Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.13.12.5 (aequorin)
 1,451 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EMD 53998 (a thiadiazinone) is an inotropic drug that produces a pronounced increase in the Ca2+ sensitivity of the contractile proteins in skinned cardiac fibers. The present study was undertaken to determine whether this effect on Ca2+ sensitivity could explain the increase in tension observed in intact ventricular muscle. The experiments were performed on isolated ferret papillary muscles that had been microinjected with aequorin to measure the intracellular Ca2+ concentration. Force and intracellular Ca2+ concentration were monitored before, during, and after application of EMD 53998. EMD 53998 (5 microM) increased developed tension by 230%; aequorin light transients increased by only 85%, and this increase was reduced and became insignificant in the presence of agents that prevent catecholamine release. When a similar increase in developed tension was produced by elevation of extracellular calcium, the aequorin light transients increased by 240%. Thus, EMD 53998 produces a substantial Ca2+ sensitization in intact ventricular muscle, and this can explain most of its inotropic effect. In addition, EMD 53998 caused a small prolongation of the time course of contraction and a small reduction of the time course of the aequorin light transient. A computer model is described that shows that both these effects can be explained by the effect of EMD 53998 on Ca2+ sensitivity. At much higher concentrations, EMD 53998 also caused an increase in resting tension. EMD 53998 is the first agent for which much of the inotropic effect in intact cardiac muscle can be accounted for by increased Ca2+ sensitivity of the contractile proteins. Inotropic agents with this mechanism of action cause increased force production with much less increase in the intracellular Ca2+ transients than conventional agents and, therefore, increase the energy efficiency of the myocardium and are less likely to cause Ca(2+)-activated arrhythmias.
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PMID:EMD 53998 sensitizes the contractile proteins to calcium in intact ferret ventricular muscle. 193 45

1. The signal transduction process mediated by cyclic AMP that leads to the characteristic positive inotropic effect (PIE) in association with a positive lusitropic effect (acceleration of rate of twitch relaxation) has been well established. Relationships between accumulation of cyclic AMP, changes in intracellular Ca2+ transients and the PIE differ, however, depending on the mechanism of particular drugs that affect different steps in the metabolism of cyclic AMP. Selective partial agonists of beta 1-adrenoceptors and inhibitors of phosphodiesterase (PDE) III cause the accumulation of less cyclic AMP for a given PIE than does isoproterenol. In addition, in aequorin-microinjected canine ventricular muscle, selective inhibitors of PDE III, OPC 18790 and Org 9731, produced smaller decreases in the responsiveness of myofilaments to Ca2+ ions than isoproterenol, while a partial agonist of beta 1-adrenoceptors, denopamine, elicits a decrease in Ca2+ responsiveness of the same extent as does isoproterenol. 2. Activation of myocardial alpha 1-adrenoceptors, as well as stimulation of receptors for endothelin and angiotensin II, which accelerates hydrolysis of phosphoinositide (PI) to result in production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) are associated with very similar inotropic regulation: (1) the dependence on the species of animals of induction of the PIE; (2) an excellent correlation between the extent of acceleration of hydrolysis of PI and the PIE; (3) isometric contraction curves associated with a negative lusitropic effect; (4) the PIE associated with increases in myofibrillar responsiveness to Ca2+ ions; and (5) the selective inhibition of the PIE by an activator of protein kinase C (PKC), phorbol 12,13-dibutyrate (PDBu), with little effect on the PIE of isoproterenol and Bay k 8644. 3. A novel class of cardiotonic agents, namely, Ca2+ sensitizers such as EMD 53998 and Org 30029, act on the Ca(2+)-binding site of troponin C, increasing the affinity of these sites for Ca2+ ions, or at the actin-myosin interface to facilitate the cycling of cross-bridges. These agents produce a PIE with little change or decrease in Ca2+ transients and may bring about a significant breakthrough in the development of drugs for reversal of myocardial failure in the treatment of congestive heart failure.
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PMID:The effects of various drugs on the myocardial inotropic response. 771 48

EMD 53998 (a thiadiazinone) is a novel inotropic substance that increases the Ca2+ sensitivity of the myofilaments in skinned cardiac fibers and has been found to have similar effects in intact cardiac muscle. However, the compound also possesses the ability to inhibit phosphodiesterase III, indicating that its actions in intact cardiac muscle are likely to be complex. The present study was carried out to investigate the possibility that the optical isomers of EMD 53998--(+)EMD 57033 and (-)EMD 57439--which have recently been shown to possess a separation of sensitization and phosphodiesterase inhibition in subcellular preparations, might also demonstrate this separation of activities in intact cardiac muscle. The experiments were performed on isolated ferret papillary muscles, which were contracting isometrically. In some preparations, the photoprotein aequorin was injected into superficial cells to measure intracellular Ca2+ as well as force. (+)EMD 57033 caused a substantial positive inotropic effect that was associated with prolongation of the twitch, reduction in the amplitude of the Ca2+ transient, and abbreviation of the Ca2+ transient. This is the profile expected of a Ca(2+)-sensitizing compound. Conversely, (-)EMD 57439 caused a less marked positive inotropic effect that was associated with an abbreviation of the twitch, an increase in the amplitude of the Ca2+ transient, and an abbreviation of the Ca2+ transient. This is the profile expected of an agent producing its inotropic effect by increasing cAMP (e.g., phosphodiesterase inhibition). The results indicate that the optical isomers of EMD 53998 possess a remarkable separation of Ca(2+)-sensitizing and phosphodiesterase-inhibiting activities in intact cardiac muscle. These actions were additive and could account for the effects observed with EMD 53998. (+)EMD 57033 appears to be the first inotropic agent that acts predominantly by increasing myofilament calcium sensitivity.
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PMID:Differential effects of the optical isomers of EMD 53998 on contraction and cytoplasmic Ca2+ in isolated ferret cardiac muscle. 850 34

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

The role of Ca2+ in cardiac excitation-contraction (E-C) coupling has been established by simultaneous measurements of contractility and Ca2+ transients by means of aequorin in intact myocardium and Ca2+ sensitive fluorescent dyes in single myocytes. The E-C coupling process can be classified into 3 processes: upstream (Ca2+ mobilization), central (Ca2+ binding to troponin C) and downstream mechanism (thin filament regulation and crossbridge cycling). These mechanisms are regulated differentially by various inotropic interventions. Positive force-frequency relationship and effects of beta-adrenoceptor stimulation, phosphodiesterase 3 inhibitors and digitalis are essentially exerted via upstream mechanism. Alpha-adrenoceptor stimulation, endothelin-1, angiotensin II, and clinically available Ca2+ sensitizers, such as levosimendan and pimobendan, act by a combination of the upstream and central/downstream mechanism. The Frank-Starling mechanism and effects of Ca2+ sensitizers such as EMD 57033 and Org 30029 are primarily induced via the central/downstream mechanism. Whereas the upstream and central mechanisms are markedly suppressed in failing myocytes and under acidotic conditions, Ca2+ sensitizers such as EMD 57033 and Org 30029 can induce cardiotonic effects under such conditions. Ca2+ sensitizers have high therapeutic potential for the treatment of contractile dysfunction in congestive heart failure and ischemic heart diseases, because they have energetic advantages and less risk of Ca2+ overload and can maintain effectiveness under pathological conditions.
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PMID:Cardiac Ca2+ signaling and Ca2+ sensitizers. 1898 94