategies of most advanced snakes. Purines constitute the perfect multifunctional toxins, participating simultaneously in all three envenomation strategies. Because they are endogenous regulatory compounds in all vertebrates, it is impossible for any prey organism to develop resistance to them. Purine generation from endogenous precursors in the prey explains the presence of many hitherto unexplained enzyme activities in snake venoms: 5'-nucleotidase, endonucleases (including ribonuclease), phosphodiesterase, ATPase, ADPase, phosphomonoesterase, and NADase. Phospholipases A(2), cytotoxins, myotoxins, and heparinase also participate in purine liberation, in addition to their better known functions. Adenosine contributes to prey immobilization by activation of neuronal adenosine A(1) receptors, suppressing acetylcholine release from motor neurons and excitatory neurotransmitters from central sites. It also exacerbates venom-induced hypotension by activating A(2) receptors in the vasculature. Adenosine and inosine both activate mast cell A(3) receptors, liberating vasoactive substances and increasing vascular permeability. Guanosine probably contributes to hypotension, by augmenting vascular endothelial cGMP levels via an unknown mechanism. Novel functions are suggested for toxins that act upon blood coagulation factors, including nitric oxide production, using the prey's carboxypeptidases. Leucine aminopeptidase may link venom hemorrhagic metalloproteases and endogenous chymotrypsin-like proteases with venom L-amino acid oxidase (LAO), accelerating the latter. The primary function of LAO is probably to promote prey hypotension by activating soluble guanylate cyclase in the presence of superoxide dismutase. LAO's apoptotic activity, too slow to be relevant to prey capture, is undoubtedly secondary and probably serves principally a digestive function. It is concluded that the principal function of L-type Ca(2+) channel antagonists and muscarinic toxins, in Dendroaspis venoms, and acetylcholinesterase in other elapid venoms, is to promote hypotension. Venom dipeptidyl peptidase IV-like enzymes probably also contribute to hypotension by destroying vasoconstrictive peptides such as Peptide YY, neuropeptide Y and substance P. Purines apparently bind to other toxins which then serve as molecular chaperones to deposit the bound purines at specific subsets of purine receptors. The assignment of pharmacological activities such as transient neurotransmitter suppression, histamine release and antinociception, to a variety of proteinaceous toxins, is probably erroneous. Such effects are probably due instead to purines bound to these toxins, and/or to free venom purines.
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PMID:Ophidian envenomation strategies and the role of purines. 1173 31


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