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)

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

This review is concerned with the roles of cyclic GMP and Ca(2+) ions in signal transduction for chemotaxis of Dictyostelium. These molecules are involved in signalling between the cell surface cyclic AMP receptors and cytoskeletal myosin II involved in chemotactic cell movement. Evidence is presented for uptake and/or efflux of Ca(2+) being regulated by cyclic GMP. The link between Ca(2+), cyclic GMP and chemotactic cell movement has been explored using "streamer F" mutants whose primary defect is in the structural gene for the cyclic GMP-specific phosphodiesterase. This mutation causes the mutants to produce an abnormally prolonged peak of cyclic GMP accumulation in response to stimulation with the chemoattractant cyclic AMP. The production and relay of cyclic AMP signals is normal in these mutants, but certain events associated with movement are (like the cyclic GMP response) abnormally prolonged in the mutants. These events include Ca(2+) uptake, myosin II association with the cytoskeleton and regulation of both myosin heavy and light chain phosphorylation. These changes can be correlated with changes in the shape of the amoebae after chemotactic stimulation. Other mutants in which the accumulation of cyclic GMP in response to cyclic AMP stimulation was absent produced no myosin II responses. A model is described in which cyclic GMP (directly or indirectly via Ca(2+) regulates accumulation of myosin II on the cytoskeleton by regulating phosphorylation of the myosin heavy and light chain kinases.
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PMID:Signal transduction and motility of Dictyostelium. 915 75

The flux of multisized fluorescein-isothiocyanate-labeled hydroxy ethyl starch (FITC-HES) macromolecules was used to assess changes in barrier function of rat pulmonary microvascular endothelial cell (RPMVEC) monolayers exposed to protein phosphatase (PP) inhibitors or cGMP analogs and atriopeptin (ANF). Two potent PP inhibitors, calyculin A (CalA) and okadaic acid (OA), increased RPMVEC permeability in a dose- and time-dependent manner, and CalA had a higher intrinsic activity than OA. In contrast, ANF and potent cGMP analogs had no effect on basal RPMVEC permeability. The phosphohistone PP activity contained in RPMVEC sonicates was inhibited by OA with an inhibition profile that suggested at least two components were present, with PP2A accounting for approximately 70% of the OA-inhibitable phosphohistone phosphatase activity. Following separation with heparin-Sepharose chromatography, PP activity exhibited equipotent inhibition by CalA and differential inhibition by OA. Differential inhibition of PP1 and PP2A by OA suggested that PP1 is involved in regulating RPMVEC barrier function. Permeabilized RPMVEC showed increased phosphorylation of several proteins in the presence of phosphatase inhibitors. Treatment with KT 5926, a myosin light chain (MLC) kinase (MLCK) inhibitor, or rolipram, a phosphodiesterase inhibitor, decreased 32P incorporation into immunoprecipitated MLC by CalA and OA. However, this effect did not abolish either the CalA- or OA-induced decrease in the RPMVEC barrier function. Localization of filamentous (F) actin was at the periphery as well as in the cytoplasm and perinuclear region, whereas nonmuscle myosin was seen in the perinuclear region. Neither of these patterns was changed in the presence of CalA. Thus, cGMP does not alter RPMVEC permeability, but inhibition of PP activity results in loss of barrier function by a mechanism independent from MLC phosphorylation.
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PMID:Inhibition of serine-threonine protein phosphatases decreases barrier function of rat pulmonary microvascular endothelial cells. 918 Aug 95

