Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:7440-70-2 (calcium)
 333,191 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Current positive inotropy therapy of heart failure is associated with major problems: digoxin and the phosphodiesterase inhibitors can cause life-threatening toxicity while beta-adrenoceptor agonists become less effective inotropic compounds as heart failure progresses. A new approach to positive inotropy is ion channel modulation. 2. An increased influx of Na+ during the cardiac action potential, as measured with DPI 201-106 and BDF 9148 which increase the probability of the open state of the Na+ channel, will increase force of contraction. 3. Activation of L-type Ca2+ channels with Bay K 8644 will increase influx of Ca2+ and increase the force of contraction. However the Ca2+ channel activators developed to date have little potential for the treatment of heart failure as they are vasoconstrictors. 4. Blocking cardiac K+ channels is a possible mechanism of positive inotropy. Terikalant inhibits the inward rectifying K+ channel, tedisamil inhibits the transient outward K+ channel and dofetilide is one of the newly developed inhibitors of the slow delayed outward rectifying K+ channel. All these drugs prolong the cardiac action potential to increase Ca2+ entry and force of contraction. 5. Thus drugs which increase Na+ influx or block K+ channels represent exciting possibilities for positive inotropy and the potential of these compounds for the treatment of heart failure needs to be fully evaluated.
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PMID:Ion channel modulators as potential positive inotropic compound for treatment of heart failure. 788 74

Inodilation, i.e., the combination of positive inotropic and vasodilating therapy, conceptually should be an ideal form of heart failure treatment. However, available orally active inodilator drugs, such as beta-agonists, dopaminergic compounds, and agents with phosphodiesterase (PDE)-inhibiting properties, have not been generally accepted for the treatment of heart failure. In contrast, there is serious concern that agents that act predominantly through PDE inhibition and thereby increase cellular cyclic AMP (cAMP) content, e.g., amrinone, milrinone, and enoximone, not only are ineffective in heart failure but also may lead to serious adverse events, i.e., arrhythmogenicity, and may increase mortality rate in advanced heart failure. Similarly, combined beta 1- and beta 2-agonists do not afford long-term clinical efficacy and also may lead to serious ventricular arrhythmias. Moreover, dopaminergic compounds that, besides dopamine-1 and dopamine-2 activation, act through beta-receptor stimulation do not consistently improve the patient's clinical condition. Thus, inodilation by way of increasing cAMP may not be the right approach, at least not in advanced heart failure, in which cAMP-dependent inotropic activity is significantly diminished. In contrast, clinical efficacy may be present when partial PDE inhibitors that also act through calcium sensitization, such as pimobendan, are administered to patients with mild to moderate or moderately severe heart failure. Moreover, adverse events may be less at the lower dose level at which, consequently, the degree of PDE inhibition is reduced. Calcium-sensitizing properties may afford an alternative, more economical way to improve contractile force in failing hearts. Hence, agents that combine calcium sensitization with a relatively low degree of PDE inhibition may well be the inodilators of choice, in particular in mild to moderate failure. Whether they improve the condition of such patients without affecting relaxation and whether they do not lead to adverse events and an increase in mortality rate have as yet to be evaluated. Furthermore, the potential beneficial effect of additional neurohumoral modulation by dopaminergic inodilator compounds and of heart rate-reducing properties of inodilators, such as OPC-8212 and DPI 201-106, needs to be clarified to assess the place, if any, of inodilator therapy in heart failure.
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PMID:Inodilator therapy for heart failure. Early, late, or not at all? 809 71

MDCK cells grown in media with normal levels of Ca2+ (approximately 2 mM) contain internalised desmosomes, referred to as desmosome-associated vacuoles (DAVs). The DAVs consist of one to three plaques retained in the plane of a surrounding vacuolar membrane, and their entry into the endocytic pathway has been investigated using HRP, cationized ferritin and BSA/gold in combination with electron microscopy and immunogold labelling of frozen sections. Endocytic tracers supplied from the apical and basolateral surfaces to filter-grown MDCK cells met in a common perinuclear compartment but DAVs were not labelled during short (5-30 minutes) pulses of marker, whether applied apically or basolaterally. Only when the tracers were taken up from the basolateral surface and then chased for periods of 2-18 hours, were DAVs labelled. It is proposed that entry of an endocytic tracer to DAVs occurs by the association of the desmosomal vacuole with late endosomes. Immunolabelling studies with antibodies to desmosomal components (to Dsg, DPI/II), to HRP and to the cation-independent mannose 6-phosphate receptor (MPR), confirmed that Dsg and DPI/II are located within DAVs and late endosomes, but not in early endosomes. Passage of Dsg, but to a lesser extent DPI/II, was detected in MPR- structures (lysosomes). DAV-like structures have also been observed in developing tissues such as mouse kidney. Such engulfment may provide a general mechanism for handling insoluble junctional proteins, particularly where rapid morphogenetic changes are occurring in the pattern of cell-cell adhesion.
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PMID:Internalisation of desmosomes and their entry into the endocytic pathway via late endosomes in MDCK cells. Possible mechanisms for the modulation of cell adhesion by desmosomes during development. 812 95

