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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of various calcium sensitizers on myosin-actin crossbridge kinetics were evaluated in intact, paced guinea-pig papillary muscle by analysing the velocity of the development of isometric tension (dT/dt) in detail. The effect on association (the whole sequence of events from troponin onward) and dissociation rates of crossbridges was estimated from the rising phase and from the early decay phase of the normalized dT/dt curve. Levosimendan, a calcium sensitizer acting through troponin C, accelerated the proportional association rate and decelerated the dissociation rate of crossbridges. The effect of levosimendan on crossbridge kinetics occurred before the peak twitch tension was achieved. Thus, the compound did not change the actual relaxation phase of twitch tension. Since the effect on the association was more pronounced than on the dissociation of crossbridges, levosimendan shifted the entire twitch tension curve to the left. Based on the dissociation rate analysis levosimendan seems to act preferentially as a calcium sensitizer at low concentrations. At high concentrations the phosphodiesterase III (PDE III) inhibitory properties of levosimendan modulated its effect on the early relaxation processes. In contrast, PDE III inhibition is probably the primary mechanism of action for MCI-154. Pimobendan, and EMD 53998 at low concentrations, whereas their direct effects on crossbridge kinetics contributed to the positive inotropic action at high concentrations. The calcium sensitizing mechanisms of these compounds seemed to be based almost exclusively on the decelerating effect on dissociation of crossbridges.
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PMID:Troponin C-mediated calcium sensitization by levosimendan accelerates the proportional development of isometric tension. 857 32

Previously, we showed, in an in situ porcine model, that the thiadiazinone derivative [+]EMD 60263, a putative Ca2+ sensitizer with minimal phosphodiesterase III inhibitory properties, increased contractility more profoundly in stunned than in nonstunned myocardium. The aim of the present investigation was to study the mechanism of action by determining the in vitro effects of [+]EMD 60263 on the Ca2+ responsiveness of the Mg(2+)-dependent ATPases of myofibrils and sarcoplasmic reticulum membrane vesicles, isolated from normal ventricle of swine and hypertrophic septum of cardiomyopathic patients. Contamination of the myofibrils with sarcoplasmic reticulum membranes was excluded by testing the effect of the sarcoplasmic reticulum Ca(2+)-pumping ATPase inhibitor thapsigargin. The plasma concentrations at which [+]EMD 60263 exerted its inotropic effect in the in situ porcine model were found to be submicromolar. [+]EMD 60263 stimulated concentration-dependently (1-10 microM) the submaximally activated Mg(2+)-ATPases (at pCa 6.1) of pig heart myofibrils. [+]EMD 60263 (10 microM) shifted the pCa50 of porcine myofibrillar Ca(2+)-stimulated, Mg(2+)-dependent ATPase from 6.00 +/- 0.05 to 6.67 +/- 0.05, whereas the [-]enantiomer EMD 60264 had no significant effect. Although the effect was much less at 1 and 3 microM, [+]EMD 60263 (10 microM) also stimulated maximal myofibrillar Mg(2+)-ATPase activity. The Hill coefficient, reflecting the steepness of the fitted pCa/Mg(2+)-ATPase curve at half-maximal activation, was not affected by [+]EMD 60263 (10 microM). [+]EMD 60263 (10 microM) had no effect on sarcoplasmic reticulum Ca(2+)-stimulated, Mg(2+)-dependent ATPase from swine heart. The thiadiazinone derivative [+]EMD 57033 (10 microM), but not its [-]enantiomer EMD 57439, had similar, although less potent, effects on pig heart myofibrillar Mg(2+)-ATPase activity as compared to [+]EMD 60263. [+]EMD 60263 (3 microM) produced a significantly larger leftward shift of the pCa2+/Mg(2+)-ATPase activity curve of myofibrils isolated from the stunned compared to the adjacent nonstunned myocardium (Delta pCa50s caused by the presence of [+]EMD 60263 amounted to +0.57 +/- 0.04 and +0.42 +/- 0.05, respectively) in the in situ porcine model. The effects of [+]EMD 60263 on myofibrillar Mg(2+)-ATPase of hypertrophic human heart were identical to those observed with porcine heart myofibrils. The results indicate that the positive inotropic action of [+]EMD 60263 observed in the in situ porcine model of stunned myocardium may be primarily due to myofilament sensitization to Ca2+, and that this compound may have a similar action on diseased human myocardium.
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PMID:The effect of a thiadiazinone derived Ca2+ sensitizer on the responsiveness of Mg(2+)-ATPase to Ca2+ in myofibrils isolated from stunned and nonstunned porcine and human myocardium. 864 45

