Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes

Yokoshiki, Hisashi; Katsube, Yukiteru; Sunagawa, Makoto; Sperelakis, Nicholas

doi:10.1016/s0014-2999(97)01108-4

Cited by 274 publications

(174 citation statements)

References 54 publications

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“…L evosimendan (Levo) is a myocardial calcium sensitizer 1,2 and vasodilator 3,4 that is being evaluated for the shortterm treatment of patients with decompensated heart failure. [5][6][7][8] Although Levo has an elimination half-life of Ϸ1 hour, its active metabolite, OR-1896, has a much longer elimination half-life of Ϸ70 to 80 hours.…”

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Sustained Hemodynamic Effects of Intravenous Levosimendan

2003

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Background-The short-term infusion of levosimendan (Levo) improves hemodynamic function in patients with decompensated heart failure. The metabolites of Levo have a prolonged half-life, and one is hemodynamically active. The goal of this study was to determine whether the hemodynamic effects of Levo are sustained during a long-term infusion and beyond the discontinuation of drug infusion. Methods and Results-Patients with decompensated heart failure received escalating infusion rates of intravenous Levo (nϭ98) or placebo (nϭ48) for 6 hours. At the end of 6 hours, 85 of the Levo-treated patients were continued on open-label drug for a total of 24 hours, at which time they were randomized 1:1 to an additional 24 hours of Levo (nϭ43) or placebo (nϭ42).The hemodynamic effects observed at 24 hours were maintained at 48 hours in both the continuation and withdrawal groups and did not differ between groups. Although the plasma concentration of Levo decreased rapidly in the withdrawal group, concentrations of the active metabolite OR-1896 were similar in the continuation and withdrawal groups at 24 hours and increased further (3.5-fold to 4-fold) and to a similar extent in both groups at 48 hours. Conclusions-The hemodynamic effects of Levo were maintained during a 48-hour continuous infusion and for at least 24 hours after discontinuation of a 24-hour infusion. The active metabolite OR-1896 increased for at least 24 hours after cessation of drug infusion and may account for the prolonged hemodynamic effects of Levo.

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Sustained Hemodynamic Effects of Intravenous Levosimendan

2003

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“…Compared with other agents for acute heart failure syndromes (AHFS), its main potential advantages are the improvement of myocardial contractility without increasing oxygen requirements, reduction of ventricular preload, and an antistunning, anti-ischemic effect by opening K ATP channels. [1][2][3] This pharmacologic profile of levosimendan offers new therapeutic possibilities in patients with AHFS. In initial dose-finding 4,5 and therapeutic trials, 6 a rapid and prolonged hemodynamic improvement with an increase in cardiac index, reduction of pulmonary capillary wedge pressure (PCWP), and reduction of peripheral vascular resistance without proarrhythmic effects were documented.…”

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European Experience on the Practical Use of Levosimendan in Patients with Acute Heart Failure Syndromes