Intracellular accumulation of inorganic phosphate (Pi) and intracellular acidosis, which occur in ischemic and hypoxic hearts, reduce the force of contraction by decreasing the responsiveness of contractile system to Ca2+. In the present study we investigated the effects of MCI-154, a Ca2+ sensitizer that can enhance crossbridge interaction, on the decline in maximal Ca2+-activated force by Pi or acidic pH in skinned fiber bundles of guinea pig hearts. MCI-154 can concentration-dependently reverse the depression in maximal Ca2+-activated force (pCa 4.4) by 20 mM Pi, which was not recovered by a higher concentration of Ca2+ ion (pCa 4.0). The effects of MCI-154 were observed even at a concentration (0.01 M) at which the drug has no effect on the pCa 4.4-induced maximal force in the absence of 20 mM Pi when given alone. MCI-154 inhibited the rightward shift of the pCa-tension relationships, with a marked decrease of maximal force produced by 20 mM Pi or acidic pH (decrease in pH from 7.0 to 6.6). MCI-154 also improved the decline in maximal Ca2+-activated force by 20 mM Pi under acidic pH, but the acidosis did not further decrease the effect of 20 mM Pi. Milrinone, a cyclic AMP-dependent phosphodiesterase inhibitor, and pimobendan, another Ca2+ sensitizer, did not improve the Pi-induced contractile failure. These results indicate that the Ca2+ sensitizer MCI-154 could reverse the contractile failure induced by Pi and/or acidic pH in a skinned fiber preparation via modulation of the strong crossbridge reaction with myosin. MCI-154 may be a promising agent for myocardial contractile failure, in which Pi and H+ progressively increase.
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PMID:MCI-154, a cardiac Ca2+ sensitizer, reverses the depression in maximal Ca2+-activated force by inorganic phosphate and acidic pH in skinned fiber of guinea pig heart. 949 98

Congestive heart failure (CHF) is a common cardiovascular disorder that is characterised, in part, by a decreased cardiac output reserve. Accordingly, there is ongoing interest in the role of positive inotropic agents (e.g. adrenergic agonists and phosphodiesterase type III inhibitors, which mediate their cardiovascular effects via a cyclic adenosine monophosphate-dependent mechanism) in the treatment of CHF. However, enthusiasm for positive inotropic therapy in CHF has been dampened by the results of clinical trials, which have shown that these drugs are associated with an increased risk of mortality. Calcium sensitising agents are a heterogeneous group of positive inotropic agents that mediate their cardiovascular actions (at least in part) by increasing the sensitivity of the contractile elements to calcium. Increased sensitivity to calcium may be related to changes in calcium binding to troponin C, or to direct effects on the actin-myosin complex. In addition, the inhibition of phosphodiesterase type III may contribute to the positive inotropic action of calcium sensitising agents. Five agents with calcium sensitising properties (pimobendan, levosimendan, MCI-154, EMD-53998 and CGP-48506) have been studied as possible therapies for CHF. All of these agents have demonstrated a positive inotropic action in isolated cardiac tissue and in animal models of CHF. In clinical trials, pimobendan, the most extensively studied of these drugs, was well tolerated and was associated with improved exercise tolerance during the first 6 months of therapy; however, it was also associated with a nonsignificant trend towards increased mortality. Because many of the calcium sensitising agents also inhibit phosphodiesterase type III activity, the long term safety of these agents is uncertain. Large-scale survival trials are required to determine the long term safety and efficacy of these agents before their role in the treatment of CHF can be defined.
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PMID:Calcium sensitising agents in heart failure. 953 20

