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)

We have observed the enhanced metabolism of inositol phospholipids in erbB transformed chicken fibroblasts. This increased metabolism seemed to be due to the activation of PI-kinase, DPI-kinase and DG-kinase activities in these cells. And also, C-kinase activity in the transformed cells was observed to be sustained as an active form. These results suggest the signal transduction system through the enhanced metabolism of inositol phospholipids was activated in the transformed cells. When the normal cells were treated with the combination of TPA, which is an activator of C-kinase, and Ca2+-ionophore A23187, the stimulation of DNA synthesis was detected. However, such treatment caused the only inhibitory effect on the cell growth of the transformed cells. On the other hand, the erbB gene product by itself dose not have significant activity of PI-kinase, DPI-kinase and DG-kinase. Therefore, erbB gene product may indirectly enhance inositol-phospholipids metabolism and induce abnormal growth of transformed cells.
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PMID:[Role of inositol phospholipids metabolism in the signal transduction of erbB gene product]. 300 67

The role of Ca2+ on 32Pi incorporation into polyphosphoinositides (PPI) of rat cortical synaptosomes was studied. Stimulation of muscarinic receptor by carbachol (1 mM) resulted in a decrease in 32Pi incorporation into phosphatidylinositol-4,5-bisphophaphate (TPI) and phosphatidylinositol-4-phosphate (DPI), and an increase in 32Pi incorporation into phosphatidylinositol (PI) and phosphatidic acid (PA), whereas no significant effect on other membrane phospholipids was found. This response could be blocked by atropine (1 microM). The stimulatory effect of carbachol required Ca2+ in the medium; the presence of 0.5 mM EGTA blocked the effect of carbachol on PPI turnover completely. Calcium ionophore A23187, at 1 microM, had a similar effect on PPI turnover by carbachol (1 mM). At higher concentrations (10-100 microM) of A23187, the PPI turnover rate was much enhanced. Depolarization of the membrane by high potassium (60 mM) in the presence of calcium resulted in an enhanced PPI turnover, which was similar to the results of the carbachol (1 mM) effect but to a lesser extent. Calcium antagonists, diltiazem and trifluoperazine, at 10 microM could block the carbachol effect on 32Pi incorporation into PPI in this preparation. Our results suggest that the enhancement of PPI turnover in rat cortical synaptosomes by carbachol, calcium ionophore or high potassium requires Ca2+, and it can be blocked by compounds which interfere with the availability of this ion, such as EGTA or calcium antagonists.
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PMID:Effects of calcium ionophore A23187 and calcium antagonists on 32Pi incorporation into polyphosphoinositides of rat cortical synaptosomes. 304 Apr 86

The effects of DPI, a new inotropic agent, were compared in trabeculae carneae from control and myopathic human hearts loaded with aequorin, a bioluminescent calcium indicator that emits light when it combines with calcium, and in saponin-skinned trabeculae carneae from the same hearts. The force-pCa curves in saponin-skinned fibers and the peak force-peak Ca2+ curves in aequorin-loaded preparations were not significantly different between the control and myopathic tissues. The force-pCa curve in the skinned and aequorin-loaded preparations from the same control hearts displayed no significant shifts with the addition of DPI. In contrast, a leftward shift was present in the force-calcium relationship in the presence of DPI in aequorin-loaded and skinned muscles from myopathic hearts, indicating an increase in the sensitivity of the myofilaments to calcium. These differences in the modulation of calcium activation between myopathic and control tissues indicate that pharmacological agents may produce differential effects in normal and diseased hearts.
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PMID:Differential effect of DPI 201-106 on the sensitivity of the myofilaments to Ca2+ in intact and skinned trabeculae from control and myopathic human hearts. 318 55

DPI 201-106 is a new oral inotropic agent that exerts its effects through a novel mechanism of action, namely, by enhancing sensitivity of myofilaments to calcium and prolonging inward sodium current. In a double-blind, randomized, placebo-controlled fashion, single oral doses (80 and 100 mg) of DPI 201-106 were administered to 15 patients with severe congestive heart failure. Dose-dependent increases in cardiac index (25%, p = 0.016), left ventricular stroke work index (24%, p = 0.018), left ventricular stroke volume index (32%,p = 0.005) and QTc interval (7%, p = 0.009) were observed. Significant effects on heart rate and systemic arterial pressure were not observed. Positive correlations of QTc interval with DPI plasma level (r = 0.64, p = 0.0001), stroke work index (r = 0.47, p = 0.0001) and ventricular ectopic activity on ambulatory electrocardiography (r = 0.49, p = 0.0001) were observed. Maximum changes occurred approximately 3 to 4 hours after ingestion and lasted more than 8 hours. Plasma drug levels were consistent with a 2-compartment model exhibiting first-order absorption and elimination kinetics. DPI 201-106 produced hemodynamic improvement in patients with severe congestive heart failure.
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PMID:DPI 201-106 for severe congestive heart failure. 331 71