Folláth

Franco

Silva-Cardoso

2005

The American Journal of Cardiology

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The novel calcium sensitizer and ATP-dependent potassium channel opener levosimendan has been introduced for routine use in several European countries. Recent reports on clinical experience confirm the positive hemodynamic results and beneficial clinical effects described in the initial dose-finding and randomized comparative therapeutic trials in patients with severe low-output heart failure. In addition, studies in small series of patients with cardiogenic shock after myocardial infarction and/or surgical interventions and postinterventional myocardial dysfunction ( Levosimendan is a new calcium-sensitizing drug that opens adenosine triphosphate-dependent potassium (K ATP ) channels with effects that increase myocardial contraction and cause vasodilation. Compared with other agents for acute heart failure syndromes (AHFS), its main potential advantages are the improvement of myocardial contractility without increasing oxygen requirements, reduction of ventricular preload, and an antistunning, anti-ischemic effect by opening K ATP channels. [1][2][3] This pharmacologic profile of levosimendan offers new therapeutic possibilities in patients with AHFS. In initial dose-finding 4,5 and therapeutic trials, 6 a rapid and prolonged hemodynamic improvement with an increase in cardiac index, reduction of pulmonary capillary wedge pressure (PCWP), and reduction of peripheral vascular resistance without proarrhythmic effects were documented. Furthermore, positive effects on long-term survival up to 6 months were observed. 6,7 Levosimendan is registered for clinical use in several countries in Europe, South America, and Asia. There are an increasing number of reports on practical experiences and therapeutic successes in different clinical situations. In this article, we summarize recent publications on therapeutic indications, dose schedules, outcomes, and tolerance. MethodsClinical reports on levosimendan therapy in patients with severe decompensated acute or chronic heart failure (HF), cardiogenic shock after myocardial infarction (MI), or cardiac interventions and perioperative administration are reviewed. These publications were mostly smaller randomized or observational trials, with good descriptions of patient inclusion criteria, levosimendan administration, and methods of clinical and/or hemodynamic evaluation. Therapeutic Efficacy of Levosimendan in Acute Heart Failure SyndromesDecompensated low-output heart failure: Decompensated low-output HF is the best documented therapeutic indication for levosimendan administered as a single intravenous infusion lasting 6 to 24 hours. Patients included in the dose-finding and comparative clinical trials 4 -6 were characterized by dyspnea (New York Heart Association [NYHA] functional class III to IV) and signs of venous and pulmonary congestion accompanied by peripheral vasoconstriction. Hemodynamic inclusion criteria were reduced cardiac index (Ͻ2.5 L/min per m 2 ) and increased PCWP (Ͼ16 mm Hg). Patients with systolic blood pressure Ͻ90 mm Hg were excluded in these initial ...

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“…Studies with levosimendan suggest that these vasodilator effects are mediated through opening of the ATP-sensitive potassium channel in vascular smooth muscle cells. 27 De Luca et al 28 evaluated the acute effects of levosimendan on coronary flow velocities in patients with severe LV dysfunction undergoing PCI for ST-segment elevation myocardial infarction. After bolus, coronary flow reserve on infarct-related arteries and on reference vessels significantly improved in patients treated with levosimendan.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Ischemic Side Effects of Levosimendan and Dobutamine with Integrated Backscatter Analysis

Duygu

Nalbantgil

Zoghi

et al. 2009

Clinical Cardiology

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Background: Levosimendan improves cardiac contractility without increasing oxygen consumption. However, its effects on ischemia were not supported with the utilization of a noninvasive parameter of myocardial characterization. Hypothesis: The changes observed in integrated backscatter (IBS) may be reflective of change in myocardial ischemia. In this study, the effect of levosimendan on ischemia detected by IBS was evaluated in patients with ischemic heart failure (HF). Methods: Patients who had LVEF <40% and NYHA III-IV symptoms of HF were included in this study. Patients were randomized to levosimendan (n = 21), or to dobutamine (n = 25) groups. The cyclic variation of integrated backscatter (CVIBS) was determined as the difference between the maximal and minimal values in a cardiac cycle, average of three consecutive beats. CVIBS was taken from the mid-anteroseptal, mid-inferior, and mid-posterolateral areas of the parasternal short axis images before the drug administration and at the end of the 24-hour infusion period. Results: Baseline characteristics and concomitant medications were similar in both groups. A significant reduction in CVIBS was detected in anteroseptal (7.6 ± 1.4 dB versus 5.9 ± 0.8 dB, p = 0.01), inferior wall (7.4 ± 0.8 dB versus 6.7 ± 1.5 dB, p = 0.03), and posterolateral wall (9.0 ± 1.2 dB versus 8.2 ± 0.6 dB, p = 0.04) after dobutamine administration, while no significant changes were observed in the levosimendan group in all walls. Conclusions: Unlike dobutamine, levosimendan may not induce myocardial ischemia as shown by CVIBS at commonly used dosages in the setting of decompensated HF without active ischemia.

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Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes

Cited by 274 publications

References 54 publications

Sustained Hemodynamic Effects of Intravenous Levosimendan

Sustained Hemodynamic Effects of Intravenous Levosimendan

European Experience on the Practical Use of Levosimendan in Patients with Acute Heart Failure Syndromes

Comparison of Ischemic Side Effects of Levosimendan and Dobutamine with Integrated Backscatter Analysis

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