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)

We characterized the Ca2+-sensitizing and phosphodiesterase (PDE)-inhibitory potentials of levosimendan and enoximone to assess their contributions to the positive inotropic effects of these drugs. In guinea pig hearts perfused in the working-heart mode, the maximal increase in cardiac output (55%, P<0.05) was attained at 50 nM levosimendan. The corresponding value for enoximone (36%) was significantly smaller (P<0.05) and was observed at a higher concentration (500 nM). In permeabilized myocyte-sized preparations levosimendan evoked a maximal increase of 55.8+/-8% (mean+/-SEM) in isometric force production via Ca2+ sensitization (pCa 6.2, EC50 8.4 nM). Enoximone up to a concentration of 10 microM failed to influence the isometric force. The PDE-inhibitory effects were probed on the PDE III and PDE IV isoforms. Levosimendan proved to be a 1300-fold more potent and a 90-fold more selective PDE III inhibitor (IC50 for PDE III 1.4 nM, and IC50 for PDE IV 11 microM, selectivity factor approximately 8000) than enoximone (IC50 for PDE III 1.8 microM, and IC50 for PDE IV 160 microM, selectivity factor approximately 90). Hence, our data support the hypothesis that levosimendan exerts positive inotropy via a Ca2+-sensitizing mechanism, whereas enoximone does so via PDE inhibition with a limited PDE III versus PDE IV selectivity.
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PMID:Two inotropes with different mechanisms of action: contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone. 1611 44

To-date positive inotropic therapy in the treatment of congestive heart failure has resulted in adverse effects on long term survival. These agents increase calcium cycling through beta-adrenergic stimulation or phosphodiesterase inhibition. An alternative method of producing positive inotropy is to increase the myofilament sensitivity to calcium. This can occur at several levels within the myofilament, and has potential benefits with respect to avoiding increased calcium cycling and producing a more favourable energy efficient positive inotropy. A potential adverse effect of increasing calcium sensitivity is slowed relaxation and diastolic dysfunction. We have learnt a considerable amount about the function of specific sites within the myofilament by the use of genetically engineered mouse models, which have shown diverse effects of various myofilament sites on global left ventricular function. Levosimendan is a novel inotropic agent that has several mechanisms of action including calcium sensitization, and is undergoing clinical trials at present. This review article will provide a comprehensive molecular, biophysical and physiological insight into the concepts underlying the myofilament force-calcium relationship and its potential as a target for positive inotropic therapy in heart failure.
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PMID:The myofilament force-calcium relationship as a target for positive inotropic therapy in congestive heart failure. 1614 98

In order to clarify the mechanisms of the positive inotropic actions of levosimendan and its optical isomer, dextrosimendan, we compared their concentration-dependent effects in intact papillary muscles, permeabilized cardiomyocytes and in purified phosphodiesterase enzyme preparations of guinea-pig hearts. In papillary muscles twitch tension increased with EC50 values of 60 nM and 2.8 microM for levosimendan and dextrosimendan, respectively. Hence, the two enantiomers exhibited a 47 times potency difference in their positive inotropic effects in a preparation where theoretically Ca2+-sensitization and phosphodiesterase inhibition could both contribute to the positive inotropic effects. In guinea-pig cardiomyocytes, levosimendan and dextrosimendan increased isometric force production (at pCa 6.2) due to Ca2+-sensitization with EC50 values of 8.4 nM and 0.64 microM, respectively, with a similar relative potency difference of 76. A major difference appeared in their relative pharmacological potencies, however, when the inhibitory effects of the two enantiomers were assayed on phosphodiesterase III, purified from guinea pig left ventricle (i.e. the phosphodiesterase isoenzyme which is dominant in that tissue). Levosimendan was a 427 times more potent phosphodiesterase inhibitor than dextrosimendan, with IC50 values of 7.5 nM, and 3.2 microM, respectively. Taken together, our data support the hypothesis that levosimendan and dextrosimendan exert their positive inotropic effects via a stereoselective Ca2+-sensitizing mechanism and not via stereoselective inhibition of phosphodiesterase III in the myocardium.
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PMID:Positive inotropic effect of levosimendan is correlated to its stereoselective Ca2+-sensitizing effect but not to stereoselective phosphodiesterase inhibition. 1643 95

