Metabolite OR-1896 Research Articles

Monitoring of Levosimendan Administration in Patients with Pulmonary Hypertension Undergoing Cardiac Surgery and Effect of Two Different Dosing Schemes on Hemodynamic and Echocardiographic Parameters.

The perioperative management of patients with pulmonary hypertension (PH) undergoing cardiac surgery represents one of the most challenging clinical scenarios. This fact mainly depends on the relationship existing between PH and right ventricular failure (RVF). Levosimendan (LS) is an inodilator that might be an effective agent in the treatment of PH and RVF. The aim of this study was to examine the impact of the duration of cardiopulmonary bypass (CPB) on the therapeutic drug monitoring of LS and to evaluate the effect of preemptive administration of LS on perioperative hemodynamic and echocardiographic parameters in cardiac surgical patients with preexisting PH. In this study, LS was administered in adult patients undergoing cardiac surgery before CPB in order to prevent exacerbation of preexisting PH and subsequent right ventricular dysfunction. Thirty cardiac surgical patients with preoperatively confirmed PH were randomized to receive either 6 μg/kg or 12 μg/kg of LS after the induction of anesthesia. The plasma concentration of LS was measured after CPB. In this study, a low sample volume was used combined with a simple sample preparation protocol. The plasma sample was extracted by protein precipitation and evaporated; then, the analyte was reconstituted and detected using specific and sensitive bioanalytical liquid chromatography with mass spectrometry (LC-MS/MS) methodology. The clinical, hemodynamic, and echocardiographic parameters were registered and evaluated before and after the administration of the drug. A fast bioanalytical LC-MS/MS methodology (a run time of 5.5 min) was developed for the simultaneous determination of LS and OR-1896, its main metabolite in human plasma. The LC-MS/MS method was linear over a range of 0.1-50 ng/mL for LS and 1-50 ng/mL for its metabolite OR-1896. Measured plasma concentrations of LS were inversely related to the duration of CPB. LS administration before CPB during cardiac surgery was effective in reducing pulmonary artery pressure and improving hemodynamic parameters after CPB, with a more pronounced and durable effect of the drug at the dose of 12 μg/kg. Additionally, administration of LS at a dose of 12 μg/kg in cardiac surgical patients with PH before CPB improved right ventricular function. LS administration decreases pulmonary artery pressure and may improve right ventricular function in patients with PH undergoing cardiac surgery.

The Effects of the Levosimendan Metabolites OR-1855 and OR-1896 on Endothelial Pro-Inflammatory Responses

The calcium sensitizer levosimendan is used for the treatment of acute decompensated heart failure. A small portion (4-7%) of levosimendan is metabolized to the pharmacologically active metabolite OR-1896 via the inactive intermediate OR-1855. In addition, levosimendan has been shown to exert positive effects on the endothelium in vitro antagonizing vascular dysfunction and inflammation. However, the function of the levosimendan metabolites within this context is still unknown. In this study, we thus investigated the impact of the metabolites OR-1896 and OR-1855 on endothelial inflammatory processes in vitro. We observed a reduction of IL-1β-dependent endothelial adhesion molecule ICAM-1 and VCAM-1 as well as interleukin (IL) -6 expression upon levosimendan treatment but not after treatment with OR-1855 or OR-1896, as assessed by western blotting, flow cytometry, and qRT-PCR. Instead, the metabolites impaired IL-1β-induced ROS formation via inactivation of the MAPK p38, ERK1/2, and JNK. Our results suggest that the levosimendan metabolites OR-1896 and OR-1855 have certain anti-inflammatory properties, partly other than levosimendan. Importantly, they additionally show that the intermediate metabolite OR-1855 does, in fact, have pharmacological effects in the endothelium. This is interesting, as the metabolites are responsible for the long-term therapeutic effects of levosimendan, and heart failure is associated with vascular dysfunction and inflammation.

Population Pharmacokinetics of Levosimendan and its Metabolites in Critically Ill Neonates and Children Supported or Not by Extracorporeal Membrane Oxygenation.

