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)

We have shown previously that mercuric chloride (HgCl2) inhibits in vitro vasopressin release from the isolated rat neurohypophysis with maximum inhibition occurring with 0.5 mM HgCl2. Associated with the inhibition of hormone release is an increase in 45Ca+2 uptake, an increase in cytosolic 45Ca+2, and a reduction of 45Ca+2 accumulation by mitochondria in the intact gland. In the present series of studies, the effect of HgCl2 on calmodulin (CM) function in neural tissue preparations is reported. Mercuric chloride (0.5 mM) reduced 45Ca+2 binding to CM purified from bovine neurohypophyses by 20% and inhibited endogenous CM-stimulated Ca,Mg-ATPase activity from rat brain mitochondria in a dose-dependent fashion. Ca,Mg-ATPase activity was inhibited by 50 and 80% with 0.5 and 5.0 mM HgCl2, respectively. CM-stimulation of Ca,Mg-ATPase activity was inhibited by calmidazolium (CMZ) with maximal inhibition seen with 0.1 mM CMZ. Reversibility of the HgCl2 interaction with CM was demonstrated using CM-stimulated phosphodiesterase (PDEase) activity from rat brain. HgCl2 inhibited both basal and CM-stimulated PDEase activity in a dose-dependent manner with maximum inhibition occurring with 1.0 mM HgCl2. Preexposure of CM to an inhibitory concentration (1.0 mM) of HgCl2 resulted in no loss of stimulatory PDEase enzyme activity. From these results, we conclude that HgCl2 reversibly interferes with 45Ca+2 binding to CM and also inhibits CM-regulated Ca+2 pumping enzyme systems in the neurohypophysis. The inhibition of vasopressin release from the intact gland in the presence of HgCl2 thus, may be associated with a disruption of calcium in the neurohypophysis.
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PMID:The effects of mercuric chloride on calmodulin-mediated Ca2+ transport in rat brain. 215 38

In vitro effects of three triorganotins--tributyltin (TBT), triethyltin (TET), and trimethyltin (TMT)--on calmodulin (CaM) activity were studied. Stimulation of Ca2(+)-ATPase of rat brain synaptic membranes and phosphodiesterase (PDE) of bovine brain were assayed as indicators of CaM activity. The rat synaptic membranes were prepared and CaM was depleted by washing with 1 mM EGTA. All the three organotins inhibited the basal as well as CaM-stimulated Ca2(+)-ATPase in a concentration-dependent manner, suggesting their interaction with calcium pump. However, CaM-stimulated Ca2(+)-ATPase was more sensitive than the basal enzyme. The order of potency of the three organotin compounds was TBT greater than TET greater than TMT. The IC50 values of Ca2(+)-ATPase (basal) were 0.63, 35, and approximately 800 microM, respectively, whereas the values for CaM-stimulated Ca2(+)-ATPase were 0.05, 0.8, and 18 microM for TBT, TET, and TMT, respectively. CaM-deficient PDE did not show any sensitivity to these three organotin compounds, while TBT and TET significantly decreased the CaM-stimulated PDE activity. TMT, which was the least effective inhibitor of Ca2+ pump, did not alter PDE activity. Further, the inhibition of CaM-stimulated Ca2(+)-ATPase activity by these organotins could be reversed by excess addition of CaM. These results suggest that the organotins interact with CaM activity, as evidenced by their potent effect on CaM-dependent Ca2(+)-ATPase and PDE activities.
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PMID:Differential effects of triorganotins on calmodulin activity. 215 84

This paper describes two fully automated assays. One for zaprinast, a cGMP specific phosphodiesterase inhibitor, which uses the Gilson-Advanced Automated Sample Processor combination, and the other for an H+/K+ ATPase inhibitor and its sulphone metabolite, which uses direct injection. Both assays were developed to support pharmacokinetic studies at therapeutic doses in small animals as well as in man. Plasma or serum (20-200 microliters) is placed directly into an autosampler and all subsequent manipulations are performed mechanically.
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PMID:Two systems for the automated analysis of drugs in biological fluids using high-performance liquid chromatography. 216 38