Several clinical studies suggest substantial limitations of currently available positive inotropic substances, including beta1-adrenoceptor agonists and phosphodiesterase III inhibitors in the short- and long-term treatment of heart failure. The reasons for these detrimental effects are related to the mechanism of action of these drugs, including increases in intracellular Ca2+ with subsequent increases in myocardial oxygen demand and arrhythmogenesis. Levosimendan, a myofilament Ca2+ sensitizer with inotropic effects, increases myocardial performance without substantial changes in oxygen consumption and with neutral effects on heart rhythm. In addition, levosimendan has vasodilatory effects that are achieved by stimulation of adenosine triphosphate-dependent potassium channels. This action may be of specific interest in the setting of myocardial ischemia. To date, levosimendan is approved in 31 countries worldwide, and more patients with heart failure have participated in randomized controlled trials with levosimendan than with any other intravenous inotropic agent.
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PMID:Levosimendan, a new inotropic and vasodilator agent. 1650 4

Phosphodiesterase inhibitors as inodilators in heart failure are associated with promotion of arrhythmias. Calcium sensitizers have been proposed for the treatment of severe decompensated heart failure. The effect of levosimendan, a calcium sensitizer, and milrinone, a phosphodiesterase inhibitor, on ventricular arrhythmias was compared in a model of acute regional myocardial ischemia and reperfusion. The left anterior descending coronary artery in dogs was occluded for 25 minutes, followed by reperfusion. The 2 drugs were administered in a hemodynamically equieffective dose (0.1 micromol/kg) 10 minutes before coronary occlusion. Levosimendan, but not milrinone, significantly attenuated the pronounced increase in the number of ventricular premature beats (-63%), tachycardia (-50%), fibrillation (-70%), and inhomogeneity of ventricular electrical activation. Levosimendan significantly improved the overall survival rate. Levosimendan has a more beneficial profile than milrinone regarding the development of ventricular arrhythmias during and after regional myocardial ischemia.
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PMID:Effect of levosimendan and milrinone on regional myocardial ischemia/reperfusion-induced arrhythmias in dogs. 1689 Dec 90

Levosimendan is a calcium sensitizer that is currently in the focus of intensive care medicine because it may be superior to standard inotropic agents in the treatment of acute myocardial insufficiency. The effects of levosimendan mainly depend on three predominant mechanisms: 1) positive inotropic effect by increasing the sensitivity of cardiac myofilaments to calcium ions, 2) vasodilatory effect by stimulation of adenosine triphosphate-sensitive potassium channels and 3) inhibition of phosphodiesterase-III. In a large number of experimental and clinical studies further possible indications for levosimendan have been described, e.g. cardioprotection during ischemia, cardiogenic shock, septic myocardial insufficiency and pulmonary hypertension. This review article critically summarizes the current scientific and clinical knowledge about levosimendan, its pharmacologic characteristics, mechanisms of action as well as indications and potential risks.
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PMID:[Role of Levosimendan in intensive care treatment of myocardial insufficiency]. 1713 Nov 37

Heart failure is a relatively important public health problem due to its increasing incidence, poor prognosis, and frequent need of re-hospitalization. Intravenous positive inotropic agents play an important role in treating acute decompensation of patients with heart failure due to left ventricular systolic dysfunction. Although frequently used, the inotropic agents beta-adrenergic agonists and phosphodiesterase inhibitors seem effective for improving symptoms in the short term; it has been shown that they increase morbidity and mortality by elevating intracellular cyclic adenosine monophosphate (cAMP) and calcium levels. Levosimendan is a new positive inotropic agent having ATP-dependent potassium-channel-opening and calcium-sensitizing effects. In studies on its effects without increasing intracellular calcium concentrations and on its effects that depend on available intracellular calcium levels, it has been shown to have favorable characteristics different from those of current inotropic agents, which exert their effects by increasing calcium concentrations. This study aims to review other important studies about levosimendan by revealing the underlying mechanisms of its activity, efficiency, and safety.
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PMID:A review of levosimendan in the treatment of heart failure. 1732 93