Levosimendan (LVSMD) is a calcium-sensitizer inotropic and vasodilator agent whose use might have a beneficial effect on the weaning of venoarterial extracorporeal membrane oxygenation (VA-ECMO). In light of LVSMD pharmacological characteristics, we hypothesized that ECMO may induce major pharmacokinetic (PK) modifications for LVSMD and its metabolites. The aim of this study was to investigate the PK of LVSMD and its metabolites, and to assess the effects of ECMO on PK parameters. We conducted a multicentric, prospective study (NCT03681379). Twenty-seven infusions of LVSMD were performed, allowing for the collection of 255 blood samples. Non-linear mixed-effects modeling software (MONOLIX®) was used to develop a parent-metabolite PK model of LVSMD and its metabolites. Most patients received a 0.2 µg/kg/min infusion of LVSMD over 24h. After elimination of non-reliable samples or concentrations below the limit of quantification, 166, 101 and 85 samples were considered for LVSMD, OR-1855 and OR-1896, respectively, of which 81, 53 and 41, respectively, were drawn under ECMO conditions. Parent-metabolite PK modeling revealed that a two-compartment model with first-order elimination best described LVSMD PK. Use of a transit compartment allowed for an explanation of the delayed appearance of circulating OR-1855 and OR-1896, with the latter following a first-order elimination. Patient weight influenced the central volume of distribution and elimination of LVSMD. ECMO support increased the elimination rate of LVSMD by 78%, and ECMO also slowed down the metabolite formation rate by 85% for OR-1855, which in turn is converted to the active metabolite OR-1896, 14% slower than without ECMO. Simulated data revealed that standard dosing may not be appropriate for patients under ECMO, with a decrease in the steady-state concentration of LVSMD and lower exposure to the active metabolite OR-1896. ECMO altered PK parameters for LVSMD and its metabolites. An infusion of LVSMD over 48h, instead of 24h, with a slightly higher dose may promote synthesis of the active metabolite OR-1896, which is responsible for the long-term efficacy of LVSMD. Further trials evaluating ECMO effects using a PK/pharmacodynamic approach may be of interest. ClinicalTrials.gov identifier number NCT03681379.

Simultaneous LC-ESI-MS/MS Quantification of Levosimendan and Its Metabolites for Therapeutic Drug Monitoring of Cardiac Surgery Patients.

Levosimendan is used in severe chronic cardiac insufficiency, also within the peri-operative setting. Real-life pharmacokinetic data in surgical patients is lacking, making therapeutic drug monitoring (TDM) of levosimendan, its pharmacologically active metabolite OR-1896, and its intermediate OR-1855 important. A simultaneous highly sensitive quantification of levosimendan and its metabolites in small-volume samples has not yet been described. Here, levosimendan (LLOQ 0.450 nM), OR-1896, and OR-1855 (LLOQ both 1.0 nM) were successfully quantified by LC-ESI-MS/MS after liquid-liquid extraction in 300 µL of blood. A short C8 column under reversed-phase conditions enabled simultaneous and fast quantification of levosimendan in the negative and the metabolites in the positive ionization mode in a single run within 2 min. Interestingly and unexpectedly, constitutional isomers of levosimendan metabolites with identical mass transitions and similar retention times were observed in surgical patients’ samples, which we identified as the metamizole metabolites 4-aminoantipyrine and 4-acetamidoantipyrine. A longer C8 column and a modified mobile phase enabled selective quantification of all analytes in a single run within 7 min. We developed, validated, and applied highly sensitive LC-ESI-MS/MS methods for simultaneous quantification of levosimendan and its metabolites, enabling efficient TDM of cardiac surgery patients even with additional metamizole administration.

Use of levosimendan in acute and advanced heart failure: short review on available real-world data.

Published data have shown potential advantages of levosimendan in the management of acute decompensated heart failure and advanced heart failure when standard medical therapies threaten hemodynamics and organ perfusion are unable to alleviate clinical symptoms. Levosimendan distinguishes itself from other catecholaminergic inotropes by its three mechanisms of action: positive inotropy, vasodilation, and cardioprotection. In addition, its pharmacokinetics allow for a longer duration of action from the metabolite OR1896 allowing for further cardiovascular therapeutic effects for several days, even after discontinuation of the parent drug.

