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)

Myofilament calcium sensitivity and maximal calcium-activated force are fundamental properties of the contractile proteins in the heart. We examined these properties in normal human right-ventricular trabeculae carneae obtained from hearts of brain-dead patients with no known cardiac disease, and from patients with end-stage heart failure undergoing cardiac transplantation. There were no differences in calcium-activation of the control and myopathic muscles from chemically-skinned trabeculae or from intact tetanized preparations. We then tested the effect of DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole - carbonitrile), a new inotropic agent, in both preparations. In myopathic muscles, 1 microM DPI sensitized the myofilaments to Ca2+, as evidenced by a significant shift of the [Ca2+]-force relationship towards lower [Ca2+], in both skinned and intact preparations. On the other hand, the same concentration of DPI did not affect the calcium-activation in control muscles in both preparations. We also found that the twitch [Ca2+]-force relationship, which has been used as an indication of myofilament sensitivity, was dissociated from the steady-state [Ca2+]-force relationship, and was shifted along the [Ca2+] axis by modulation in the time-course of the twitch and [Ca2+]i, and not by the sensitivity of the myofilaments to Ca2+. Protein kinase C stimulation differentially altered the responsiveness of the myofilaments to Ca2+ in normal and myopathic muscle fibers. We propose that even though calcium activation and maximal calcium-activated force are unaltered in myopathic hearts there are changes in thin filament regulation in myopathic hearts that result in altered responses to agents that directly act on the thin filaments, and that the potential for force development is similar in normal and myopathic human hearts.
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PMID:Responsiveness of the myofilaments to Ca2+ in human heart failure: implications for Ca2+ and force regulation. 149 67

Elevation of cytosolic sodium is thought to be correlated with an increase in force of contraction due to an activation of sodium-calcium exchange. We investigated the inotropic response mediated by the new sodium-channel activator BDF 9148 (0.01-100 mumol/l) on failing human myocardium. Force of contraction was studied using electrically driven human papillary muscle strips from moderately (NYHA II-III, mitral valve replacement) and terminally (NYHA IV, heart transplantation) failing hearts. We also investigated the effects in auricular trabeculae from non-failing hearts (aortocoronary bypass operation). Results were compared with inotropic responses to DPI 201-106 (DPI, 0.1-3 mumol/l), Ca2+ (1.8-15 mmol/l) and isoprenaline (0.001-1 mumol/l). Carbachol (100 mumol/l) and adenosine (1000 mumol/l) were examined in the presence of BDF 9148 and isoprenaline. Both sodium-channel activators, BDF 9148 and DPI 201-106, increased force of contraction in a dose-dependent manner in papillary muscle strips as well as in auricular trabeculae. BDF 9148 and DPI 201-106 were more effective (max. PIE NYHA II-III 1.6 +/- 0.2 mN, NYHA IV 5.9 +/- 0.7 mN, P less than 0.05) and more potent (EC50 (in mumol/l): NYHA IV 0.35, 0.19-0.66; NYHA II-III 1.85, 1.37-2.41) in terminally failing as compared to moderately failing left ventricular myocardium. Moreover, the positive inotropic effects of BDF 9148 were greater than those of DPI 201-106 in NYHA IV (max. PIE 2.7 +/- 0.3 mN, P less than 0.05). In NYHA IV, BDF 9148 was as effective as CA2+ (max. PIE 5.1 +/- 0.4 mN). In the same hearts, the positive inotropic effects of isoprenaline were reduced in NYHA IV (max. PIE 2.1 +/- 0.3 mN) compared to NYHA II-III (max. PIE 3.4 +/- 0.4 mN, P less than 0.05). Adenosine as well as carbachol did not affect the positive inotropic response of BDF 9148 or DPI 201-106 but reduced the effectiveness of isoprenaline (P less than 0.05). In myocardial membranes, BDF 9148 was 1000-fold less effective in competition experiments with 3H-ouabain than ouabain. We conclude that (1) sodium-channel activators may produce a significant cAMP-independent positive inotropic effect in left ventricular myocardium from failing human hearts; (2) the inotropic effect of sodium-channel activators were more potent and more effective in NYHA IV as compared to NYHA II-III. The degree of myocardial failure does not reduce the effectiveness of the sodium-channel activator BDF 9148.
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PMID:Evidence for a sustained effectiveness of sodium-channel activators in failing human myocardium. 165 40

