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)

(Na(+)-K+)ATPase is necessary for the maintenance of the membrane potential. The activity of this enzyme was studied in purified plasma membranes from a glucose-responsive rat insulinoma. Ouabain-sensitive (Na(+)-K+)ATPase activity showed expected ATP dependency with a Km of 0.4 mM. It was also dependent on Mg2+ (Km range 70-80 microM). In the presence of Mg and ATP, half-maximal activity was obtained at a Na concentration of 30 mM and the enzyme activity increased sigmoidally with a Hill coefficient of 1.5. No direct effect on enzyme activity was observed with the insulin secretagogues glucose, fructose, glyceraldehyde, and ketoisocaproate, or with dibuturyl-cAMP and the phosphodiesterase-inhibitor isobutyl methyl xanthine. It is concluded that (Na(+)-K+)ATPase is not directly influenced by known secretagogues associated with insulin release by the beta cell.
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PMID:The function of (Na(+)-K+)ATPase in the beta cell: characterization of the enzyme in a glucose-responsive insulinoma. 132 2

The action of two antiarrhytmic drugs, moracizine (MOR, CAS 31883-05-3) and ethacizine (ETHA, CAS 33414-33-4) on receptors of potential-operated CA-channels has been investigated. ETHA binding to verapamil receptors was more effective than that of MOR (IC50 = 0.53 +/- 0.08 mumol/l, respectively). The Hill coefficient for ETHA binding was similar to that of verapamil (0.64 +/- 0.09 and 0.60 +/- 0.10, respectively). Interaction of ETHA and MOR with dihydropyridine receptors in concentrations up to 10 mumol/l was similar that of verapamil, however, MOR was less potent. MOR and ETHA did not interact with calmodulin and troponin C at concentrations up to 100 mumol/l. The influence of MOR and ETHA on enzymes dependent on Ca-binding proteins (phosphodiesterase and actomyosin ATPase) was not observed up to 100 mumol/l. Comparison of clinical and electrophysiological data with these results allows the conclusion that ETHA exerts Ca-blocking effects by the interaction with verapamil receptors on potential-operated Ca-channels.
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PMID:Effect of moracizine and ethacizine on receptors of potential-operated calcium channels and calcium-binding proteins. 132 68

OPC-18790 [(+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]- 2(1H)-quinolinone], a novel positive inotropic agent, was investigated in several in vitro and in vivo experiments to elucidate its cardiovascular effects and its mechanism of action. In isolated blood-perfused dog heart preparations, OPC-18790 increased contractile force at 10 to 1,000 nmol i.a.; increased coronary arterial blood flow at 30 to 1,000 nmol; and decreased sinus rate slightly at 1,000 nmol. Atrio-ventricular nodal conduction was slightly facilitated with OPC-18790 (10 to 1,000 nmol), whereas ventricular automaticity tended to decrease. OPC-18790 (10(-6) to 10(-4) M) increased contractile force in isolated ventricular muscles of dogs, cats, rabbits and guinea pigs but not rats. OPC-18790 increased left ventricular contractile force dose-dependently in anesthetized open-chest dogs and in conscious dogs with slight or no changes in heart rate and blood pressure. The positive inotropic effect of OPC-18790 was not affected by beta-blockade. OPC-18790 (10(-5) to 10(-4) M) prolonged the duration of action potential in guinea pig papillary muscles. Na+, K(+)-ATPase was not inhibited, but peak-III phosphodiesterase (low Km cyclic AMP specific fraction, inhibited by cyclic GMP) was inhibited by OPC-18790 (IC50 = 0.41 x 10(-6) M) in dog myocardium. However, such an inhibitory action of phosphodiesterase can hardly be reconciled with the lack of a positive chronotropic effect shown by OPC-18790. Thus, these results suggest that OPC-18790 may have an additional mechanism. The cardiovascular effects revealed by this study suggest that OPC-18790 may exert a beneficial effect in the treatment of congestive heart failure.
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PMID:Cardiovascular actions of OPC-18790: a novel positive inotropic agent with little chronotropic action. 132 45