Physiological and pharmacological interventions are used to regulate cardiac contractile functions via modulation of Ca2+ signaling. The relevant regulatory mechanisms have recently been assessed in detail by use of novel experimental procedures, which include simultaneous measurements of intracellular levels of Ca2+ ions and contractile force in intact myocardial preparations loaded with the intracellular Ca2+ indicator aequorin and fluorescent dyes, namely, fura-2, indo-1 and fluo-3. Association with or dissociation from intracellular Ca2+ transients of contractile activity is taken as evidence that reflects the primary mechanism of action of individual inotropic interventions. In addition, motility assays of actin-myosin interactions in vitro have made it possible to define the site of action of Ca2+ sensitizers as troponin C and the interaction of the troponin-tropomyosin complex with actin or the actin-myosin interface at crossbridges. Frank-Starling mechanism operates at the level of the binding of Ca2+ ions to troponin C and subsequent regulatory processes, while the force-frequency relationship is mainly ascribed to an alteration in the intracellular mobilization of Ca2+ ions. Cardiotonic agents can be classified as follows: 1) agents that act via a cyclic AMP-dependent or a cyclic AMP-independent mechanism; and 2) agents that facilitate the intracellular mobilization of Ca2+ ions or increase in myofibrillar sensitivity to Ca2+ ions. Regulatory mechanisms mediated via the phosphorylation of functional proteins induced by cyclic AMP, which is responsible for the actions of novel cardiotonic agents, beta 1-adrenoceptor partial agonist and selective inhibitors of phosphodiesterase (PDE) III, have currently been clarified in more detail. Ca2+ sensitizers are of extreme therapeutic interest because of their ability to increase myocardial contractility without an increase in activation energy; they are devoid of risks of arrhythmogenicity and myocardial cell death from intracellular Ca2+ overload; and they effectively reverse contractile dysfunction under pathophysiological situations, such as acidosis or myocardial stunning.
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PMID:Changes in intracellular Ca2+ mobilization and Ca2+ sensitization as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells. 960 80

Levosimendan is a pyridazinone-dinitrile derivative belonging to a new class of cardiac inotropic drugs, Ca++ sensitizers. Levosimendan is also a vasodilator both in vitro and in vivo, but its mechanism is not well understood. The cardiac target protein of levosimendan, troponin C, is a Ca++-binding EF-hand protein. This raises the possibility that levosimendan may also interact with smooth muscle EF-hand proteins, such as, calmodulin, the regulatory myosin light chains, or S100 proteins. We investigated the effects of levosimendan on [Ca++]i, and force in porcine coronary arteries, with receptor-mediated (U46619) or KCl stimulation. At high levels of stimulation, levosimendan decreased force without changing or increasing [Ca++]i, measured with the Ca++-sensitive fluorescent probe fura-2 in the intact artery. With lower levels of U46619, levosimendan (1 microM) lowered force by 70% and reduced [Ca++]i by 38%. The relationship between force and [Ca++]i for KCl stimulation are significantly rightward shifted, indicating Ca++ desensitization by levosimendan. In contrast, the phosphodiesterase III inhibitor, milrinone, does not shift the force-Ca++ relations but elicits relaxation via lowering [Ca++]i. There was little change in pHi, indicating that the Ca++ desensitization by levosimendan was not attributable to decreasing pHi. Levosimendan relaxes coronary arteries and lowers [Ca++]i by mechanisms different than milrinone. Our results indicate a lowering of [Ca++]i by levosimendan consistent with opening of potassium channels and a relaxation that is independent of [Ca++]i. Our evidence points to a novel mechanism that might involve the direct effect of levosimendan on the smooth muscle contractile or regulatory proteins themselves.
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PMID:Levosimendan, a calcium sensitizer in cardiac muscle, induces relaxation in coronary smooth muscle through calcium desensitization. 986 86

Cyclic nucleotide-dependent vasorelaxation is associated with increases in the phosphorylation of a small heat shock-related protein, HSP20. We hypothesized that phosphorylation of HSP20 in vascular smooth muscles is associated with alterations in the macromolecular associations of HSP20. Treatment of bovine carotid artery smooth muscles with the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, and the adenylate cyclase activator, forskolin, led to increases in the phosphorylation of HSP20 and dissociation of macromolecular aggregates of HSP20. However, 3-isobutyl-1-methylxanthine and forskolin treatment of a muscle that is uniquely refractory to cyclic nucleotide-dependent vasorelaxation, human umbilical artery smooth muscle, did not result in increases in the phosphorylation of HSP20 or to dissociation of macromolecular aggregates. HSP20 can be phosphorylated in vitro by the catalytic subunit of cAMP-dependent protein kinase (PKA) in both carotid and umbilical arteries and this phosphorylation of HSP20 is associated with dissociation of macromolecular aggregates of HSP20. Activation of cyclic nucleotide-dependent signaling pathways does not lead to changes in the macromolecular associations of another small heat shock protein, HSP27. Interestingly, the myosin light chains (MLC20) are in similar fractions as the HSP20, and phosphorylation of HSP20 is associated with changes in the macromolecular associations of MLC20. These data suggest that increases in the phosphorylation of HSP20 are associated with changes in the macromolecular associations of HSP20. HSP20 may regulate vasorelaxation through a direct interaction with specific contractile regulatory proteins.
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PMID:Phosphorylation of the small heat shock-related protein, HSP20, in vascular smooth muscles is associated with changes in the macromolecular associations of HSP20. 1003 21