1. We studied the stereoselectivity of the effects of the enantiomers of the cardiotonic agent DPI 201-106 (4-[3'-(4"-benzhydryl-1"-piperazinyl)-2'-hydroxypropoxy]-1H-indole-2- carbonitrile, DPI) and its methyl-for-carbonitrile analogue BDF 8784 on cardiac calcium currents (ICa) of guinea-pig ventricular myocytes. The actions of the S- and R-enantiomers were compared with those of the racemate. 2. Racemic, S- and R-DPI depressed ICa in a concentration-dependent manner, the IC50 values were 1.1 mumol l-1 for racemic and S-DPI, and 1.2 mumol l-1 for R-DPI, respectively. Racemic, S- and R-BDF 8784 also reduced ICa, the respective IC50 values were 3.6 mumol l-1 for racemic BDF 8784, 1.3 mumol l-1 for S-BDF 8784 and 1.1 mumol l-1 for R-BDF 8784. 3. Neither the DPI nor the BDF 8784 enantiomers alter the time course of inactivation of ICa. The steady-state inactivation curve for ICa was shifted along the voltage axis to negative membrane potentials. The block of ICa was dependent on the membrane potential and increased with membrane depolarization. 4. Our findings indicate that DPI and BDF 8784 inhibit ICa in a non-stereoselective manner, which contrasts the opposite effects of the DPI enantiomers on Na+ channels.
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PMID:Inhibition of the myocardial Ca(2+)-current (ICa) by the enantiomers of DPI 201-106 and BDF 8784. 166 40

1. The cardiotonic agent BDF 9148 (4-[3'-(1''-benzhydryl-azetidine-3''-oxy)-2'-hydroxypropoxy]-1H-indole- 2-carbonitrile) is structurally related to DPI 201-106 (4-[3'-(4''-benzhydryl-1''-piperazinyl) -2'-hydroxypropoxy]-1H-indole-2-carbonitrile) which is known to modify cardiac sodium channels. In guinea-pig papillary muscles, both compounds increase force of contraction with similar concentration-response curves. Like DPI 201-106, BDF 9148 prolongs the action potential duration in a tetrodotoxin-sensitive manner. With high concentrations (greater than 3 microM), however, the action potential duration shortens again. In order to elucidate the underlying changes in membrane currents, we have investigated the effects of BDF 9148 in isolated ventricular myocytes of the guinea-pig heart. 2. In isolated cells, a concentration of 1 microM BDF 9148 prolonged the action potential duration and markedly enhanced unloaded cell shortening, indicating that the procedure of cell isolation does not abolish the effect of the drug. 3. Membrane currents were studied with the single electrode voltage clamp technique. With clamp steps from -80 mV to -40 mV, BDF 9148 (1 microM) induced a slowly decaying inward current which was suppressed by tetrodotoxin. Therefore, like DPI 201-106, BDF 9148 slows the inactivation of the sodium channels. 4. In order to quantify the effects of BDF 9148 and DPI 201-106 on sodium current inactivation, we have measured the inward current amplitude still present at 100 ms after a depolarizing clamp step from -80 mV to -30 mV. Both drugs increased this current component in a concentration-dependent manner; however, BDF 9148 had a larger effect in the low concentration range.5. The calcium current was inhibited by BDF 9148 and DPI 201-106 in a concentration-dependent manner; the pD2 values were 5.70 and 5.95, respectively.6. The two compounds are thought to produce similar positive inotropic effects by imposing a sodium load on the muscle cells via modification of the sodium channels. The differences in action potential duration could be due to different contributions of ionic currents other than sodium or calcium currents and of pump and exchange currents. At present, there is not sufficient data to identify clearly distinct current components responsible for the differences in action potential prolongation.
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PMID:Characterization of the effects of the new inotropic agent BDF 9148 in isolated papillary muscles and myocytes of the guinea-pig heart. 166 82

