![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CARDIOVASCULAR
Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
62.6 ng/ml); metabolites were infused at one-half log-unit lower doses and responses compared to dobutamine (β1-agonist) and milrinone (phosphodiesterase 3 inhibitor). Peak concentrations of levosimendan, OR-1896, and OR-1855 at the end of the high dose were 323 ± 14, 83 ± 2, and 6 ± 2 ng/ml, respectively (OR-1855 rapidly metabolized to OR-1896; peak = 82 ± 3 ng/ml). Levosimendan and OR-1896 produced dose-dependent reductions in blood pressure and peripheral resistance with a rank potency, based on ED15 values, of OR-1896 (0.03 µmol/kg) > OR-1855 > levosimendan > milrinone (0.24 µmol/kg); an ED15 for dobutamine could not be defined. Only dobutamine produced increases in pulse pressure (30 ± 5%) and rate-pressure product (34 ± 4%). All of the compounds, with the exception of OR-1855, elicited dose-dependent increases in dP/dt with a rank potency, based on ED50 values, of dobutamine (0.03 µmol/kg) > levosimendan > OR-1896 > milrinone (0.09 µmol/kg), although only levosimendan produced sustained increases in cardiac output (9 ± 4%). Thus, levosimendan and OR-1896 are hemodynamically active at sub- to supratherapeutic concentrations (whereas the effects of OR-1855 in the rat are thought to be predominantly mediated by conversion to OR-1896) and produce direct inotropic effects and also direct relaxation of the peripheral vasculature, which clearly differentiates them from dobutamine, which does not elicit K+ channel activation, suggesting a more balanced effect on the cardiac-contractile state and K+ channel-mediated changes in vascular resistance.
). Indeed, an increase in contractile function by increasing intracellular calcium has traditionally been the common paradigm of many inotropic drugs, including digoxin, adrenergic-β1-agonists, and phosphodiesterase inhibitors. However, their clinical value is limited by the narrow therapeutic index of these agents, associated toxicity including arrhythmias, and only modest efficacy in chronic therapy (Lehmann et al., 2003). In contrast, levosimendan and other calcium-sensitizing agents are able to enhance the contractile status of the heart (mechanism recently reviewed in Antoniades et al., 2007) without concomitant elevations in calcium, and thus, they represent a potentially valuable alternative to increasing left ventricular function in the treatment of cardiac dysfunction and heart failure without the cardiovascular risks associated with increased intracellular-free calcium (Lehmann et al., 2003). However, it should be noted that some studies have suggested that levosimendan might actually increase Ca2+ transients (Takahashi and Endoh, 2002), and it has also been suggested that phosphodiesterase 3 (PDE3) inhibitory activity might also contribute to the positive inotropic effects of the compound (Sato et al., 1998), suggesting a complex mechanism of action that might result in clinical benefit versus classic inotropic agents (Endoh and Hori, 2006). Reducing load on the heart is achieved by many drugs used today through the targeted relaxation of the vasculature and the subsequent reduction in peripheral resistance through various mechanisms, including activation of K+ channels (KATP and BKCa) (Chatterjee, 1987), an effect also ascribed to levosimendan.
Traditionally, polypharmacology in patients was necessary to directly target both mechanisms (increasing ventricular contractile status and unloading the heart). However, levosimendan, (R)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl] hydrazono]propanedinitrile, is a calcium sensitizer with potent vasodilatory properties (De Luca et al., 2006). Levosimendan increases myocardial contractility (Lilleberg et al., 1995) by increasing the affinity of troponin-C for Ca2+ (Pollesello et al., 1994; Sorsa et al., 2001), reduces filling pressure (Lilleberg et al., 1995), and dilates both the peripheral and coronary vessels (Pataricza et al., 2000; Kaheinen et al., 2001) through activation of KATP channels in vascular smooth muscle cells (Yokoshiki et al., 1997a; Sorsa et al., 2001). In addition, levosimendan may elicit activation of mitochondrial KATP channels (Kopustinskiene et al., 2001, 2004) that have been implicated in cardioprotection (Gross and Fryer, 1999, 2000; Fryer et al., 2001).