Modification of levosimendan-induced suppression of atrial natriuretic peptide secretion in hypertrophied rat atria

This study aimed to determine the effects of levosimendan, a calcium sensitizer, on atrial contractility and atrial natriuretic peptide (ANP) secretion and its modification in hypertrophied atria. Isolated perfused beating rat atria were used from control and isoproterenol-treated rats. Levosimendan and its metabolite OR-1896 caused a positive inotropic effect and suppressed ANP secretion in rat atria. Similar to levosimendan, the selective phosphodiesterase 3 (PDE3) or PDE4 inhibitor also suppressed ANP secretion. Suppression of ANP secretion by 1 µM levosimendan was abolished by PDE3 inhibitor, but reversed by PDE4 inhibitor. Levosimendan-induced suppression of ANP secretion was potentiated by KATP channel blocker, but blocked by KATP channel opener. Levosimendan alone did not significantly change cyclic adenosine monophosphate (cAMP) efflux in the perfusate; however, levosimendan combined with PDE4 inhibitor markedly increased this efflux. The stimulation of ANP secretion induced by levosimendan combined with PDE4 inhibitor was blocked by the protein kinase A (PKA) inhibitor. In isoproterenol-treated atria, levosimendan augmented the positive inotropic effect and ANP secretion in response to an increased extracellular calcium concentration ([Ca+]o). These results suggests that levosimendan suppresses ANP secretion by both inhibiting PDE3 and opening KATP channels and that levosimendan combined with PDE4 inhibitor stimulates ANP secretion by activating the cAMP–PKA pathway. Modification of the effects of levosimendan on [Ca+]o-induced positive inotropic effects and ANP secretion in isoproterenol-treated rat atria might be related to a disturbance in calcium metabolism.

The inotropic effect of the active metabolite of levosimendan, OR-1896, is mediated through inhibition of PDE3 in rat ventricular myocardium.

AimsWe recently published that the positive inotropic response (PIR) to levosimendan can be fully accounted for by phosphodiesterase (PDE) inhibition in both failing human heart and normal rat heart. To determine if the PIR of the active metabolite OR-1896, an important mediator of the long-term clinical effects of levosimendan, also results from PDE3 inhibition, we compared the effects of OR-1896, a representative Ca2+ sensitizer EMD57033 (EMD), levosimendan and other PDE inhibitors.MethodsContractile force was measured in rat ventricular strips. PDE assay was conducted on rat ventricular homogenate. cAMP was measured using RII_epac FRET-based sensors.ResultsOR-1896 evoked a maximum PIR of 33±10% above basal at 1 μM. This response was amplified in the presence of the PDE4 inhibitor rolipram (89±14%) and absent in the presence of the PDE3 inhibitors cilostamide (0.5±5.3%) or milrinone (3.2±4.4%). The PIR was accompanied by a lusitropic response, and both were reversed by muscarinic receptor stimulation with carbachol and absent in the presence of β-AR blockade with timolol. OR-1896 inhibited PDE activity and increased cAMP levels at concentrations giving PIRs. OR-1896 did not sensitize the concentration-response relationship to extracellular Ca2+. Levosimendan, OR-1896 and EMD all increased the sensitivity to β-AR stimulation. The combination of either EMD and levosimendan or EMD and OR-1896 further sensitized the response, indicating at least two different mechanisms responsible for the sensitization. Only EMD sensitized the α1-AR response.ConclusionThe observed PIR to OR-1896 in rat ventricular strips is mediated through PDE3 inhibition, enhancing cAMP-mediated effects. These results further reinforce our previous finding that Ca2+ sensitization does not play a significant role in the inotropic (and lusitropic) effect of levosimendan, nor of its main metabolite OR-1896.