Neither stratifying (primary keratinocytes) nor simple (Madin-Darby canine kidney [MDCK] and Madin-Darby bovine kidney [MDBK]) epithelial cell types from desmosomes in low calcium medium (LCM; less than 0.1 mM), but they can be induced to do so by raising the calcium level to physiological concentrations (standard calcium medium [SCM], 2 mM). We have used polyclonal antisera to the major bovine epidermal desmosome components (greater than 100 kD) in a sensitive assay involving immunoprecipitation of the components from metabolically labeled MDCK cell monolayers to investigate the mechanism of calcium-induced desmosome formation. MDCK cells, whether cultured in LCM or SCM, were found to synthesize the desmosome protein, DPI and desmosome glycoproteins DGI and DGII/III with identical electrophoretic mobility, and also, where relevant, with similar carbohydrate addition/processing and proteolytic processing. The timings of these events and of transport of DGI to the cell surface were similar in low and high calcium. Although the rates of synthesis of the various desmosome components were also similar under both conditions, the glycoprotein turnover rates increased dramatically in cells cultured in LCM. The half-lives decreased by a factor of about 7 for DGI and 12 for DGII/III and, consistent with this, MDCK cells labeled for 48 h in SCM had three and six times the amount of DGI and DGII/III, respectively, as cells labeled for 48 h in LCM. The rate of turnover and the levels of DPI were changed in the same direction, but to much lesser extents. Possible mechanisms for the Ca2+-dependent control of desmosome formation are discussed in the light of this new evidence.
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PMID:Structure and assembly of desmosome junctions: biosynthesis and turnover of the major desmosome components of Madin-Darby canine kidney cells in low calcium medium. 368 Mar 84

The effects of the calcium entry blockers nifedipine, (-)-verapamil and the dihydropyridine derivative PY 108-068 were evaluated on the increase in diastolic pressure of pithed normotensive rats caused by the selective alpha 1-adrenoceptor agonists cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine, (-)-amidephrine and St 587 [(2-chloro-5-trifluoromethylphenylimino)-2-imidazolidine] as well as by the mixed alpha 1/alpha 2-adrenoceptor agonists clonidine and DPI [(3,4-dihydroxyphenylimino)-2-imidazolidine]. The calcium entry inhibitors (up to 3 mg/kg) caused 3- to 5-fold, parallel rightward shifts of the log dose-pressor effect curves to cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine and (-)-amidephrine accompanied by only a slight depression of the maximal pressor response. In contrast, the calcium entry inhibitors produced a dose-dependent profound depression of both maximum and slope of the log dose-pressor response curves to St 587 and clonidine. For DPI about 10- and 100-fold parallel displacements to the right without reduction of the maximum were found following treatment with 1 and 3 mg/kg of nifedipine, respectively. Infusion of vasopressin to counteract the vasodilatory action produced by the calcium entry inhibitors did not significantly change the pattern of interference observed under the conditions of decreased baseline diastolic pressure. The results indicate that alpha 1-adrenoceptor-mediated vasoconstriction in the pithed normotensive rat, which is characterized by its sensitivity to blockade by prazosin and its relative insensitivity to antagonism by yohimbine or rauwolscine, can be subdivided into two distinct processes which are differentially influenced by blockade of calcium entry.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential effect of calcium entry blockers on alpha 1-adrenoceptor-mediated vasoconstriction in vivo. 614 29

Exposure of rabbit neutrophils to formyl-methionyl-leucyl-phenylalanine (FMLP) induced the efflux of 45Ca2+ from pre-labeled cells which was almost complete within 30 s. On the other hand, FMLP-induced 45Ca2+ influx did not become apparent until 60 s after stimulation. When [3H]arachidonic acid-labeled neutrophils were stimulated with FMLP, the radioactivities in phosphatidylinositol 4,5-biphosphate (TPI) and phosphatidylinositol 4-phosphate (DPI) significantly decreased in parallel with the induction of 45Ca2+ efflux. In contrast, degradation of polyphosphoinositides in [3H]glycerol-labeled neutrophils was not significant until 60 s. Taken together, these results indicate that the early degradation of polyphosphoinositides, especially of those rich in arachidonic acid is closely associated with the initial efflux of calcium in FMLP-stimulated rabbit neutrophils. The study of resynthesis of polyphosphoinositides by measuring 32Pi incorporation into these lipids is also presented.
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PMID:Coupling of polyphosphoinositide breakdown with calcium efflux in formyl-methionyl-leucyl-phenylalanine-stimulated rabbit neutrophils. 631 26