The positive inotropic effects of the sodium channel modulators, DPI 201-106 and BDF 9148, were tested in atrial preparations from guinea-pig, rat and man. In rat, the racemate and S enantiomer of both DPI 201-106 and BDF 9148 displayed the same efficacy as did increased extracellular Ca2+, but in guinea-pig and man, the efficacy varied between 60 and 90% of the maximum Ca2+ response. In all three species, BDF 9148 was significantly more potent than DPI 201-106 by approximately one order of magnitude. The same was evident for the S enantiomers. The R enantiomers did not inhibit the effects of the S enantiomers. We have shown pronounced differences in the efficacy and potency of the enantiomers of DPI 201-206 and BDF 9148, which may be useful for future radioligand binding studies.
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PMID:Inotropic actions of BDF 9148 and DPI 201-106 and their enantiomers in guinea-pig, rat and human atria. 844 39

A number of new positive inotropic agents with diverse mechanisms of action have been discovered over the past 20 years. Most of these cardiotonic drugs exhibit characteristic electrophysiologic profiles. This prompted us to propose a classification scheme based on electrophysiologic principles, modifying the categories recently suggested by another author. Class I actions designate positive inotropic mechanisms that enhance the transmembrane calcium current by various means, such as beta-receptor stimulation (dobutamine, class I/A), phosphodiesterase inhibition (milrinone, class I/B), direct stimulation of adenylate cyclase (forskolin, class I/C), or direct modulation of calcium channel gating (BAY K 8644, class I/D). Class II action includes mechanisms that lead to elevation of intracellular sodium activity either by inhibiting the Na,K pump (digitalis, class II/A) or by increasing transmembrane sodium influx (DPI 201-106, class II/B). Class III action involves a mechanism by which sensitivity of the myofilaments to calcium increases (EMD 53998, levosimendan). This mechanism is not associated with apparent electrophysiologic manifestations. Positive inotropism due to lengthening of the cardiac repolarization (almokalant) is considered as class IV action. The possible clinical implications of the various positive inotropic mechanisms are also discussed.
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PMID:Classification of positive inotropic actions based on electrophysiologic characteristics: where should calcium sensitizers be placed? 890 29

The importance of protein phosphatases in the maintenance of cytoskeletal structure is supported by the serious liver injury caused by microcystin-LR, a hepatotoxic inhibitor of type-1 and type-2A serine/threonine protein phosphatases. We used the microcystin-LR-induced cell injury as a model to study the roles of protein dephosphorylation in maintaining cytoskeletal structure and cellular interactions in primary rat hepatocyte cultures. Confocal microscopy revealed that the first visible effect of microcystin-LR is disruption of desmoplakin organization at the cell surface, indicating dissociation of desmosomes. This effect is followed by a dramatic reorganization of both the intermediate filament (keratins 8 and 18) and microfilament networks, resulting in a merged structure in which the intermediate filaments are organized around a condensed actin core. Keratin 8, keratin 18 and desmoplakin I/II are the major cytoskeleton-associated targets for microcystin-LR-induced phosphorylation. Hyperphosphorylation of keratin 8 and 18 is accompanied by an increased keratin solubility, which correlates with the observed morphological effects. Phosphopeptide mapping shows that four specific tryptic phosphopeptides are highly phosphorylated predominantly in the soluble pool of keratin 18, whereas keratin 8 shows no indications of such assembly state-specific sites. Phosphopeptide maps of keratins phosphorylated in vivo and in vitro indicate that Ca2+/calmodulin-dependent kinase may be involved in regulating the serine-specific phosphorylation of both keratin 8 and keratin 18, while cAMP-dependent protein kinase does not seem to play a major role in this context. Taken together, our results show that the interactions between keratin intermediate filaments and desmosomes as well as the assembly states of their main constituent proteins, are directly regulated by serine/threonine kinase/phosphatase equilibria.
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PMID:Protein phosphatases maintain the organization and structural interactions of hepatic keratin intermediate filaments. 901 Jul 81

This study was undertaken to establish a culture of junctional epithelial cells derived from gingival tissue attached to the tooth surface and to characterize these cells immunocytochemically and ultrastructurally. Primary cultures of cells were obtained from the junctional tissue explanted on type I collagen-coated dishes and immersed in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum (FBS). Cells were subcultured with conditioned serum-free keratinocyte medium (keratinocyte-SFM + 5% FBS) on dishes coated with solubilized extract of the basement membrane. After 24 hours, the medium was changed to keratinocyte-SFM (0.09 mM Ca2+). The cell-doubling time was 40.5 hours. As a control, cells from gingival tissue were cultured by the same method. Cells from junctional tissue and gingival tissue were compared immunocytochemically using monoclonal antibodies to keratin, vimentin, and desmoplakins I and II and using Dolichos biflorus agglutinin (DBA). The keratin AE1 and AE3 was expressed by all of culture cells. The vimentin (specific for the intermediate filament of mesenchymal cells) was also expressed by all cells. The expression pattern of keratin 19 was observed not only by cells from junctional tissue but also by cells from gingival tissue. All keratin peptides were expressed in both cells. However, DBA reacted only with cells from the junctional tissue. Anti-desmoplakin I and II reacted with both cells, however, the staining patterns differed. DBA-positive cultured epithelial cells from the junctional tissue showed poor tonofilament bundles and were rich in cytoplasmic organelles. These findings suggest that junctional epithelial cells can be isolated from junctional tissue and cultured under improved conditions.
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PMID:Culture and characterization of human junctional epithelial cells. 910 Jan 98

