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 inotropic state of the myocardium can be enhanced via an increase in cell Ca2+ loading or in myofilament responsiveness to Ca2+. Although different pharmacological agents combine these properties, no presently available drug acts predominantly as a myofilament sensitizer in situ. We have investigated the effects and the mechanism of action of novel diazinone derivatives, EMD 54622, EMD 53998, and EMD 54650 (developed by E. Merck, Darmstadt), on guinea pig myocardial preparations. Force- and ATPase-pCa relations in skinned fibers show differing potencies of these agents on myofilament sensitization: EMD 54622 greater than EMD 53998 much greater than EMD 54650. This is in contrast to their relative potencies to inhibit isolated myocardial phosphodiesterase III: EMD 54650 greater than EMD 53998 greater than EMD 54622. In isolated hearts studied at constant coronary flow, each of the three diazinone derivatives had a positive inotropic effect. In enzymatically dissociated left ventricular myocytes loaded with the Ca2+ probe indo-1, the positive inotropic effect of EMD 54622 occurred with no change in the amplitude of the cytosolic [Ca2+] (Cai) transient. In contrast, both EMD 53998 and EMD 54650 enhanced Cai transient and twitch contraction amplitudes. Length-indo-1 fluorescence relations were analyzed to determine the effects of the three substances on myofilament responsiveness to Ca2+. EMD 54622 enhanced and EMD 54650 had no effect on myofilament responsiveness to Ca2+. Less uniform results were obtained with EMD 53998 (in two of five cells the myofilament responsiveness to Ca2+ was increased, whereas in three other cells it was unaltered). Our results indicate that structural changes in the diazinone molecule shift the mechanism of action for the positive inotropic effect of the diazinone derivatives in the intact cell from a predominant myofilament sensitization (EMD 54622) to an enhancement in cell Ca2+ loading and an augmentation in the Cai transient (EMD 54650).
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PMID:Novel diazinone derivatives separate myofilament Ca2+ sensitization and phosphodiesterase III inhibitory effects in guinea pig myocardium. 153 76

EMD 53 998, a novel thiadiazinone derivative, increases the contractile force of cardiac tissue in vitro through both an inhibition of phosphodiesterase III (PDE III) and a sensitization of cardiac contractile proteins to Ca2+. Guinea pig ventricular PDE III is selectively inhibited by EMD 53 998 (IC50 = 60 nM) without major effects on other PDE isoenzymes. Consonant with this is an increase in cAMP content of rat ventricular cells and a potentiation by EMD 53 998 of the cAMP-elevating action of isoprenaline (increase by 50% at 1.3 microM). Sensitization to Ca2+ by EMD 53 998 (3-30 microM) finds its expression in a leftward shift of the Ca2+ response curve for force generation in skinned fibers from porcine ventricular muscle and failing human heart as well as for activation of bovine cardiac myofibrillar actomyosin ATPase. Interestingly, EMD 53 998 elevates the maximum of the Ca(2+)-response curve for both parameters. Pimobendan studied under identical conditions was 100 times less potent than EMD 53 998. EMD 53 998 increases force development of guinea pig papillary muscle in a concentration-dependent manner with an EC50 of 3.6 microM, thus being 10 times more potent than pimobendan. In contrast to pimobendan, the positive inotropic effect of EMD 53 998 is barely affected by carbachol. Further evidence for a Ca(2+)-sensitizing effect of EMD 53 998 is provided by an additional increase in force generation in the presence of supramaximal isoprenaline concentrations. It is concluded that the positive inotropic action of EMD 53 998 is mediated through both cAMP-independent and cAMP-dependent mechanisms, with the former probably prevailing. We are not aware of other compounds with a similarly high Ca(2+)-sensitizing potency. On these grounds. EMD 53 998 appears to be a promising inotropic agent.
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PMID:The novel cardiotonic agent EMD 53 998 is a potent "calcium sensitizer". 171 87