The inotropic actions of various drugs known to increase force of contraction in isolated mammalian cardiac muscle were investigated in electrically driven (1 Hz) guinea-pig left atria under both normal [K+]o (4.7 mM) and high [K+]o (22 mM). Under normal [K+]o a concentration-dependent increase in force of contraction could be confirmed with the beta-adrenoceptor agonist, isoprenaline, the cyclase activator, forskolin, the inhibitors of the cyclic AMP-phosphodiesterase (PDE), amrinone, IBMX, and OPC 8212, the Na+ channel activators, DPI 201-106, SDZ 210-921, veratridine, and ATX II, the Na(+)-ionophore monensin, the inhibitor of Na+/K(+)-ATPase, ouabain, and the Ca2+ channel activators, Bay K 8644, CGP 28 H 392, and SDZ 202-791. Partial depolarization of the muscle preparations by increasing [K+]o in the organ bath to 22 mM completely abolished the positive inotropic action of the Na+ channel-activating drugs. In contrast, the effects of the other compounds were still present, although changes in the maximal force development were observed. The efficacy of the PDE inhibitors amrinone and IBMX were slightly increased; the maximal effects of isoprenaline, monensin, forskolin, and OPC 8212 were unchanged; the effect of ouabain decreased to about half maximal values; while the efficacy of the Ca2+ channel activators were either unchanged (CGP 28 392) or decreased (Bay K 8644 and SDZ 202-791). The results suggest that inactivation of cardiac fast Na+ channels by partially depolarizing isolated, electrically driven atria is a suitable model to distinguish between cardiotonic agents acting through activation of Na+ channels and those with other mechanisms of action.
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PMID:Identification of cardiotonic sodium channel activators by potassium depolarization in isolated guinea-pig atria. 170 Feb 27

We examined the relationship between free Ca2+ and developed force in chemically skinned fibers from control and pressure-overload hypertrophied (POH) hearts of ferrets in the absence and presence of DPI 201-106 (4-([3-(4-diphenyl-methyl-l-piperazinyl)-2-hydroxypropoxy]-1H-indole-2- carbonitrile), a positive inotropic and negative lusitropic agent. Force production in both control and hypertrophied fibers increased with Ca2+ concentration ([Ca2+]) over a range from 10(-7) M to 10(-4) M, and did not differ significantly in response to Ca2+ under isometric conditions. The [Ca2+] required for half-maximal activation ([Ca2+]50%) was estimated to be 1.84 x 10(-6) M in control muscles and 1.76 x 10(-6) M in POH muscles. The maximal Ca2(+)-activated force was significantly higher in the POH group (3.68 +/- 0.27 g/mm2) as compared to the control muscles (2.41 +/- 0.56 g/mm2. A DPI concentration of 10(-6) M shifted the force-pCa relation leftward by 0.13-0.18 pCa units in the control hearts, and by 0.40-0.45 pCa units in the hypertrophied hearts. In the concentration range between 10(-8) M and 10(-5) M, DPI induced a concentration dependent increase in force production that reached about 40% in the hypertrophied hearts and only 18% in the control hearts at pCa 6. The influence of DPI on the myofibrillar Ca2+ binding may be due to the effect of the drug on the troponin T-tropomyosin complex. In view of our results, we propose that hypertrophied hearts may demonstrate an adaptational change in the contractile proteins at the level of the thin myofilaments. This adaptational change may result in altered contractile performance and response to agents that potentially act at the level of the myofilaments. Further, alteration at the level of the myofilaments may not be detected by standard force-[Ca2+] relationships.
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PMID:Modulation of calcium-activation in control and pressure--overload hypertrophied ferret hearts: effect of DPI 201-106 on myofilament calcium responsiveness. 182 88

Single myocytes isolated from the guinea-pig ventricle were used under voltage-clamp conditions to study the activity of a newly developed drug, R56865, a benzothiazolamine derivative, against digitalis toxicity. Multicellular Purkinje preparations were used in some experiments. The drug blocked the transient inward current (TI) with an apparent KD of 7.5 X 10(-8) M. The blockade was not due to a direct effect on the Na+, Ca2+ exchange current or on the non-selective cation current, the two components of TI. Blockade of TI was accompanied in time with inhibition of after-contractions, which suggests that the drug has an effect on Ca(2+)i transients. At concentrations effective on TI the drug did not block Ca2+ currents or Na+ currents; however the Na+ current was inhibited after the cells had been pretreated with DPI 201-106. It is suggested that the inhibitory effect on TI may be due to an effect on the release of Ca2+ from the sarcoplasmic reticulum or to a reduction in Ca2+ overload via blockade of the Na+ channel.
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PMID:Block of the transient inward current by R56865 in guinea-pig ventricular myocytes. 187 80