Antibodies against purified Ca2+-transport ATPase from human erythrocytes were raised in rabbits. Immunodiffusion experiments revealed that precipitating antibodies had been developed. The immunoglobulin fraction inhibited solely the calmodulin-dependent fraction of erythrocyte Ca2+-transport ATPase activity, whereas the basal (in the absence of added calmodulin) activity of the enzyme was not significantly affected by the antibodies. The antibodies produced similar doseresponse curves for the calmodulin- and the oleic acid-stimulated enzyme. However, the immunoglobulin fraction was considerably less effective in inhibiting Ca2+-transport ATPase activated by limited proteolysis. The results obtained with our antibodies are compatible with the interpretation that at least one subpopulation of the antibodies attacks the enzyme at or close to the calmodulin-binding site of the ATPase. The antibodies also inhibited the calmodulin-regulated Ca2+-transport ATPase from pig smooth-muscle plasma membrane, though with lower potency. However, the immunoglobulin fraction failed to suppress pig cardiac sarcoplasmicreticulum Ca2+-transport ATPase activity in the concentration range investigated. In addition, the activity of phosphodiesterase from rat brain, another enzyme modulated by calmodulin, was not at all affected by the immunoglobulin fraction.
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PMID:Antibodies against erythrocyte Ca2+-transport ATPase specifically inhibit the calmodulin-dependent fraction of the enzyme's activity. 240 60

The Na- and Cl-absorbing goby posterior intestinal epithelium is composed predominantly of mitochondria-rich, tall columnar cells. Glass intracellular microelectrode recording technique was applied to absorptive cells of this relatively leaky epithelium to measure apical cell membrane potential difference (psi mc) and apical membrane fractional resistance. As determined by ion-substitution studies, absorptive cells are characterized by a large, Ba2+-inhibitable apical K conductance, which is a major factor determining psi mc and smaller Cl and Na conductances. Inhibition of the apical Na-Cl-coupled influx directly by furosemide or indirectly by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine produced hyperpolarization of psi mc, consistent with the greater apical membrane conductance to Cl than Na. The urophysial neurosecretory peptide urotensin II, which stimulates Na-Cl-coupled absorption, markedly depolarized psi mc in posterior intestinal tissues from 5% seawater-adapted gobies. This response is consistent with a stimulatory effect of urotensin II at the apical membrane carrier rather than at the basolateral Na-K-ATPase. Urotensin II is without effect on psi mc in tissues from seawater-adapted fish and somatostatin, a natural analogue of urotensin II, is without effect on tissues from fish adapted to either salinity. This specificity parallels that determined using radiotracer fluxes.
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PMID:Ion transport in goby intestine: cellular mechanism of urotensin II stimulation. 241 Nov 49

Milrinone is a new inotropic agent for the treatment of refractory congestive heart failure. Our understanding of the mechanisms(s) of action of this synthetic cardiotonic drug is incomplete. We examined the effects of milrinone and the parent compound amrinone on sarcoplasmic reticulum function (45Ca-uptake and Ca-ATPase); radioligand binding to adenosine, beta-adrenergic, and cholinergic muscarinic receptors; cyclic AMP accumulation; and inhibition of various forms of cyclic AMP phosphodiesterases. Comparisons were made to observe how these effects correlate with the inotropic response of heart. Milrinone was shown to be a potent phosphodiesterase inhibitor that was 40 times more potent than amrinone and 10 times more potent at inhibiting the high-affinity (Km = 0.23 microM) form (Ki = 22 microM) than the low-affinity (Km = 140 microM) form (Ki = 225 microM) of cyclic AMP phosphodiesterase in heart. The potency of milrinone as a phosphodiesterase inhibitor was the same in the presence and absence of calcium. Concentrations of milrinone that increased cyclic AMP accumulation also produced positive inotropy. A comparison of milrinone with amrinone and methylxanthines revealed the order of potency to be isobutylmethylxanthine greater than milrinone greater than theophylline greater than caffeine greater than amrinone. Milrinone and amrinone had no effect on 45Ca-uptake or Ca-ATPase activity in myocyte sarcoplasmic reticulum. However, milrinone did bind weakly to adenosine receptors (KD = 466 microM) but not to cholinergic muscarinic or beta-adrenergic receptors. Also, in combination with isoproterenol high concentrations of milrinone blocked the negative inotropic response to the adenosine agonist phenylisopropyladenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biochemical mechanisms for the inotropic effect of the cardiotonic drug milrinone. 242 30