We have investigated the mechanism of action of a novel positive inotropic agent, the thiadiazinone derivative 5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydrochinolin-6-yl)-6- methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-on (EMD 53998). This substance inhibits phosphodiesterase III and, in skinned myocardial fibers, it increases myofilament sensitivity to Ca2+. However the effects of EMD 53998 on intact myocardial preparations are still undefined. In isolated rat hearts EMD 53998 (0.5 to 5 microM) had a dose-dependent effect to increase left ventricular systolic pressure. In isolated left ventricular myocytes loaded with the ester derivative of the Ca2+ probe indo-1, EMD 53998 (0.5 to 5 microM) enhanced twitch amplitude without increasing the associated indo-1 transient. The myofilament responsiveness to Ca2+ was assessed as the relationship between twitch and the indo-1 transient amplitudes as the latter is varied by altering the bathing [Ca2+], or stimulation pattern. EMD 53998 reversibly shifted this relationship to the left which indicates that for indo-1 transients of the same amplitude in the absence and presence of the drug, twitch amplitude was enhanced by EMD 53998. In isolated myocytes studied in the absence of electrical stimulation, EMD 53998. (1.5 to 5 microM) had a concentration-dependent effect to markedly and reversibly decrease cell length without increasing indo-1 fluorescence ratio. Thus, the cellular basis for the positive inotropic action of EMD 53998 in rat myocardium is related to the unique effect of this substance to enhance myofilament responsiveness to Ca2+ and not to an increase in the indo-1 transient amplitude.
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PMID:A novel positive inotropic substance enhances contractility without increasing the Ca2+ transient in rat myocardium. 188 Aug 16

The role of structural features of sulmazole, an imidazo(4,5-b)pyridine, in its inotropic action was examined by comparison with its reduced (4-methylthiophenyl) analog EMD 46512 and the corresponding imidazo(4,5-c)pyridine isomers isomazole and EMD 41000 on isolated guinea-pig papillary muscles and right atria and on Na,K-ATPase and phosphodiesterase III isolated from guinea-pig hearts. The pyridine nitrogen position in sulmazole was crucial for affinity to Na,K-ATPase (IC50 = 350 microM) because the imidazo(4,5-c)pyridines had little effect. Participation of Na,K-ATPase inhibition in sulmazole's inotropic effect (EC50 = 180 microM) was suggested by synergism with the Na channel activator germitrine. The methylsulfinyl oxygen at the phenyl ring decreased the affinity to Na,K-ATPase of sulmazole 40-fold: The reduced analog EMD 46512 was a potent inhibitor of Na,K-ATPase (IC50 = 8.5 microM) and a more potent inotropic agent (EC50 = 8.2 microM) that appeared to act predominantly through Na,K-ATPase inhibition. Micromolar through Na,K-ATPase inhibition. Micromolar IC50s for inhibition of phosphodiesterase III were 49 (sulmazole), 34 (EMD 46512), 18 (isomazole), and 13 (EMD 41000). Participation of this mechanism in the inotropic effect of sulmazole, isomazole, and EMD 41000, but not EMD 46512, was indicated by augmentation of slow action potentials, synergism with histamine, inhibition by carbachol, and (with the exception of EMD 41000) a positive chronotropic effect on the right atrium. Sulmazole appeared to combine the actions of its 4-methylthiophenyl analog EMD 46512 (an inhibitor of Na,K-ATPase) and of its imidazo(4,5-c)pyridine isomer isomazole (an inhibitor of phosphodiesterase III).
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PMID:Imidazopyridines: roles of pyridine nitrogen position and methylsulfinyl oxygen for in vitro positive inotropic mechanism and chronotropic activity. 247 14