EComment. Preoperative levosimendan administration in cardiac surgery patients

According to its dual mode of action, levosimendan is both a calcium sensitizer, hence enhancing myocardial contractility without increasing the concentration of intracellular calcium, and a potassium adenosine triphosphate(ATP)-dependent channel opener, leading to vasodilation, which reduces left ventricular afterload and improves blood flow to vital organs [1]. Levosimendan exerts vasodilatory and possible anti-ischaemic and cardioprotective effects by opening of the ATP-dependent potassium-channel. Levosimendan may facilitate weaning from cardiopulmonary bypass (CPB) by both its inotropic and lusitropic properties. It enhances both systolic and diastolic left and right ventricular performance [1]. Levosimendan has a half-life of 1 hour, meaning that it is quickly eliminated from plasma. However, it has an active metabolite (OR-1896), which is formed by intestinal bacteria. OR-1896 has a similar haemodynamic profile to its parent compound, but a longer half-life of 70-80 hours. These pharmacokinetic features provide plausible explanations for the prolonged haemodynamic effects of levosimendan metabolites, which last for up to 7-9 days after discontinuation of a 24-h infusion of levosimendan [2]. We read with great interest the paper by Angadi et al. [3], regarding levosimendan use in paediatric cardiac surgey patients. They suggest that levosimendan is beneficial in improving cardiac performance and reducing the left ventricular afterload. It is promising as a rescue drug on the named-patient basis for a potential clinical benefit in low cardiac ouput syndrome (LCOS) and postcardiac surgeries. We agree with their implications and also would like to add a short comment on preoperative levosimendan administration. Currently, the use of levosimendan in cardiac surgery has gradually increased and is studied more in adults than in children. In cardiac surgery patients, candidates to receive levosimendan include low preoperative left ventricular ejection fraction (LVEF)(<35%), high-risk patients (emergency operation, decompensated heart failure), weaning failure from CPB, scheduled for mechanical assist device (intra-aortic balloon pump/left ventricular assist device), or postoperative LCOS [1]. Levosimendan is often used to improve peri- and postoperative haemodynamics to reduce morbidity and hospital stay. Levosimendan may be administered preoperatively, intraoperatively (before, during, or after CPB), or postoperatively. The timing depends on the logistic utilities of the hospital and the haemodynamic target [1]. Current dosing regimes use levosimendan perioperatively. However, during CPB, there is hypoperfusion in the hepatosplenic region, which may affect intestinal function. Thus, patients receiving levosimendan perioperatively may not have the active metabolite OR-1896. In our retrospective study [4] we reported early results of 18 patients receiving preoperative levosimendan that underwent coronary artery bypass grafting (CABG) with LVEF of 35% or less. Levosimendan infusion was given at a rate of 0.2 microgram/kg/min without a loading dose. It started 12 h before surgey. There was no in-hospital mortality. Levosimendan infusion was tolerated well in all patients. There were significant amelioration in haemodynamic parameters and diuresis. All patients showed no stormy postoperative recovery. In the prospective randomized study by Leppikangas et al. [5], levosimendan improved haemodynamics during the 4 day postoperative period, when infused a day before surgery. The formation of metabolites was documented for this 4 day postoperative period. We think that preoperative levosimendan administration may improve haemodynamic function and clinical outcome in patients with poor left ventricular function undergoing CABG. Conflict of interest: none declared

Levosimendan and its metabolite OR-1896 elicit KATP channel-dependent dilation in resistance arteries in vivo

BackgroundLevosimendan and its long-lived metabolite OR-1896 produce vasodilation in different types of vessels by activating ATP-sensitive (KATP) and other potassium channels. MethodsIn the present study we applied intravital videomicroscopy to investigate the in situ effects of levosimendan and OR-1896 on the diameters of real resistance arterioles (rat cremaster muscle arterioles with diameters of ~ 20μm). ResultsLevosimendan and OR-1896 induced concentration-dependent (1nM – 100μM) dilations to similar extents in these arterioles (maximal dilation from 23±2 to 33±2μm and from 22±1 to 32±1μm, respectively). The arteriolar dilations induced by the selective KATP channel opener pinacidil (1nM – 10μM) (maximal dilation from 22±4μm to 35±3μm) were diminished in the presence of the selective KATP channel blocker – glibenclamide (5μM) (maximal diameter attained: 22±1μm). Glibenclamide also counteracted the maximal dilations in response to levosimendan or OR-1896 (to 23±3μm or 22±5μm, respectively). ConclusionsIn conclusion, this is the first demonstration that levosimendan and OR-1896 elicit arteriolar dilation in vivo, via activation of KATP channels in real resistance vessels in the rat.