Phototransduction in Drosophila is mediated by a G-protein-coupled phospholipase C transduction cascade in which each absorbed photon generates a discrete electrical event, the quantum bump. In whole-cell voltage-clamp recordings, cAMP, as well as its nonhydrolyzable and membrane-permeant analogs 8-bromo-cAMP (8-Br-cAMP) and dibutyryl-cAMP, slowed down the macroscopic light response by increasing quantum bump latency, without changes in bump amplitude or duration. In contrast, cGMP or 8-Br-cGMP had no effect on light response amplitude or kinetics. None of the cyclic nucleotides activated any channels in the plasma membrane. The effects of cAMP were mimicked by application of the non-specific phosphodiesterase inhibitor IBMX and the adenylyl cyclase activator forskolin; zaprinast, a specific cGMP-phosphodiesterase inhibitor, was ineffective. Bump latency was also increased by targeted expression of either an activated G(s) alpha subunit, which increased endogenous adenylyl cyclase activity, or an activated catalytic protein kinase A (PKA) subunit. The action of IBMX was blocked by pretreatment with the PKA inhibitor H-89. The effects of cAMP were abolished in mutants of the ninaC gene, suggesting this nonconventional myosin as a possible target for PKA-mediated phosphorylation. Dopamine (10 microM) and octopamine (100 microM) mimicked the effects of cAMP. These results indicate the existence of a G-protein-coupled adenylyl cyclase pathway in Drosophila photoreceptors, which modulates the phospholipase C-based phototransduction cascade.
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PMID:Modulation of the light response by cAMP in Drosophila photoreceptors. 1051 99

Dictyostelium strains in which the gene encoding the cytoplasmic cAMP phosphodiesterase RegA is inactivated form small aggregates. This defect was corrected by introducing copies of the wild-type regA gene, indicating that the defect was solely the consequence of the loss of the phosphodiesterase. Using a computer-assisted motion analysis system, regA(-) mutant cells were found to show little sense of direction during aggregation. When labeled wild-type cells were followed in a field of aggregating regA(-) cells, they also failed to move in an orderly direction, indicating that signaling was impaired in mutant cell cultures. However, when labeled regA(-) cells were followed in a field of aggregating wild-type cells, they again failed to move in an orderly manner, primarily in the deduced fronts of waves, indicating that the chemotactic response was also impaired. Since wild-type cells must assess both the increasing spatial gradient and the increasing temporal gradient of cAMP in the front of a natural wave, the behavior of regA(-) cells was motion analyzed first in simulated temporal waves in the absence of spatial gradients and then was analyzed in spatial gradients in the absence of temporal waves. Our results demonstrate that RegA is involved neither in assessing the direction of a spatial gradient of cAMP nor in distinguishing between increasing and decreasing temporal gradients of cAMP. However, RegA is essential for specifically suppressing lateral pseudopod formation during the response to an increasing temporal gradient of cAMP, a necessary component of natural chemotaxis. We discuss the possibility that RegA functions in a network that regulates myosin phosphorylation by controlling internal cAMP levels, and, in support of that hypothesis, we demonstrate that myosin II does not localize in a normal manner to the cortex of regA(-) cells in an increasing temporal gradient of cAMP.
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PMID:The internal phosphodiesterase RegA is essential for the suppression of lateral pseudopods during Dictyostelium chemotaxis. 1093 Apr 71


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