Levosimendan can be administered to patients intravenously. Indeed, the i.v. formulation of levosimendan has been investigated in several clinical trials in subjects with decompensated heart failure (Kivikko and Lehtonen, 2005), whereby both efficacy and tolerability have been demonstrated in patients with heart failure resulting from either an ischemic or nonischemic etiology (Follath et al., 2002; Moiseyev et al., 2002). Efficacious plasma concentrations of levosimendan were assessed in an open-label, nonrandomized, Phase II study in patients diagnosed with heart failure (New York Health Association III–IV); a 24-h continuous infusion of levosimendan produced peak plasma concentrations of 62.6 ng/ml, and peak concentrations of OR-1896 and OR-1855, the two primary circulating metabolites of levosimendan, reached 5.5 and 6.8 ng/ml, respectively (Kivikko et al., 2002).
Because of the reduction of levosimendan to OR-1855 in humans and subsequent acetylation to OR-1896 (Antila et al., 2004, 2007), the contribution of the parent versus each metabolite to the hemodynamic and cardiovascular effects observed in patients can not be definitively described. However, in the rat, levosimendan is not readily metabolized to any relevant circulating metabolite (K. C. Marsh, unpublished observation). Moreover, a comprehensive assessment of the effects of levosimendan and its metabolites (in relation to plasma concentrations achieved) on cardiovascular function has not been fully described in the rat. Thus, the present study sought to characterize the effects of levosimendan, OR-1896, and OR-1855 on myocardial and hemodynamic function in the rat at plasma concentrations deemed therapeutic to supratherapeutic. Results were compared to two other agents routinely prescribed in the treatment of heart failure: the β1 agonist dobutamine and the PDE3 inhibitor milrinone (Endoh and Hori, 2006; Shin et al., 2007).
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
). In brief, polyethylene tubing (PE240) was placed in the trachea to keep the airway patent, and rats continued to breathe spontaneously. Vascular catheters (PE50) were placed in the femoral arteries to measure mean arterial pressure (MAP) and heart rate (HR) and to collect blood samples; rate-pressure product, an index of myocardial oxygen consumption, was calculated as (MAP x HR) x 100–1, and pulse pressure was calculated as systolic pressure – diastolic pressure. Femoral vein catheters (PE50) were used for compound administration and saline infusion to maintain hydration. A specialized transducer tip catheter was placed in the right carotid artery and advanced into the left ventricle of the heart for measurement of left ventricular pressure; dP/dt at 50 mm Hg, an index of cardiac contractility, was derived from the left ventricular pressure trace. Through a laparotomy, a pulsed-Doppler cuff-type flow probe was placed around the upper abdominal aorta just below the diaphragm but above the renal arteries for measurement of peripheral cardiac output (PCO) defined as full cardiac output – cardiac output to the carotid, coronary, brachiocephalic, and subclavian vessels. Post-hoc vascular resistance was calculated as MAP/PCO. Body temperature was monitored throughout the experiment and maintained between 37 and 37.5°C by using a heating pad. The primary hemodynamic variables were computed using commercial software and a signal processing workstation (Ponemah; Gould Instrument Systems, Inc., Cleveland, OH).
|
|
|
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
) (represented by the dotted line in Fig. 2); infusion of levosimendan produced no detectable concentrations of OR-1896 or OR-1855. Peak concentrations of OR-1896 and OR-1855 were 84 ± 2 and 6 ± 2 ng/ml, respectively. In rats administered OR-1855, the majority of the compound was rapidly metabolized to OR-1896 (peak concentration = 82 ± 3 ng/ml); the hemodynamic effects of OR-1855 alone could not be clearly delineated in the present study due to conversion to the OR-1896 active metabolite. However, for completeness, the hemodynamic effects upon OR-1855 are shown in all subsequent figures. Baseline mean arterial pressure, pulse pressure, HR, rate-pressure product, vascular resistance, dP/dt, and peripheral cardiac output were not different among the six treatment groups (Table 1; one-way ANOVA, Dunnett's t test versus vehicle).
|
|
Reductions in systemic vascular resistance were paralleled by dose-dependent decreases in mean arterial pressure for all compounds tested, with the exception of dobutamine (Fig. 4, A–E). The efficacious dose to elicit a 10% reduction in blood pressure was as follows: levosimendan, 0.10 µmol/kg; OR-1896, 0.02 µmol/kg; OR-1855, 0.02 µmol/kg; and milrinone, 0.09 µmol/kg (Fig. 4F). An ED10 value for dobutamine could not be calculated.