A protein kinase, stimulated by cytidine 3',5'-cyclic monophosphate, is conventionally assayed by monitoring the incorporation of radiolabelled phosphate from adenosine triphosphate into a histone substrate. Here the assay of the protein kinase is carried out by positive-ion fast-atom bombardment mass spectrometric analysis of the enzyme incubation mixture after the reaction has been terminated. The data so obtained show good agreement with data obtained by the conventional radiometric assay: the intrinsic advantage of the mass spectrometric assay is the capacity for multiple component monitoring; the ability of the kinase to bind competing cyclic nucleotides together with integral adenosine triphosphatase (ATPase) and phosphodiesterase activity can also be assessed.
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PMID:Quantitation by fast-atom bombardment mass spectrometry: assay of cytidine 3',5'-cyclic monophosphate-responsive protein kinase. 133 90

1. Experiments were carried out to examine the biochemical changes, such as contractile protein biochemistry and membrane bound enzyme alterations associated with skeletal muscles of myd/myd. 2. Our studies demonstrate that there was a progressive decline in myofibrillar ATPase activity, and this decrease is greatest in 30 weeks old animals of myd/myd as compared to controls. 3. The proteolytic activity of myofibrils isolated from myd/myd was significantly higher than controls. 4. There was no significant difference in Ca2+ ATPase activity of myosin and actin-activated myosin ATPase activity of myd/myd and their controls. 5. Mg2+ ATPase and Na(+)+K(+)-ATPase of myodystrophic SL showed significant increase compared to controls. 6. Isoproterenol stimulated adenylate cyclase activity was significantly lower in the SL of dystrophic mice compared to controls. 7. GTP+isoproterenol stimulate adenylate cyclase was significantly higher in control SL and SR when compared to SL and SR isolated from myd/myd. 8. Guanylate cyclase activity was greater in myodystrophic mice both in the absence and presence of Triton X-100. cGMP and cAMP phosphodiesterase activities were greater in dystrophic mice as compared to controls. 9. These observations suggest that there are significant changes in myofibrillar ATPase, myofibrillar protease and membrane bound enzymes of myd/myd compared to control.
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PMID:Myofibrillar and membrane-bound enzymes in skeletal muscle from myodystrophic mice. 135 51

Dopamine decreases tubular sodium reabsorption, attributed in part to Na/K-ATPase inhibition in the proximal convoluted tubule (PCT). Because the final regulation of sodium excretion occurs in the collecting duct, where we have demonstrated specific dopamine DA1 binding sites, we examined the effects of dopamine, and of DA1 and DA2 receptor agonists on the Na/K pump in the microdissected rat cortical collecting duct (CCD) and in Madin-Darby canine kidney (MDCK) cells, a line derived from the dog distal nephron. Dopamine inhibited pump activity in CCD by approximately 40%-50%, an effect proportionally larger than in the PCT. Unlike in the latter, the effect of dopamine was reproduced by the DA1 agonist fenoldopam, which inhibited the CCD pump in dose-dependent manner (maximum, 10 microM). The DA2 agonist quinpirole was without effect, either alone or in combination with fenoldopam. These actions on Na/K-ATPase paralleled in reciprocal fashion effects on adenylate cyclase: dopamine or fenoldopam, but not quinpirole, produced a significant increase in cAMP content, and the stimulation by dopamine was blocked by SCH 23390. Inhibitors of cAMP phosphodiesterase (3-isobutyl-1-methyl-xanthine and theophylline), as well as forskolin and dibutyryl-cAMP, mimicked the effect of dopamine on the pump, underscoring the role of increased cAMP in this phenomenon. Both dopamine and fenoldopam inhibited Na/K-ATPase activity in MDCK cells. The results indicate that besides the PCT dopamine inhibits Na/K-ATPase activity in cells of the distal nephron, where its effect on the pump appears to be more pronounced and is mediated by activation of the DA1 receptor. The natriuretic effect of dopamine is probably exerted at both proximal and distal nephron sites.
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PMID:Dopamine inhibits Na/K-ATPase in single tubules and cultured cells from distal nephron. 135 25