Inhibitors of phosphodiesterase type III (PDE III) enhance cardiac contractile force by elevating the intracellular calcium concentration [Ca2+]i by impairing cAMP degradation thus increasing cAMP levels. The drugs are more effective in healthy than in failing hearts since basal cAMP production is diminished in the latter. However, long term treatment with PDE-III inhibitors does not appear to be beneficial due to increased risk of potentially lethal arrhythmias caused by augmentation of [Ca2+]i[1). This risk should be absent in Ca2+ sensitizers. Recently, thiadiazinone derivatives have been synthetized in which the potency for Ca2+ sensitization is many-fold larger than the potency for PDE-III inhibition. The Ca(2+)-sensitizing action resides in the [+]-enantiomers, while the [-]-enantiomers show weak PDE-III inhibition. In the enantiomer pair [+]-EMD 60263 and [-]-EMD 60264, only the former concentration-dependently increased force of contraction in isolated cardiac preparations and myocytes. In the Langendorff-perfused guinea-pig heart, force was reversibly increased, whereas [-]-EMD 60264 even produced a negative inotropic response despite of its PDE inhibitory activity. Heart rate, however, was reduced by both enantiomers. Perfusion pressure remained unaffected. The effects were fully reversible upon wash-out of the enantiomers. [+]-EMD 60263 also enhanced cell shortening of human myocytes from both normal and failing hearts. In contrast to the opposite effects on contractility, both enantiomers prolong the action potential duration by blocking the rapidly activating component of the delayed rectifier K+ current. Thus they also possess class III antiarrhythmic activity. The therapeutic potential of these agents has yet to be assessed in clinical studies.
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PMID:Phosphodiesterase inhibition and Ca2+ sensitization. 873 54

(+)-(5-Methyl-6-phenyl)-1,3,5,6-tetrahydro-3,6-methano-1, 5-benzodiazocine-2,4-dione (CAS 165755-40-8, CGP 48506) is a novel Ca2+ sensitizing agent devoid of any other positive inotropic mechanism, particularly phosphodiesterase (PDE) III inhibition. 5-(1-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-met hyl-3, 6-dihydro-2H-1,3,4-thiadiazin-2-one (CAS 120223-04-3, EMD 53998) is a PDE III inhibitor with a Ca2+ sensitizing activity residing in its (+)-enantiomer, EMD 57033 (CAS 147527-31-9). In skinned fibres and electrically stimulated left ventricular strips from idiopathic dilated human hearts, New York Heart Association (NYHA) class IV, the Ca2+ sensitizing and inotropic effects of the benzodiazocine CGP 48506 and the thiadiazinones EMD 53998 or EMD 57033 were compared. Both CGP 48506 and EMD 53998 induce a left shift of the Ca2+ activation curve of force towards lower Ca2+ concentrations in skinned fibres, which indicates Ca2+ sensitization. Only EMD 53998, but not CGP 48506, increases skinned fibre force at both minimum (resting) and maximally activating Ca2+ concentrations. This is taken as an argument for a principal difference in the mechanisms of the Ca2+ sensitizing actions of the two compounds. CGP 48506 is shown not to influence the amplitude of the Ca2+ transient in rat cardiomyocytes. On the other hand, both CGP 48506 and EMD 57033 show comparable, though quantitatively different, positive inotropic effects in electrically stimulated left ventricular strip preparations. It is unclear whether the PDE III inhibitory component of the profile of actions of EMD 57033 may play a role in preventing the increase in diastolic tension as expected from the skinned fibre experiments. It is noteworthy that both Ca2+ sensitizing agents act as positive inotropic compounds in the end-stage failing human heart where other inotropic agents like beta 1-adrenergic agonists or PDE inhibitors have been described to fail.
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PMID:Ca2+ sensitization in idiopathic dilated human myocardium. Differential in vitro effects of (+)-(5-methyl-6-phenyl)-1,3,5,6-tetrahydro-3,6-methano-1,5-benzodiazoci ne-2,4-dione, a novel purely Ca2+sensitizing agent, and (+)-5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-meth yl-3, 6-dihydro-2H-1,3,4-thiadiazin-2-one on skinned fibres and isolated ventricular strips. 876 48