The cardiac and hemodynamic effects of (+/-)-DPI 201-106 (0.6 mg/kg), S(-)-DPI (0.3 mg/kg), R(+)-DPI (0.3 mg/kg), and their vehicle were compared in chronically implanted conscious dogs. (+/-)-DPI and S(-)-DPI induced qualitatively and quantitatively similar effects, increasing LV dP/dt, cardiac output and stroke volume and reducing total peripheral resistance. In contrast, R(+)-DPI decreased only stroke volume. It is concluded that (a) the positive inotropic effects of (+/-)-DPI in vivo are caused by its S(-) enantiomer, and (b) the peripheral vasodilating effects of (+/-)-DPI may not be linked to the drug's calcium antagonist properties.
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PMID:Cardiac and hemodynamic effects of S(-)- and (R(+)-DPI 201-106 and of racemic DPI 201-106 in conscious dogs. 207

The effects of certain drugs on the binding of divalent cations to Ca(2+)-specific and Ca/Mg sites on cardiac and skeletal troponin C molecules were investigated by fluorescence and circular dichroism spectroscopy. Nicardipine and two new cardiotonic agents, APP 201-533 and DPI 201-106, interact with the N-terminal domain of troponin C, and either do not affect or, in the case of DPI 201-106, slightly increase the affinity of the Ca(2+)-specific site of troponin C for Ca2+ ion. Compound 48/80 seems to interact with the central alpha-helix of skeletal troponin C and affects the cation-binding properties of both the Ca(2+)-specific and the Ca/Mg sites of the protein. Trifluoperazine and calmidazolium (R24571) interact with the C-terminal domain of troponin C and increase the affinity of the Ca/Mg sites located there. At high concentrations these compounds interact with the N-terminal domain of troponin C and increase the affinity of the Ca(2+)-specific site. According to fluorescence spectroscopy data, R24571 induces conformational changes in troponin C similar to those evoked by troponin I. The experimental data suggest that the drugs studied act in similar ways with troponin C and calmodulin.
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PMID:Drug interaction with cardiac and skeletal muscle troponin C. 213 Sep 16

Intracellular Ca2+ release and reuptake are necessary for normal contraction and relaxation of the human heart. Intracellular Ca2+ transients were recorded with aequorin during isometric contraction of myocardium from patients with end-stage heart failure. In contrast to controls, contractions and Ca2+ transients of muscles from failing hearts were markedly prolonged, and the Ca2+ transients exhibited two distinct components. Muscles from the failing hearts showed a diminished capacity to restore a low resting Ca2+ level during diastole. These data obtained in actively contracting human myocardium suggest that intracellular Ca2+ handling is abnormal and might cause both systolic and diastolic dysfunction in heart failure. The inotropic effectiveness of drugs that act to increase intracellular levels of cyclic adenosine monophosphate (AMP), such as beta-adrenergic agonists and phosphodiesterase inhibitors, was markedly reduced in muscles from patients with heart failure. In contrast, the effectiveness of inotropic stimulation with drugs that act by cyclic AMP-independent mechanisms, such as the cardiotonic steroids and DPI 201-106, were preserved. Stimulation of intracellular cyclic AMP production by the adenylate cyclase activator forskolin restored the inotropic response to phosphodiesterase inhibitors. These studies indicate that an abnormality in cyclic AMP production may be a fundamental defect in patients with end-stage heart failure that may markedly diminish the effectiveness of agents that depend on generation of this nucleotide for a positive inotropic effect. Moreover, deficient production of cyclic AMP seems, at least in part, to account for the reversal of the force-frequency relation that characterizes failing myocardium. Of interest, direct measurement of total cellular cyclic AMP content and protein kinase activity did not reveal significant differences between the control and myopathic tissue, suggesting the presence in human ventricular muscle of physiologically distinct compartmentalized pools of cyclic AMP. Finally, changes in the sensitivity of the contractile apparatus to Ca2+ also seem to play an important role in the differential responsiveness to drugs of myopathic versus normal human myocardium.
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PMID:Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure. 215 79


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