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 LATS and TSH on the cyclic nucleotide content and enzymatic activity in rat thyroid was observed during the continuous administration of LATS or TSH for 6 days. Serum T4 and T3 levels were increased significantly compared with the saline controls. The cyclic nucleotide (cAMP and cGMP) levels and enzyme activities per wet weight of tissue were determined. The thyroid weight in both the LATS and TSH groups increased approximately two-fold, but cAMP and cGMP content per wet weight did not significantly change. Neither cyclic nucleotide showed any significant change in plasma. The cAMP-PDE activity in the thyroid significantly increased in both the LATS and TSH groups, but the cGMP-PDE activity was unchanged. Neither was cyclic nucleotide-PDE activity changed in the plasma. The ATPase activity in the thyroid increased markedly in both the LATS and TSH groups, while 5'-nucleotidase activity did not change. These data suggest that LATS and TSH appear to have a stimulatory effect on the metabolism of cAMP, but do not affect the metabolism of cGMP.
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PMID:Changes in cyclic nucleotides of rat thyroid by chronic administration of LATS and TSH. 21 Jun 9

As part of a search for new cardiotonic agents significantly sensitising the myocardial contractile proteins to calcium, together with cardiac cyclic AMP-PDE inhibitory activity, we have discovered that novel 5-substituted 3,6-dihydrothiadiazin-2-ones may fulfill both properties. The sensitising effect of the contractile proteins to calcium, assessed by the shift in the calcium sensitivity of canine cardiac myofibrillar magnesium-dependent ATPase, is determined by steric and electronic requirements. The requirements for phosphodiesterase inhibition, especially that of a near-planar arrangement for the phenyl and thiadiazin-2-one ring are consistent with those already described for analogous pyridazinones. The synthesis and structure-activity relationships are discussed.
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PMID:A novel class of cardiotonic agents: synthesis and biological evaluation of 5-substituted 3,6-dihydrothiadiazin-2-ones with cyclic AMP phosphodiesterase inhibiting and myofibrillar calcium sensitizing properties. 131 Jan 13

EMD 53 998, a novel thiadiazinone derivative, increases the contractile force of cardiac tissue in vitro through both an inhibition of phosphodiesterase III (PDE III) and a sensitization of cardiac contractile proteins to Ca2+. Guinea pig ventricular PDE III is selectively inhibited by EMD 53 998 (IC50 = 60 nM) without major effects on other PDE isoenzymes. Consonant with this is an increase in cAMP content of rat ventricular cells and a potentiation by EMD 53 998 of the cAMP-elevating action of isoprenaline (increase by 50% at 1.3 microM). Sensitization to Ca2+ by EMD 53 998 (3-30 microM) finds its expression in a leftward shift of the Ca2+ response curve for force generation in skinned fibers from porcine ventricular muscle and failing human heart as well as for activation of bovine cardiac myofibrillar actomyosin ATPase. Interestingly, EMD 53 998 elevates the maximum of the Ca(2+)-response curve for both parameters. Pimobendan studied under identical conditions was 100 times less potent than EMD 53 998. EMD 53 998 increases force development of guinea pig papillary muscle in a concentration-dependent manner with an EC50 of 3.6 microM, thus being 10 times more potent than pimobendan. In contrast to pimobendan, the positive inotropic effect of EMD 53 998 is barely affected by carbachol. Further evidence for a Ca(2+)-sensitizing effect of EMD 53 998 is provided by an additional increase in force generation in the presence of supramaximal isoprenaline concentrations. It is concluded that the positive inotropic action of EMD 53 998 is mediated through both cAMP-independent and cAMP-dependent mechanisms, with the former probably prevailing. We are not aware of other compounds with a similarly high Ca(2+)-sensitizing potency. On these grounds. EMD 53 998 appears to be a promising inotropic agent.
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PMID:The novel cardiotonic agent EMD 53 998 is a potent "calcium sensitizer". 171 87