The interaction of several phenothiazines, benzodiazepines, butyrophenones, polycyclic neuroleptics and tricyclic antidepressants with calmodulin and troponin C was investigated using the fluorescent dye 3,3'-dipropylthiocarbocyanine iodide. In the presence of Ca2+, trifluoperazine (2-trifluoromethyl-10-[3-(1-methylpiperazinyl-4)propyl]-phenothiaz ine dihydrochloride, TFP), which is commonly used as a selective calmodulin inhibitor, half maximally increased the fluorescence of the complex formed of the fluorescent dye with calmodulin at a concentration of 4 mumol/l, and with troponin C at 24 mumol/l. TFP completely inhibited the calmodulin dependent stimulation of cyclic nucleotide phosphodiesterase with a Ki of 4 mumol/l and decreased the maximum Ca2+ dependent troponin C mediated activation of actomyosin ATPase by 35% at a concentration of 100 mumol/l. Metofenazate (3,4,5-trimethoxybenzoate-2-chlor-10-(3-[(beta-oxyethyl) piperazinyl-4]-propyl)phenothiazine diethanesulfonate, methophenazine, MP) produced half maximal fluorescence enhancement of the calmodulin dye complex at a concentration of 6 mumol/l and did not influence the fluorescence of the troponin C dye complex at concentrations of up to 1000 mumol/l. MP also completely inhibited the calmodulin dependent stimulation of phosphodiesterase with a Ki of 7 mumol/l but it had not effect on maximum Ca2+ stimulation of actomyosin ATPase. MP increased the Ca2+ sensitivity of skinned cardiac muscle with an about 10fold lower potency than TFP. In view of these results, we propose MP as a useful tool for distinction between processes mediated by either calmodulin or troponin C.
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PMID:Metofenazate as a more selective calmodulin inhibitor than trifluoperazine. 244 25

The new calmodulin antagonist, CGS-9343B, was found to inhibit both histamine plus 3-isobutyl-1-methylxanthine and carbachol-induced [14C]aminopyrine accumulation in dispersed, fundic mucosal cells of rats. The IC50 value for CGS-9343B inhibition of histamine plus 3-isobutyl-1-methylxanthine-induced [14C]aminopyrine accumulation was 306 nM. The drug was more potent than the H2-histamine receptor antagonist, cimetidine (1128 nM), less potent than the nonspecific calmodulin antagonists, trifluoperazine and fenoctimine (IC50 = 40 and 224 nM, respectively), and equipotent with the H+, K+-adenosine triphosphatase inhibitor, omeprazole (365 nM). CGS-9343B showed an IC50 of 369 nM for carbachol-induced [14C]aminopyrine accumulation in dispersed mucosal cells. CGS-9343B must be added to cells before or simultaneously with acid secretagogues in order to be effective. The drug did not reverse previously stimulated secretion. Unlike trifluoperazine and fenoctimine, CGS-9343B had anticamodulin activity for inhibition of calmodulin-activated (Type I) phosphodiesterase in the same range of potency as observed for the inhibition of aminopyrine accumulation. In anesthetized rats and dogs the i.v. infusion of CGS-9343B did not block histamine plus pentagastrin-stimulated acid secretion. However, i.a. administration of CGS-9343B to anesthetized rats produced a significant inhibition of acid secretion. In vivo the order of potency was omeprazole greater than cimetidine much greater than CGS-9343B. These data provide evidence for involvement of calmodulin in the acid secretory process and suggest that the pursuit of selective calmodulin antagonists such as CGS-9343B may prove useful for understanding the regulation of the hydrogen ion secretory process.
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PMID:Inhibition of gastric acid secretion in vivo and in vitro by a new calmodulin antagonist, CGS 9343B. 246 57