Dual, activatory and inhibitory, effects of a cardiotonic drug DPI 201-106 on Na+ channels were compared with the redox properties of the DPI itself and of the constituents of its molecule, indole and piperazine. The indole component accepted electrons from radical intermediates of the light excited dye; the piperazine part of DPI acted as an electron donor in the same radical reactions. These data extend the previously obtained results which characterized organic blockers of Na+ and Ca2+ channels as electron donors, whereas activators of these channels were shown to be electron acceptors in test radical reactions. The whole DPI 201-106 molecule revealed both the electron-donor and electron-acceptor activity. The described electrophysiological effects of this compound (G. Wang et al., 1989) are discussed within the framework of the Na+ channel redox model (B. Marinov, 1991).
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PMID:A possible role of the redox interactions in the dual, activatory and inhibitory, action of DPI 201-106 on the potential-dependent Na+ channels. 923 69

The aim of the study was to explore the possible interrelationship between reactive oxygen species (ROS) formation and cPLA2 activation and the mediator role that [Ca2+]i may play in these processes in the human keratinocyte cell line, HaCaT. HaCaT cells can be invoked to transiently produce ROS by epidermal growth factor (EGF), thapsigargin (TPG) and the Ca(2+)-ionophore, A23187. These 3 agonists transiently increase [Ca2+]i with characteristic kinetics and magnitude. TPG and A23187 each activates on its own [3H]AA release from prelabeled cells, whereas EGF on its own has no effect on [3H]AA release. However, EGF augments [3H]AA release invoked by TPG or A23187 several fold. EGF activates MAP kinase cascades in HaCaT cells, leads to ROS formation and induces relatively small (1.6 fold) elevation in [Ca2+]i, whereas A23187 and TPG lead to a substantial elevation in [Ca2+]i (2.5 to 5 fold) and to ROS formation. Both have a minor effect on MAP kinase activation. The synergism in PLA2 activation by EGF and TPG or A23187, and the sensitivity of [3H]AA release to N-acetylcysteine (NAC) and dithiothreitol (DTT) (potent reducing agents) or to DPI (an inhibitor of FAD-dependent oxidases) lead to the suggestion that ROS formation, elevation of [Ca2+]i and PLA2 activation are causally related. Since we show that elevation of [Ca2+]i is a prerequisite for both ROS and PLA2 activation, it is possible that these processes contribute to the toxicity (apoptosis) exerted by chronic elevation of [Ca2+]i.
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PMID:Crosstalk between elevation of [Ca2+]i, reactive oxygen species generation and phospholipase A2 stimulation in a human keratinocyte cell line. 956 Nov

1. We previously described voltage-dependent ionic currents and hypoxia chemosensitivity in cultured pulmonary neuroepithelial body (NEB) cells isolated from fetal rabbit. Here we use fresh neonatal rabbit lung slices (200-400 micrometer thick) to characterize the electrophysiological properties of 'intact' NEBs with patch-clamp, whole-cell recording. 2. Under voltage clamp, outward currents were partially inhibited by TEA (20 mM), 4-amino pyridine (4-AP; 2 mM) and cadmium (Cd2+; 100 micrometer), suggesting the presence of both Ca2+-dependent (IK(Ca)) and Ca2+-independent (IK(V)) components. 3. Inward currents, carried by voltage-dependent Ca2+ channels and also, in occasional cells (approximately 11%), by TTX-sensitive Na+ channels, were also detected in intact NEB cells. 4. Hypoxia (PO2 = 15-20 mmHg) reduced the outward K+ current by approximately 34% during voltage steps from -60 to +30 mV, while inward Ca2+ or Na+ currents were not affected by hypoxia. Hypoxia suppressed roughly equally both IK(Ca) and IK(V) components of outward current, and no further inhibition of K+ currents was seen with either TEA and 4-AP + hypoxia. 5. Diphenylene iodonium (DPI; 1 microM) suppressed outward K+ current by approximately 42%, and DPI + hypoxia had no additional effect on the K+ current. 6. Direct application of H2O2 augmented outward K+ current; for a voltage step from -60 mV to +30 mV, 0.25 mM H2O2 increased K+ current by approximately 37%. 7. These results indicate that intact neonatal NEB cells express hypoxic chemosensitivity and introduce the rabbit lung slice preparation as an new model for investigating the role of airway O2 chemoreceptors.
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PMID:Selective modulation of membrane currents by hypoxia in intact airway chemoreceptors from neonatal rabbit. 983 22


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