Levosimendan is a new calcium sensitizer with inotropic and vasodilatory actions mediated by the sensitization of contractile proteins to calcium, opening of potassium channels and inhibition of phosphodiesterase-3. Its alternative mechanisms of action to those of other traditional inotropes provide a new approach in the management of decompensated heart failure. In contrast to dobutamine, levosimendan does not increase myocardial oxygen demand and, therefore, it is thought to have a lower potential to induce increases in myocardial ischemia and cardiac arrhythmias. The commonly used inotropic agent dobutamine increases myocardial contractility at the expense of increased myocardial oxygen consumption and, therefore, it can result in poor outcomes. Although dobutamine may also have favorable hemodynamic and symptomatic effects, levosimendan has been shown to be superior to dobutamine in increasing cardiac output and decreasing pulmonary capillary wedge pressure in patients with decompensated heart failure. In the presence of concomitant beta-blocker therapy, these favorable effects were present or even more pronounced during treatment with levosimendan, but not dobutamine. However, the mortality benefit of levosimendan observed in earlier trials has not been confirmed in recent, larger clinical trials. A distinct advantage of levosimendan over dobutamine is its prolonged hemodynamic effects, which last for up to 7-9 days. There are more data on the safety of levosimendan in ischemic patients than with any other inotropic drug and, therefore, levosimendan seems to be safe and effective in patients with ischemic heart disease when used at the recommended doses. Despite advances in heart failure therapy, many patients experience clinical deterioration, or do not respond to a single inotropic drug. Increasing evidence suggests the use of levosimendan in combination with dobutamine in patients with decompensated heart failure that is refractory to dobutamine alone.
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PMID:The use of levosimendan in comparison and in combination with dobutamine in the treatment of decompensated heart failure. 1737 21

Levosimendan, a novel agent developed for the treatment of acute and decompensated heart failure, exerts potent positive inotropic action and peripheral vasodilatory effects. The mechanism of vasodilation by levosimendan may involve reduction of Ca2+ sensitivity of contractile proteins in vascular smooth muscle, the lowering of intracellular free Ca2+, the potential inhibition of phosphodiesterase (PDE) III, and an opening of K+ channels. Although the importance and relative contribution of each of these mechanisms of vasorelaxation is unclear and may be different in various vessels and dependent on the dose of levosimendan, the important roles of K+-channel opening and Ca2+ desensitization in vascular smooth muscle are obvious, whereas the role of PDE inhibition remains to be defined. This review article briefly discusses the current research data on the mechanism of levosimendan-induced vasodilation with an emphasis on the types of the blood vessels and the K+ channels. It also summarizes the current experimental and clinical knowledge of the use of levosimedan in the treatment of heart failure.
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PMID:Vasodilating mechanisms of levosimendan: involvement of K+ channels. 1745 12

Levosimendan enhances cardiac contractility via Ca(2+) sensitization and induces vasodilation through the activation of ATP-dependent K(+) and large-conductance Ca(2+)-dependent K(+) channels. However, the hemodynamic effects of levosimendan, as well as its metabolites, OR-1896 and OR-1855, relative to plasma concentrations achieved, are not well defined. Thus levosimendan, OR-1896, OR-1855, or vehicle was infused at 0.01, 0.03, 0.1, and 0.3 mumol.kg(-1).30 min(-1), targeting therapeutic to supratherapeutic concentrations of total levosimendan (62.6 ng/ml). Results were compared with those of the beta(1)-agonist dobutamine and the phosphodiesterase 3 inhibitor milrinone. Peak concentrations of levosimendan, OR-1896, and OR-1855 were 455 +/- 21, 126 +/- 6, and 136 +/- 6 ng/ml, respectively. Levosimendan and OR-1896 produced dose-dependent reductions in mean arterial pressure (-31 +/- 2 and -42 +/- 3 mmHg, respectively) and systemic resistance without affecting pulse pressure, effects paralleled by increases in heart rate; OR-1855 produced no effect at any dose tested. Dobutamine, but not milrinone, increased mean arterial pressure and pulse pressure (17 +/- 2 and 23 +/- 2 mmHg, respectively). Regarding potency to elicit reductions in time to peak pressure and time to systolic pressure recovery: OR-1896 > levosimendan > milrinone > dobutamine. Levosimendan and OR-1896 elicited dose-dependent increases in change in pressure over time (118 +/- 10 and 133 +/- 13%, respectively), concomitant with reductions in left ventricular end-diastolic pressure and ejection time. However, neither levosimendan nor OR-1896 produced increases in myocardial oxygen consumption at inotropic and vasodilatory concentrations, whereas dobutamine increased myocardial oxygen consumption (79% above baseline). Effects of the levosimendan and OR-1896 were limited to the systemic circulation; neither compound produced changes in pulmonary pressure, whereas dobutamine produced profound increases (74 +/- 13%). Thus levosimendan and OR-1896 are hemodynamically active in the anesthetized dog at concentrations observed clinically and elicit cardiovascular effects consistent with activation of both K(+) channels and Ca(2+) sensitization, whereas OR-1855 is inactive on endpoints measured in this study.
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PMID:Comparative effects of levosimendan, OR-1896, OR-1855, dobutamine, and milrinone on vascular resistance, indexes of cardiac function, and O2 consumption in dogs. 1798 6


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