[3H]LY186126, an analogue of the cardiotonic agent indolidan, was shown to bind reversibly and with high affinity (Kd = 4 nM) to a single class of binding sites within canine myocardial vesicles. Binding site density measured in various cardiac membrane fractions correlated well with Ca2+-ATPase activity (r = 0.94; p less than 0.01), but not with Na+,K+-ATPase or azide sensitive ATPase, indicating a localization of these sites within sarcoplasmic reticulum membranes. Divalent cations were required for binding and displayed the following order of activation: Zn2+ greater than Mn2+ greater than Mg2+ greater than Ca2+. Differential activation of [3H]LY186126 binding by various divalent cations was due to alterations in binding site density, rather than affinity. cGMP and selective inhibitors of type IV membrane-bound phosphodiesterase (SR-PDE), for example, indolidan, milrinone, imazodan, and enoximone, selectively displaced bound [3H]LY186126 caffeine, theophylline, and rolipram were relatively impotent as inhibitors of radiolabel binding. Kd values from displacement curves were highly correlated with IC50 values for inhibition of SR-PDE (r = 0.92; p less than 0.001). In addition, Kd values correlated well with published ED50 values for increases in cardiac contractility in pentobarbital-anesthetized dogs (r = 0.94; p less than 0.001). The results support the hypothesis that [3H]LY186126 labels the pharmacological receptor for the class of positive inotropic agents characterized as isozyme-selective phosphodiesterase inhibitors. Furthermore, the data suggest that the identity of the site labeled by [3H]LY186126 is SR-PDE, the type IV isozyme of cardiac phosphodiesterase located in the sarcoplasmic reticulum.
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PMID:Characterization and pharmacological relevance of high affinity binding sites for [3H]LY186126, a cardiotonic phosphodiesterase inhibitor, in canine cardiac membranes. 254 18

The possible interaction between amiodarone, a potent antiarrhythmic and antianginal agent, and calmodulin (CaM) was investigated by three avenues of approach: (a) Effect of amiodarone on cardiac and vascular Ca2+/calmodulin-activated cyclic nucleotide phosphodiesterase (CaM-PDE); (b) Effect on the CaM-activated (Ca2+ + Mg2+)-ATPase from human erythrocytes; (c) Direct interaction between amiodarone and calmodulin measured by the effect of the drug on the fluorescence of 9-anthroylcholine (9AC) bound to calmodulin. Results show that amiodarone did not interact with basal activities of CaM-PDE and other isolated CaM-insensitive PDE forms as well as with (Ca2+ + Mg2+)-ATPase. Amiodarone inhibited calmodulin-activation of aortic CaM-PDE (Ki = 650 nM, substrate cGMP) and calmodulin-activation of erythrocyte ghosts (Ca2+ + Mg2+)-ATPase (IC50 = 4.5 microM) in an apparently competitive manner. Amiodarone decreased the fluorescence of the hydrophobic probe 9AC bound to calmodulin (IC50 = 5 microM). It is concluded that amiodarone is a potent calmodulin antagonist.
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PMID:Amiodarone is a potent calmodulin antagonist. 254 10

K-252a, an indole carbazol compound of microbial origin, inhibited activation of bovine brain phosphodiesterase induced by calmodulin (CaM), sodium oleate, or limited proteolysis with almost equal potency. Kinetic analysis revealed that the CaM-activated phosphodiesterase (CaM-PDE) was competitively inhibited by K-252a with respect to CaM. On the other hand, inhibition of the trypsin-activated phosphodiesterase was competitive with respect to cyclic AMP. Addition of a lower amount of phosphatidylserine or sodium oleate to the reaction medium was efficacious in attenuating the inhibition of the CaM-PDE by W-7, compound 48/80, or calmidazolium but, in contrast, had no effect on the inhibition by K-252a. Furthermore, CaM-independent systems such as [3H]nitrendipine receptor binding or Na+ + K+-ATPase were influenced less by K-252a compared with W-7, compound 48/80 and calmidazolium. In conclusion, K-252a is an inhibitor of CaM-dependent cyclic nucleotide phosphodiesterase and it appears that it inhibits the enzyme not only via CaM antagonism but possibly also by interfering with the enzyme.
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PMID:The effect of K-252a, a potent microbial inhibitor of protein kinase, on activated cyclic nucleotide phosphodiesterase. 285 86