We measured the effects of the benzodiazocine derivative, CGP-48506 (5-methyl-6-phenyl-1,3,5,6-tetrahydro-3,6-methano-1, 5-benzodiazocine-2,4-dione), on contraction of intact myocytes and permeabilized fibers of rat ventricular muscle. CGP-48506 is unique in that it is able to sensitize cardiac myofilaments to Ca2+, but unlike all other agents in this class, it is not an inhibitor of type III phosphodiesterase. When added to isolated intact myocytes, CGP-48506 significantly increased the amplitude of cell shortening with little or no change in the Ca2+ transient, as determined by the fluorescence ratio of fura 2. The late phase of the relation between fura 2 ratio and cell length was shifted to the left in the presence of CGP-48506. CGP-48506 also induced a relatively small decrease in diastolic length. However, compared with the thiadiazinone EMD-57033, CGP-48506 had a much smaller effect on diastolic length at concentrations in which there was a bigger inotropic effect. When added to solutions bathing detergent-extracted (skinned) fiber bundles, CGP-48506 increased maximum force. CGP-48506 also increased submaximal force and shifted the pGa-force relation to the left. However, compared with EMD-57033, there was less of an effect of CGP-48506 on force at relatively high pCa values. CGP-48506 did not alter Ca2+ binding to myofilament troponin C. CGP-48506 was able to reverse inhibition of contraction induced by butanedione monoxime both in intact cells and in skinned fiber bundles. Our results indicate that CGP-48506, like EMD-57033, is a positive inotropic agent working through a direct effect downstream from troponin C. CGP-48506, however, appears to have a unique mechanism resulting in less effect on diastolic function.
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PMID:CGP-48506 increases contractility of ventricular myocytes and myofilaments by effects on actin-myosin reaction. 876 30

We investigated the effect of a new Ca++ sensitizer, MCI-154, which is known to increase myofibrillar Ca++ sensitivity and maximal Ca(++)-activated force, on Ca++ transients and left ventricular (LV) function in indo-1-loaded Langendorff guinea plg hearts subjected to a reduction in coronary perfusion pressure from 80 to 40 mm Hg. During low-flow ischemia, LV contractility decreased by 50%, whereas systolic and diastolic indo-1 fluorescence ratios increased by 10%. The treatment with MCI-154 (10(-10) to 10(-6) M) 15 min after ischemia effectively restored the depressed LV function with little effect on indo-1 ratio. EMD 53998 (10(-9) to 10(-6) M), which also acts on maximal Ca(++)-activated force, restored LV function with a minimal impact on indo-1 ratio, but at 10(-5) M, EMD 53998 caused diastolic dysfunction, and its beneficial effect on systolic function disappeared. The relation between indo-1 ratio and LV contractility showed that MCI-154 and EMD 53998 restored ischemic contractile failure by Ca(++)-sensitizing action. It was noted that the restoration of LV dysfunction by MCI-154 or EMD 53998 was more pronounced than that by pimobendan, which acts primarily on Ca++ sensitivity. In contrast, the phosphodiesterase inhibitor milrinone restored LV function, but it doubled the increase in indo-1 ratio during ischemia. These findings suggest that a decrease in myofilament Ca++ responsiveness may be an important cause of ischemic contractile failure and that the restoration of depressed Ca++ responsiveness by intervention such as MCI-154 may be a promising approach for restoring the depressed function.
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PMID:Restoration of ischemic contractile failure of indo-1-loaded guinea pig heart by a calcium sensitizer, MCI-154. 885 74

1. We studied the effects of flash photolysis on the novel enantiomeric cardiac inotropes EMD 57033 (a calcium sensitizer) and EMD 57439 (a phosphodiesterase III inhibitor) in rat isolated ventricular trabeculae. 2. In skinned trabeculae, EMD 57439 had no effect on force production, consistent with lack of an active cyclic AMP system in this preparation. In contrast, EMD 57033 potentiated force at partial and maximal activation. A single flash of near u.v. light given at partial activation (30-70%) reduced force potentiation by 52.4 +/- 5.2%. No effect was produced by flashes in the presence of EMD 57439 or in the absence of either drug. 3. The time course of relaxation induced by EMD 57033 photolysis was indistinguishable from that obtained on deactivating the muscle by rapidly lowering Ca2+ using photolysis of the caged chelator of calcium, diazo-2. 4. In intact, twitching trabeculae, EMD 57033 increased diastolic and peak force and slowed relaxation. These effects were simultaneously reduced by a light flash. In these muscles EMD 57439 reduced force, without affecting the twitch time course. These effects were also reduced by a light flash. 5. The u.v. absorbance spectra of EMD 57033 and EMD 57439 were identical. After photolysis optical density decreased substantially and the peak shifted from 320 nm to 280 nm. 6. The proton n.m.r. spectra of these compounds were identical. The main change post-photolysis was a decrease in the proton signal associated with the enantiomeric carbon atom. 7. This novel manipulation of the molecular structure of EMD 57033 and EMD 57439 within an experiment thus provides direct evidence linking calcium sensitization to a particular molecular structure. The three main effects of the sensitizer on the twitch were simultaneously abolished and may be mechanistically linked. Flash photolysis may be a useful tool for further investigations of the actions of these compounds. In particular, flash photolysis of the sensitizer represents a novel method of rapidly deactivating cardiac muscle.
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PMID:Photolysis of the novel inotropes EMD 57033 and EMD 57439: evidence that Ca2+ sensitization and phosphodiesterase inhibition depend upon the same enantiomeric site. 886 40