Pharmacology of levosimendan: inotropic, vasodilatory and cardioprotective effects

Positive inotropic agents are frequently used in acute decompensated heart failure (ADHF) due to left ventricular systolic dysfunction. These agents are known to improve cardiac performance and peripheral perfusion in the short-term treatment. However, several preclinical and clinical studies emphasized detrimental effects of these drugs on myocardial oxygen demand and on sympathetic tone entailing arrhythmogenesis. Levosimendan is an inotropic agent with an original mechanism of action. This review focuses on major data available for levosimendan. A literature search was conducted in the PubMed database by including studies published in English using combinations of the following key words, levosimendan, inotropic drugs and acute heart failure. Furthermore, bibliographies of selected references were also evaluated for relevant articles. The collection for this review was limited to the most recently available human and animal data. Levosimendan's vasodilatory and cardioprotective effects are mediated by calcium sensitization of contractile proteins and opening of adenosine triphosphate (ATP)-dependent K+ channels in vascular smooth muscle cells and on mitochondrial ATP-sensitive potassium [mito.K(ATP)] channels. This inotropic agent has mild PDE inhibitory action. Unlike other inotropic agents, levosimendan improves cardiac performance without activating the sympathetic nervous system. Moreover, there are evidences that levosimendan has additional anti-inflammatory and anti-apoptotic properties that prevent cardiac toxicity and contributes to positive hemodynamic response of the drug. Four randomized trials evaluated the effects of levosimendan on mortality in patients with acute decompensated chronic heart failure; nevertheless, a clear benefit has not been demonstrated so far. Although levosimendan is indicated for the treatment of ADHF (class of recommendation IIa, level of evidence B), it is has not been approved in all countries. This review summarizes the characteristics and the current knowledge of the literature on levosimendan and its active metabolite OR-1896.

Perioperative Use of Levosimendan: Best Practice in Operative Settings

LEVOSIMENDAN HAS BEEN USED in clinical practice since 2000, especially in the care of heart-failure patients. It probably is the most studied inotropic agent ever, with 83 randomized controlled trials published about adult critically ill patients 1 Landoni G. Biondi-Zoccai G. Greco M. et al. Effects of levosimendan on mortality and hospitalization A meta-analysis of randomized controlled studies. Crit Care Med. 2012; 40: 634-646 Crossref PubMed Scopus (178) Google Scholar (PubMed search updated January 6, 2012). The molecular mechanisms of levosimendan action recently have been described in detail elsewhere 2 Papp Z. Edes I. Fruhwald S. et al. Levosimendan: Molecular mechanisms and clinical implications consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012; ([Epub ahead of print]) PubMed Google Scholar and are based on, but not limited to, the Ca2+-sensitizing effect in the cardiac myofilaments. Pleiotropic effects include activation of adenosine triphosphate–sensitive sarcolemmal K+ channels of smooth muscle cells (linked to vasodilation) and activation of adenosine triphosphate–sensitive K+ channels in cardiovascular mitochondria (involved in a cardioprotective effect). The active long-lived metabolite OR-1896, also an inodilator, 3 Erdei N. Papp Z. Pollesello P. et al. The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles. Br J Pharmacol. 2006; 148: 696-702 Crossref PubMed Scopus (63) Google Scholar , 4 Szilágyi S. Pollesello P. Levijoki J. et al. The effects of levosimendan and OR-1896 on isolated hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea pig. Eur J Pharmacol. 2004; 486: 67-74 Crossref PubMed Scopus (100) Google Scholar allows the cardiovascular effects of levosimendan to persist up to 7 to 9 days after the discontinuation of a 24-hour infusion of the drug. 5 Lilleberg J. Laine M. Palkama T. et al. Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure. Eur J Heart Fail. 2007; 9: 75-82 Crossref PubMed Scopus (100) Google Scholar

Acetylation status does not affect levosimendan's hemodynamic effects in heart failure patients

Objective. Levosimendan is indicated for acute heart failure. The formation of levosimendan's active metabolite OR-1896 is dependent on the acetylator status. We evaluated whether acetylator status affects the hemodynamic responses after levosimendan infusion. Methods. Forty-one NYHA III to IV heart failure patients were divided into rapid and slow acetylators by population kinetic modeling. Invasive hemodynamics and plasma concentrations of levosimendan and its metabolites were followed serially. Results. Fifty-six percent of the patients were rapid and 44% slow acetylators. Levosimendan induced increases in heart rate and cardiac output, and decreases in pulmonary capillary wedge pressure (PCWP) and blood pressure, which were sustained at 24 hours after stopping the infusion. At this time, levosimendan levels were undetectable, and OR-1896 levels were about two-fold higher in rapid acetylators. However, hemodynamic effects were similar; mean(SEM) change from baseline in cardiac output was +2.0(0.3) vs. +1.6(0.3) l/min (p = 0.309), and in PCWP −8(2) vs. −7(1) mmHg (p = 0.536), in rapid and slow acetylators, respectively. Conclusion. The sustained hemodynamic effects of levosimendan are similar irrespective of acetylator status.