The cardiovascular effects of NKH477 (6-(3-dimethylaminopropionyl)forskolin hydrochloride), a novel water-soluble forskolin derivative, were investigated in dogs. Intravenous (i.v.) injections of NKH477 (1-30 micrograms/kg) caused dose-related increases in left ventricular dP/dtmax (LVdP/dtmax), coronary and femoral artery blood flow (CBF, FBF), heart rate (HR), and myocardial oxygen consumption (MVO2) and a dose-related decrease in blood pressure (BP) in anesthetized dogs. The regression analysis between CBF and MVO2 showed that NKH477 did not influence substantially the balance of oxygen supply and demand. Infusions of NKH477 (0.15-0.6 microgram/kg/min i.v.) also increased LVdP/dtmax, cardiac output (CO), and HR and decreased BP, pulmonary arterial diastolic pressure, and total peripheral resistance (TPR) in a dose-dependent manner. In contrast to forskolin, NKH477 administered intraduodenally (0.05-0.2 mg/kg) and orally (0.15 and 0.3 mg/kg) clearly exhibited cardiovascular actions, as it did in i.v. administration, indicating that NKH477 is orally active. No arrhythmias were induced by NKH477 in any study. NKH477, like forskolin, showed adenylate cyclase stimulant activity in guinea pig ventricular membrane but did not inhibit Na+, K(+)-ATPase or phosphodiesterase (PDE) activity. Thus, NKH477 can be characterized as a potent, orally active, water-soluble forskolin derivative, which suggests that NKH477 is a useful inodilator for treatment of heart failure, especially in the severe stage with beta-adrenoceptor downregulation.
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PMID:Cardiovascular and adenylate cyclase stimulant properties of NKH477, a novel water-soluble forskolin derivative. 138 Jun 7

This study analyses the effects of Amrinone (bipyridine derivative with phosphodiesterase inhibitor properties) on the myofibrillar apparatus of rat myocardium. Thin trabeculae were isolated from the right ventricle and chemically demembranated. Force development and shortening velocity were measured during maximal calcium activations (pCa = 4.45) in control conditions and in the presence of 1-3 mM Amrinone. Maximum shortening velocity was obtained both from extrapolation of the force-velocity curve and with the slack test method. Amrinone was found to significantly reduce maximum shortening velocity and force development. Myofibrils and myosin were prepared from rat ventricular myocardium and their ATPase activity was assessed in control conditions and in the presence of Amrinone (0.3-6 mM). Ca-Mg dependent myofibrillar ATPase activity which was determined at low ionic strength was depressed by Amrinone in a dose-dependent way. Ca-stimulated ATPase activity determined at high ionic strength in myofibril or myosin preparations was not affected. Furthermore, Amrinone did not influence the pCa-ATPase activity curve of the myofibrillar preparations. A comparison between the inhibitory effects of Amrinone on myofibrils prepared from euthyroid rats and myofibrils prepared from hypothyroid rats was carried out. The ATPase activity was significantly less depressed in myofibrils prepared from hypothyroid rats than in those prepared from euthyroid rats. These results provide the first evidence of an effect of Amrinone on ATP splitting and force generation in the myofilament system of cardiac muscle.
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PMID:Effects of Amrinone on shortening velocity, force development and ATPase activity of demembranated preparations of rat ventricular myocardium. 144 24