Chlorpromazine (CPZ) at dosages of 10 mg/kg body weight (b.wt.) affected the cytochemical localization of cAMP-dependent phosphodiesterase (cAMP PDE) activity in the synapses of the rat frontal cortex. Postsynaptic cAMP PDE activity was inhibited, and presynaptic activity increased. CPZ also inhibited membrane-bound ATPase activity in the frontal cortex. The activity of Na+-K+-ATPase was significantly (P less than 0.005) inhibited in isolated plasma membranes from the rat frontal cortex. CPZ exposure also affected the cytochemical localization of cations with potassium pyroantimonate. Precipitate, which could be removed with 5 mm EGTA, was decreased in the mitochondria and synaptic vesicles in presynaptic areas after CPZ treatment. The incorporation of 45Ca2+ into slices of the rat frontal cortex was also significantly (P less than 0.001) inhibited by CPZ. This ultrastructural study shows that CPZ may affect biochemical events in an opposite manner in the pre- and post-synaptic areas of some neurons of the frontal cortex.
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PMID:Effect of chlorpromazine on the localization of cAMP phosphodiesterase. 299 Jan 46

CI-914 is a novel positive inotropic agent whose cardiotonic activity is not due to inhibition of Na+, K+-ATPase or to stimulation of cardiac beta-receptors. CI-914 also has no direct effect on sarcoplasmic reticulum, mitochondria or adenylate cyclase activity. CI-914 does, however, exert a potent inhibitory effect on cardiac phosphodiesterase activity. In evaluating the effect of this agent on the different molecular forms of phosphodiesterase present in cardiac muscle, CI-914 was found to selectively inhibit PDE III, which is a low Km, cAMP-specific form of the enzyme (IC50 = 6.1 microM). This inhibitory effect was found to be competitive with respect to the substrate. Papaverine and theophylline on the other hand were found to inhibit all three forms of phosphodiesterase present in cardiac muscle. The role of phosphodiesterase inhibition in mediating the positive inotropic response to CI-914 is supported by the finding that this agent: (i) significantly elevates cyclic AMP levels in ventricular tissue; (ii) shifts the normal concentration-response to the beta-receptor stimulant isoproterenol to the left: and (iii) restores contractility to K+-depolarized papillary muscles.
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PMID:Studies aimed at elucidating the mechanism of action of CI-914, a new cardiotonic agent. 300 93

Okadaic acid (OA) isolated from black sponge (Halichondria) caused tonic contractions of human umbilical arteries and rabbit aorta both in the presence and absence of Ca2+. This tonic contraction was not affected by Ca2+ chelator, Ca2+ entry blockers and La3+. In addition, the antagonists of alpha-adrenoceptors, histamine, serotonin and ACh receptors had no effect on the OA-induced contraction. High K, ouabain and indomethacin failed to inhibit the response to OA. However, the combination of anaerobic conditions and absence of glucose abolished the response to OA. OA had no effect on the myosin B ATPase and saponin-treated skinned fibers of rabbit aorta. The contractile action of OA may not also be related to calmodulin-related PDE and mitochondrial respiration. In conclusion, although the precise mode of action is not evident at the present time, OA, in its unique pharmacological action--that of producing sustained contraction independent of extracellular Ca2+--may alter the handling of Ca2+ to intracellular store sites.
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PMID:Unique vasocontraction of okadaic acid isolated from black sponge, independent of extracellular Ca2+. 359 72

The saponin fraction prepared from the methanolic extract of Allium chinense bulbs exhibited inhibitory activities on cyclic AMP phosphodiesterase (cAMP PDE) (43.5%) and Na+/K+ ATPase (59.3%) at a sample concentration of 100 micrograms ml-1, respectively. Attempted purification of the active fraction through column chromatography on silica gel and ODS silica gel resulted in the isolation of six steroidal saponins, one of which appeared to be a new compound and one to be the first isolation from a natural source. (25R,S)-5 alpha-Spirostan-3 beta-ol tetrasaccharide showed inhibitory activities on both cAMP PDE and Na+/K+ ATPase, while (25R)-3 beta-hydroxy-5 alpha-spirostan-6-one di- and tri-saccharides inhibited only cAMP PDE.
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PMID:Steroidal saponins from Allium chinense and their inhibitory activities on cyclic AMP phosphodiesterase and Na+/K+ ATPase. 749 69


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