The cardiovascular properties of MS-857 [4-acetyl-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone ], a novel cardiotonic agent, were investigated in anesthetized and conscious dogs. MS-857 (1-100 micrograms/kg i.v.) produced a significant and dose-dependent increase in cardiac contractility with relatively small changes in heart rate and blood pressure. This indicates a sizable separation between positive inotropic and other effects of MS-857. Oral administration of MS-857 to conscious dogs (0.1-1 mg/kg) also produced a sustained increase in cardiac contractility in a dose-dependent manner. The total duration of action was longer than 7 h at a dose of 1 mg/kg p.o. There occurred no arrhythmias and no changes in animal behavior. After chronic oral administration, MS-857 completely retained its activities, indicating the lack of tachyphylaxis. In the acute heart failure models induced by either propranolol or pentobarbital, MS-857 reversed the cardiac depressant effects of these drugs. Moreover, MS-857 also significantly improved the pentobarbital-induced heart failure in the heart-lung preparation. MS-857 did not inhibit the Na+, K+-ATPase, but inhibited the phosphodiesterase (PDE) III selectively, both of which were prepared from the dog ventricular muscle. Thus, MS-857 can be characterized as a potent nonsympathomimetic, nonglycoside cardiotonic drug with a selective inhibitory activity on PDE III. The cardiovascular properties revealed by this study strongly suggest that MS-857 will exert a beneficial effect in the treatment of congestive heart failure.
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PMID:Cardiovascular properties of MS-857, a new and potent cardiotonic agent, on normal and failing hearts. 246 58

The role of structural features of sulmazole, an imidazo(4,5-b)pyridine, in its inotropic action was examined by comparison with its reduced (4-methylthiophenyl) analog EMD 46512 and the corresponding imidazo(4,5-c)pyridine isomers isomazole and EMD 41000 on isolated guinea-pig papillary muscles and right atria and on Na,K-ATPase and phosphodiesterase III isolated from guinea-pig hearts. The pyridine nitrogen position in sulmazole was crucial for affinity to Na,K-ATPase (IC50 = 350 microM) because the imidazo(4,5-c)pyridines had little effect. Participation of Na,K-ATPase inhibition in sulmazole's inotropic effect (EC50 = 180 microM) was suggested by synergism with the Na channel activator germitrine. The methylsulfinyl oxygen at the phenyl ring decreased the affinity to Na,K-ATPase of sulmazole 40-fold: The reduced analog EMD 46512 was a potent inhibitor of Na,K-ATPase (IC50 = 8.5 microM) and a more potent inotropic agent (EC50 = 8.2 microM) that appeared to act predominantly through Na,K-ATPase inhibition. Micromolar through Na,K-ATPase inhibition. Micromolar IC50s for inhibition of phosphodiesterase III were 49 (sulmazole), 34 (EMD 46512), 18 (isomazole), and 13 (EMD 41000). Participation of this mechanism in the inotropic effect of sulmazole, isomazole, and EMD 41000, but not EMD 46512, was indicated by augmentation of slow action potentials, synergism with histamine, inhibition by carbachol, and (with the exception of EMD 41000) a positive chronotropic effect on the right atrium. Sulmazole appeared to combine the actions of its 4-methylthiophenyl analog EMD 46512 (an inhibitor of Na,K-ATPase) and of its imidazo(4,5-c)pyridine isomer isomazole (an inhibitor of phosphodiesterase III).
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PMID:Imidazopyridines: roles of pyridine nitrogen position and methylsulfinyl oxygen for in vitro positive inotropic mechanism and chronotropic activity. 247 14


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