Phospholipase C from human platelets was found to catalyze the Ca2+-dependent degradation of phosphatidylinositol (PI), phosphatidylinositol 4'-phosphate (DPI), and phosphatidylinositol 4',5'-bisphosphate (TPI) at Ca2+ concentrations from 150 microM to 5 mM. Both DPI and TPI inhibited the hydrolysis of [2-3H]inositol-labeled PI (250 microM) in a concentration-dependent manner. The use of DPI and TPI from beef brain, both of which have fatty acid compositions different from that of soybean PI, permitted an assessment of the inhibitory effect of polyphosphoinositides on the hydrolysis of PI by phospholipase C. Fatty acid analysis of the diacylglycerols formed demonstrated that DPI and TPI, when incubated in mixture with PI, were competitive substrates for PI hydrolysis. Increasing the DPI/PI ratio from 0 to 0.3 caused a shift in the degradation of PI to DPI without greatly affecting the formation of 1,2-diacylglycerol. TPI alone, or in mixture with PI, was a poor substrate for phospholipase C. Increasing the TPI/PI ratio from 0 to 0.21, on the other hand, inhibited both PI degradation (greater than or equal to 95%) and overall formation of 1,2-diacylglycerol (greater than or equal to 82%). Kinetic analysis revealed that TPI acts as a mixed-type inhibitor with a Ki of about 10 microM. The Ka for Ca2+ in PI hydrolysis was profoundly increased from 5 to 180 microM when TPI (36 microM) was included with PI (250 microM). Optimum PI degradation under these conditions was only attained when the calcium concentration approached 4 mM. Analysis of phospholipids from unstimulated human platelets from five different donors revealed DPI/PI and TPI/PI ratios of 0.42 and 0.16, respectively. These findings, combined with the observed inhibition of PI hydrolysis by TPI at a TPI/PI ratio of 0.16, would suggest that in unstimulated platelets phospholipase C activity may be inhibited by greater than or equal to 75%. Changes in 33P-prelabeled phospholipids of intact platelets upon stimulation with thrombin indicated a transient decline in 33P label of both TPI and DPI (15 s) followed by an increase in [33P]phosphatidic acid but no change in [33P]PI. The finding that DPI is selectively degraded by phospholipase C in mixture with PI at DPI/PI ratios determined to be present in unstimulated platelets indicates that DPI may be more important than PI in the formation of 1,2-diacylglycerol which is believed to serve as precursor of arachidonic acid for thromboxane biosynthesis. Furthermore, the results suggest that in human platelets TPI may serve as modulator for the formation of 1,2-diacylglycerol from inositol phospholipids.
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PMID:Possible regulation of phospholipase C activity in human platelets by phosphatidylinositol 4',5'-bisphosphate. 632 Jul 36

Surgical denervation of rat vas deferens causes supersensitivity in that the tissue sensitivity and the maximum response to a variety of agonists increase. To understand the molecular mechanism of supersensitivity in smooth muscle, norepinephrine(NE)-induced alteration in phospholipid metabolism was studied using control and denervated vasa deferentia. When the tissue was stimulated by NE, only [32P]Pi incorporation into phosphatidic acid(PA) was increased in proportion to the increase in NE concentration without any significant effect on that into other phospholipids. This PA labeling was significantly accelerated by denervation. In the denervated tissue, PA labeling was stimulated by lower concentrations of NE and the maximum response to NE was increased compared to the control. The breakdown of phosphatidylinositol 4-monophosphate(DPI) and phosphatidylinositol 4,5-diphosphate (TPI) was also accelerated by NE. But the influence of denervation on this NE-induced DPI and TPI was not marked. Therefore, it is likely that denervation clearly enhanced NE-induced PA labeling without an appreciable effect on that of the other phospholipids. Furthermore, the absolute amount of PA was also increased by NE, and this increase was exaggerated by denervation. Considering that PA can behave as a Ca2+ ionophore in the plasma membrane, these results suggest that the stimulated accumulation of PA plays an important role in receptor-linked supersensitivity in smooth muscle.
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PMID:Increase in norepinephrine-induced formation of phosphatidic acid in rat vas deferens after denervation. 684 32

The effects of BDF 9148 and its parent compound DPI 201-106 were compared in guinea pigs and rat cardiac tissue because these tissues possess long and short action potentials (AP), respectively, and have different excitation-contraction coupling mechanisms. Conventional electrophysiologic techniques were used to study drug effects on AP, sodium current, and force of contraction (Fc). In guinea pig and rat papillary muscle, BDF 9148 and DPI 201-106 increased Fc; BDF 9148 was more potent than DPI 201-106. In guinea pig, but not in rat muscle, DPI 201-106 significantly prolonged AP duration (APD) to a greater degree than did BDF 9148. In rat cardiac muscle, both agents were more potent but increased Fc to a lesser degree than in guinea pig cardiac muscle and led to Ca2+ overload, as evidenced by after-contractions and contracture. BDF 9148 failed to increase Fc at low frequencies in guinea pig but was effective at all frequencies in rat muscle. In isolated myocytes, substance effects on sodium current were similar in both species. In guinea pigs, but not in rats, DPI 201-106 prolongs APD to a greater degree than does BDF 9148. Both agents produce a greater positive inotropic effect in guinea pigs than in rats, which may be due to species differences in excitation-contraction coupling.
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PMID:Differential effects of BDF 9148 and DPI 201-106 on action potential and contractility in rat and guinea pig myocardium. 752 82


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