The two isomers of the positive inotropic compound EMD 53998, (+)EMD 57033 and (-)EMD 57439, possess selective calcium sensitizing and phosphodiesterase (PDE) inhibitory properties, respectively. We measured the pharmacological responses to both enantiomers in isolated rat cardiac and vascular tissues and in muscles from severely failing human hearts. We also measured positive inotropic and chronotropic responses to EMD 57033 in cardiac tissues from rats with thyroid dysfunction, diabetes, or hypertension. Both compounds increased force of contraction in isolated rat cardiac tissues, although the ventricular response to EMD 57439 was only approximately 10% that of calcium chloride. Forskolin pretreatment potentiated responses to both compounds in atria but only to EMD 57439 in ventricles. Hyperthyroidism increased ventricular responses to EMD 57033 relative to calcium chloride; hypothyroidism and diabetes decreased these responses. Ventricular responses were unchanged in hypertensive rats. Both enantiomers produced positive inotropy in human isolated right atrial trabeculae, although the maximal increases were only 14% (EMD 57033) and 26% (EMD 57439) that of calcium chloride. In rat thoracic aortic rings, both enantiomers produced relaxation; the responses due to EMD 57033 were endothelium dependent. Thus, calcium sensitization produces positive inotropy and vascular relaxation in rats. Positive chronotropic responses to EMD 57033 are most likely due to PDE inhibition. The limited inotropic response in severely failing human myocardium, together with possible vasorelaxation, may provide cardiac support in heart failure without an excessive increase in cardiac O2 demand.
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PMID:Calcium sensitization as a positive inotropic mechanism in diseased rat and human heart. 752 44

The novel cardiotonic EMD 53,998 increases contractile force in vitro through both inhibition of phosphodiesterase III (PDE III) activity and increase in the responsiveness of the contractile proteins to calcium ("calcium sensitization"). Because EMD 53,998 is a racemate, the possibility arose that the two modes of action do not reside equally in the enantiomers. Therefore, the effects of the racemate and its two enantiomers [(+)EMD 57,033 and (-)EMD 57,439] were analyzed in guinea pig and rat cardiac tissue with respect to Ca2+ sensitization (Ca(2+)-induced force development in skinned cardiac myofibers and myofibrillar ATPase activity) and PDE III inhibition (isolated PDE isoenzymes and cyclic AMP level in isolated cardiac myocytes). In addition, the positive inotropic effects were compared in isometrically contracting papillary muscles. Enhancement of force of contraction (Fc) in submaximally activated skinned fibers showed a selectivity for the (+)enantiomer with EC50 = 1.7, 4.8, and > 100 microM for EMD 57,033, EMD 53,998, and EMD 57,439, respectively. Ca2+ concentration for half-maximal activation was decreased by 0.5 log units, and Cmax was increased by 15% at 10 microM EMD 57,033. Similarly, myofibrillar ATPase activity was most potently enhanced by the (+)enantiomer, with EC50 values of 1.8, 2.5, and > 30 microM for EMD 57,033, EMD 53,998, and EMD 57,439, respectively. PDE III activity was inhibited with greater potency by the (-)enantiomer, with IC50 values of 0.05, 0.06, and 1.94 microM for EMD 57,439, EMD 53,998, and EMD 57,033, respectively. The cyclic AMP content of isoprenaline-stimulated rat cardiac myocytes was increased by 50% at 13.6 and 0.71 microM for EMD 57,033 and EMD 57,439, respectively. In intact guinea pig papillary muscle, the positive inotropic effect of the (+)enantiomer was insensitive to isoprenaline pretreatment; in contrast, the (-)enantiomer showed only a weak positive inotropic action which was strongly enhanced in the presence of isoprenaline. We conclude that one of the two different mechanisms underlying the overall positive inotropic activity of EMD 53,998 can be assigned, almost exclusively, to one of the two enantiomers. Thus, the (-)enantiomer EMD 57,439 is a "pure" PDE III inhibitor with almost no Ca2+ sensitizing activity; the (+)enantiomer EMD 57,033 is a potent Ca2+ sensitizer with only a weak PDE III inhibitory activity as compared with the racemate. In contrast to other compounds with mixed activity, EMD 57,033 is unique in possessing both a high absolute potency at the level of the contractile elements and a favorable relation of Ca2+ sensitization to PDE inhibition.
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PMID:The two mechanisms of action of racemic cardiotonic EMD 53998, calcium sensitization and phosphodiesterase inhibition, reside in different enantiomers. 768 12