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

Calcium sensitizers may influence myocardial energetics by their action on calcium turnover and on crossbridge behavior. Using a myothermal method, the effects of the Ca2+ sensitizer EMD-53998 on calcium cycling, crossbridge behavior, and myocardial energy turnover were compared with the effects of an increase in extracellular calcium from 1.25 to 7.5 mM and with the effects of the catecholamine isoproterenol. All three inotropic interventions increased isometric force development in right ventricular rabbit papillary muscles. Relaxation time was decreased with isoproterenol, unchanged with high calcium, and increased with EMD 53998. Calcium cycling-related energy consumption, as measured by tension-independent heat, increased by 234% with high calcium, by 439% with isoproterenol, and by 77% with EMD 53998. In contrast to high calcium and isoproterenol, EMD 53998 increased economy of crossbridge cycling by increasing the force-time integral of the individual crossbridge cycle. The data indicate that EMD 53998 acts by phosphodiesterase inhibition and myofilament calcium sensitization. The latter effect is in part mediated by alteration of crossbridge behavior. Because of its effects on calcium cycling and crossbridge function myocardial energy turnover was reduced significantly with EMD 53998, whereas energy turnover was unchanged with high calcium and was increased with isoproterenol. The new calcium sensitizer levosimendan was investigated in isolated failing human myocardium. Levosimendan dose-dependently increased isometric tension. The inotropic effect was associated with increased rate of relaxation and reduced relaxation time. Measurements of intracellular calcium using the photoprotein aequorin suggest that levosimendan acts by increasing myofilament calcium sensitivity and by increasing cAMP due to phosphodiesterase inhibition. However, the contribution of the cAMP system to the action of levosimendan appears to be rather small. Therefore, the finding of a positive lusitropic effect of levosimendan may be consistent with the notion that levosimendan binds to troponin-C and increases calcium sensitivity only at high (systolic) intracellular calcium concentrations.
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PMID:Effects of calcium sensitizers on intracellular calcium handling and myocardial energetics. 890 30

This review summarizes some of the problems with inotropic agents and describes the new concept of increasing cardiac myofilament sensitivity to Ca2+. Presently used inotropic agents act by increasing the intracellular concentration of Ca2+ in cardiac myocytes by either cAMP-dependent or cAMP-independent mechanisms. There is concern that elevation of cAMP and/or cytosolic Ca2+ might be proarrhythmic and increase mortality in patients with congestive heart failure (CHF). Ca2+ sensitization represents a new approach to the treatment of CHF. Drugs that sensitize the contractile proteins to Ca2+ enhance myocardial contractility without changes in the cytosolic Ca2+ concentration. Ca2+ sensitization can be achieved by an increased affinity of troponin-C for Ca2+ (pimobendan), by stabilization of the Ca2+ -induced conformational change of troponin-C (levosimendan) or by direct interference with the myosin-actin interaction (MCI-154, EMD 53998, and EMD 57033). Ca2+ sensitization reduces the risk for Ca2+ overload and has a favorable effect on myocardial oxygen consumption. Inhibition of cardiac relaxation is a possible adverse effect of Ca2+ sensitizers owing to an expected higher level of contractile tension during diastole. However, most of the reported Ca2+ sensitizers have additional phosphodiesterase (PDE) III-inhibitory activity, which is associated with a positive lusitropic effect, but from the standpoint of mortality PDE inhibition might not be beneficial in the long run. Most Ca2+ sensitizers have a hemodynamic profile characteristic of inodilators. Clinical data on Ca2+ sensitizers are yet very sparse but ongoing clinical trials are awaited.
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PMID:Will calcium sensitizers play a role in the treatment of heart failure? 890 35


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