The inotropic state of the myocardium can be enhanced via an increase in cell Ca2+ loading or in myofilament responsiveness to Ca2+. Although different pharmacological agents combine these properties, no presently available drug acts predominantly as a myofilament sensitizer in situ. We have investigated the effects and the mechanism of action of novel diazinone derivatives, EMD 54622, EMD 53998, and EMD 54650 (developed by E. Merck, Darmstadt), on guinea pig myocardial preparations. Force- and ATPase-pCa relations in skinned fibers show differing potencies of these agents on myofilament sensitization: EMD 54622 greater than EMD 53998 much greater than EMD 54650. This is in contrast to their relative potencies to inhibit isolated myocardial phosphodiesterase III: EMD 54650 greater than EMD 53998 greater than EMD 54622. In isolated hearts studied at constant coronary flow, each of the three diazinone derivatives had a positive inotropic effect. In enzymatically dissociated left ventricular myocytes loaded with the Ca2+ probe indo-1, the positive inotropic effect of EMD 54622 occurred with no change in the amplitude of the cytosolic [Ca2+] (Cai) transient. In contrast, both EMD 53998 and EMD 54650 enhanced Cai transient and twitch contraction amplitudes. Length-indo-1 fluorescence relations were analyzed to determine the effects of the three substances on myofilament responsiveness to Ca2+. EMD 54622 enhanced and EMD 54650 had no effect on myofilament responsiveness to Ca2+. Less uniform results were obtained with EMD 53998 (in two of five cells the myofilament responsiveness to Ca2+ was increased, whereas in three other cells it was unaltered). Our results indicate that structural changes in the diazinone molecule shift the mechanism of action for the positive inotropic effect of the diazinone derivatives in the intact cell from a predominant myofilament sensitization (EMD 54622) to an enhancement in cell Ca2+ loading and an augmentation in the Cai transient (EMD 54650).
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PMID:Novel diazinone derivatives separate myofilament Ca2+ sensitization and phosphodiesterase III inhibitory effects in guinea pig myocardium. 153 76

Calmodulin (CaM) mediates the Ca(2+)-dependent activation of many enzyme systems in accordance with its cellular localization. We have described previously a muscarinic receptor-mediated translocation of CaM from membranes into the cytosol of SK-N-SH human neuroblastoma cells. To explore the potential targets (CaM-binding proteins, CaMBP) for CaM upon translocation, a photoreactive CaM derivative was introduced into living SK-N-SH cells using a scrape-loading technique. Scrape-loading incorporated rhodamine isothiocyanate-labeled CaM with an efficiency of 38%. CaM-diazopyruvamide (CaM-DAP), a Ca(2+)-dependent and CaM-specific probe, was also introduced into the cells. The muscarinic agonist carbachol stimulated a translocation of CaM from membranes into cytosol in CaM-DAP-loaded SK-N-SH cells. Upon photochemical cross-linking, cross-linked adducts of CaM-CaMBP were detected by immunoblotting with anti-CaM antibody. Carbachol stimulated increased photoaffinity labeling of three proteins with relative adduct molecular masses of 70, 120, and 180 kDa. The time course of labeling for the 70- and 120-kDa adducts showed maximal increased by 15-30 min. The 180-kDa adduct displayed a slower time course of maximal labeling, with increases maintained for 2-4 h. Subtracting the molecular mass of CaM, carbachol stimulated binding to CaMBPs of 55, 105, and 163 kDa. Predominant cellular CaMBP were identified using a biotinylated CaM overlay procedure. Western blot analysis indicated the expression of specific CaM-dependent enzymes such as calcineurin, phosphodiesterase, the beta-isoform (rat brain) of CaM kinase II, and Ca(2+)-ATPase. Numerous cytoskeletal CaMBP were expressed such as microtubule-associated protein-2, spectrin, tubulin, caldesmon, adducin, and neuromodulin. Of the CaMBP expressed, phosphodiesterase, calcineurin, caldesmon, and adducin cross-linked with CaM-DAP in the loaded SK-N-SH cells. Carbachol stimulated the time-dependent CaM-DAP labeling of calcineurin and adducin. This study demonstrates the novel incorporation of a photoreactive CaM derivative into living cells, as well as muscarinic receptor-activated CaM-DAP interaction with several cellular CaMBP. We postulate that carbachol-stimulated CaM translocation in SK-N-SH cells may affect the activity of CaM-dependent enzymes and may alter aspects of cytoskeletal function.
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PMID:Carbachol stimulates binding of a photoreactive calmodulin derivative to calmodulin-binding proteins in intact SK-N-SH human neuroblastoma cells. 155 1


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