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

Thiadiazinones are cardiotonic agents that have potent, direct, and stereoselective actions on the myofilament response to Ca2+ in intact myocardium. Their mechanism of action is unknown. We studied the effects of racemic thiadiazinone, EMD 53998 (5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolyl]-6-meth yl-3,6- dihydro-2H-1,3,4-thiadiazin-2-one), and its enantiomers on Ca2+ signaling in myocytes, myofilaments, and myofilament proteins. Intact canine ventricular myocytes responded to the positive enantiomer, EMD 57033, with an increase in the extent of shortening during twitch contractions without increasing the peak amplitude of the Ca2+ transient. The negative enantiomer, EMD 57439, also increased the extent of shortening, but in this case there was a concentration-dependent increase in the peak amplitude of the Ca2+ transient. This is predicted from in vitro data showing that this enantiomer is a relatively potent inhibitor of phosphodiesterase activity. There was no effect of EMD 57439 on the relation between pCa and actomyosin Mg-ATPase activity of canine heart myofibrils. In contrast, EMD 57033 shifted the pCa-Mg-ATPase activity relation to the left. There was no effect of either enantiomer on Ca2+ binding to myofilament troponin C. Moreover EMD 57033, but not EMD 57439, stimulated actomyosin ATPase activity of myofilament preparations in which either troponin or troponin-tropomyosin had been extracted. EMD 57033 had no effect on Mg-ATPase activity of pure ventricular myosin. EMD 57033 also stimulated the velocity of actin filament sliding on myosin heads adhered to nitrocellulose-coated glass coverslips. We propose that the action of EMD 57033 is at the actin-myosin interface on a "receptor" that may be on actin or the crossbridge. Drug binding to this domain appears to reverse the inhibition of actin-myosin interactions by troponin-tropomyosin and also to promote transition of crossbridges from weak to strong force-generating states.
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PMID:Stereoselective actions of thiadiazinones on canine cardiac myocytes and myofilaments. 822 92

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

Inotropic agents are used widely for pharmacological bridging of the failing heart either until recovery after surgical intervention or until transplantation. EMD 57033 is a novel specific Ca++ sensitizing agent with purportedly minor phosphodiesterase (PDE) III-inhibiting properties. It acts as an inotropic agent without raising intracellular Ca++ levels. In turn, the PDE III-inhibitor enoximone has been used for several years to treat low cardiac output syndrome. However, little is known about its effects on postischemic reperfused (stunned) myocardium. We investigated the effects of EMD 57033 (EMD; 30 microM) and enoximone (E20 micrograms/ml) on stunned myocardium. The experiments were performed on 16 isolated rabbit hearts perfused with an erythrocyte suspension (hematocrit = 30%; [Ca++] = 2.5 mM). Hearts were reperfused after a 20 min no-flow ischemia. Measurements were performed at control, 30 min after the onset of reperfusion, and after administration of one of the drugs. Both agents significantly improved the depressed systolic function [left ventricular pressure (LVP)max from 61 +/- 12 to 93 +/- 18 mmHg, and its derived pressure (dP/dt)max from 860 +/- 220 to 1340 +/- 300 mmHg/s and LVPmax from 78 +/- 9 to 83 +/- 15 mmHg, and its derivative dP/dtmax from 1040 +/- 230 to 1385 +/- 300 mmHg/s, respectively] and early relaxation (dP/dtmin from 810 +/- 250 to 1260 +/- 345 mmHg/s and from 1000 +/- 200 to 1135 +/- 295 mmHg/s, respectively) that occurred during postischemic reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison between the effects of a novel Ca++ sensitizer and a phosphodiesterase inhibitor on stunned myocardium. 853 Nov 13


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