Relationship Between the Pharmacokinetics of Levosimendan and Its Effects on Cardiovascular System

Levosimendan, a Ca(2+) sensitizer, has emerged as an alternative option of pharmacologic inotropic support in patients with decompensated heart failure. In contrast to classic inotropes, rather than interfering with intracellular Ca(2+) levels in myocytes, levosimendan improves cardiac performance via Ca(2+) sensitization and K(+) channel-mediated peripheral vasodilatation. A two compartment pharmacokinetic model with zero-order input and first-order elimination has been found to describe best the pharmacokinetics of levosimendan. Although oral levosimendan has high bioavailability (approximately equal to 85%), in clinical practice it has been hitherto administered intravenously. Levosimendan has total clearance 175-250 mL/h/kg and most importantly a short half-life (about 1.5 hours). Therefore, this drug has a special pharmacokinetic interest: It is one of the few drugs used in cardiovascular medicine, whose prolonged action is not due to the drug itself but it is mainly due to its active metabolite OR-1896 (approximately 80 hours half life). Other metabolites with possible pharmacologic effect are N-conjugated OR-1855 (M7), N-hydroxylated OR-1855 (M8), N-hydroxylated OR-1896 (M10), O-glucuronide OR-1896 (M9) and O-sulfate (M11) of N-hydroxylated OR-1896. Initial reports on levosimendan's use in severe heart failure were positive and levosimendan has already been routinely used for the treatment of patients with decompensated heart failure, while it has been included to the European Society of Cardiology guidelines for the treatment of acute heart failure (class of recommendation IIb, level of evidence B). However, recent clinical trials have failed to demonstrate a clear benefit of levosimendan on survival, compared to other classic inotropic agents in patients requiring inotropic support. In this review article we provide a pharmacokinetic approach for the use of levosimendan in cardiovascular system by discussing its metabolism and mainly the pharmacology of its active metabolites in humans.

Clinical Pharmacology of Levosimendan

Levosimendan has been developed for the treatment of decompensated heart failure and is used intravenously when patients with heart failure require immediate initiation of drug therapy. It increases cardiac contractility and induces vasodilatation. The pharmacokinetics of levosimendan are linear at the therapeutic dose range of 0.05-0.2 microg/kg/minute. The short half-life (about 1 hour) of the parent drug, levosimendan, enables fast onset of drug action, although the effects are long-lasting due to the active metabolite OR-1896, which has an elimination half-life of 70-80 hours in patients with heart failure (New York Heart Association functional class III-IV). Although levosimendan is administered intravenously, it is excreted into the small intestine and reduced by intestinal bacteria to an amino phenolpyridazinone metabolite (OR-1855). This metabolite is further metabolised by acetylation to N-acetylated conjugate (OR-1896). The circulating metabolites OR-1855 and OR-1896 are formed slowly, and their maximum concentrations are seen on average 2 days after stopping a 24-hour infusion. The haemodynamic effects after levosimendan seem to be similar between fast and slow acetylators despite the fact that the enzyme N-acetyltransferase-2, which is responsible for the metabolism of OR-1855 to OR-1896, is polymorphically distributed in the population. Levosimendan reduces peripheral vascular resistance and has direct contractility-enhancing effects on the failing left ventricle. It also improves indices of diastolic function and seems to improve the function of stunned myocardium. Despite an improvement in ventricular function, levosimendan does not increase myocardial oxygen uptake significantly. An increase in coronary blood flow and a reduction in coronary vascular resistance have been observed. Levosimendan reduces plasma brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels substantially, and a decrease in plasma endothelin-1 has been observed. Levosimendan also exerts beneficial effects on proinflammatory cytokines and apoptosis mediators. The effects of a 24-hour levosimendan infusion on filling pressure, ventricular function and BNP, as well as NT-proBNP, last for at least 7 days.

728 The levosimendan metabolite OR-1896 elicits vasodilation by activating the KATP and BKCa channels in isolated arterioles of the rat

728 The levosimendan metabolite OR-1896 elicits vasodilation by activating the KATP and BKCa channels in isolated arterioles of the rat