Relative to vehicle controls, levosimendan, OR-1896, OR-1855, and milrinone all produced dose-dependent reductions in pulse pressure (systolic pressure – diastolic pressure); peak reductions in pulse pressure were –41 ± 6, –35 ± 12, –41 ± 12, and –30 ± 5% below baseline, respectively (Fig. 5, A–C and E). In contrast, dobutamine produced marked increases in pulse pressure at doses between 0.03 and 0.3 µmol/kg (maximal increase = 30 ± 5% above baseline) (Fig. 5D).
|
|
Levosimendan produced dose-dependent increases in dP/dt at 50 mm Hg (dP/dt50; Fig. 7A). At the end of each dosing period, dP/dt50 increased to 10 ± 4, 25 ± 5, 43 ± 4, and 72 ± 8% above baseline, respectively. Increases in dP/dt50 produced by OR-1896 were less pronounced than those of levosimendan, and changes in dP/dt50 produced by OR-1855 were not statistically different from vehicle-treated rats. In contrast, dobutamine produced large and dose-dependent increases in dP/dt50 at all of the doses tested (to 13 ± 4, 55 ± 3, 101 ± 5, and 108 ± 8% above baseline, respectively). The efficacious dose to elicit a 50% increase in dP/dt50 was calculated as follows: levosimendan, 0.38 µmol/kg; OR-1896, 0.14 µmol/kg; dobutamine, 0.03 µmol/kg; and milrinone, 0.09 µmol/kg; an ED50 value for OR-1855 could not be calculated (Fig. 7B).
|
Only levosimendan produced consistent increases in peripheral cardiac output, an effect beginning at the 0.30 µmol/kg dose; at plasma concentrations of levosimendan observed clinically, levosimendan increased cardiac output by 9 ± 4% above baseline (value at 90 min or 89 ± 5 ng/ml; Fig. 8A). At supratherapeutic concentrations, increases in cardiac output were exacerbated (to 20 ± 7% above baseline at 120 min, 323 ± 15 ng/ml). Milrinone also produced more modest and less consistent increases in cardiac output (peak increase = 6 ± 3% above baseline), whereas cardiac output was not increased in the presence of OR-1896, OR-1855, or dobutamine (Fig. 8, B–E).
|
), levosimendan seems to be responsible for the majority of the inotropic and vasodilatory effects (levosimendan = 15% increase in dP/dt and 8.5% fall in peripheral resistance at 62.6 ng/ml versus 4% increase in dP/dt and 2% fall in peripheral resistance for OR-1896 at 5.5 ng/ml; Fig. 9, inset). In addition, when analyzed as change in dP/dt50 versus change in peripheral vascular resistance, dobutamine delineates itself as a more potent positive inotropic agent, whereas the regression profiles of levosimendan, OR-1896, and OR-1855 are more in line with that of milrinone, suggesting a more balanced effect on the cardiac-contractile state and K+ channel-mediated changes in vascular resistance (Fig. 10).
|
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
; Kivikko et al., 2002; Ng and Akhter, 2005). Thus, an i.v. infusion dosing regimen was used in the present study in rats to effectively capture the hemodynamic and cardiovascular effects of levosimendan as well as its metabolites, infused separately, over a large, dynamic range of plasma concentrations deemed therapeutic to supratherapeutic. We demonstrate in anesthetized rats that levosimendan and its circulating metabolite OR-1896 produce dose-dependent reductions in peripheral vascular resistance and mean arterial pressure without affecting pulse pressure, effects paralleled by increases in left ventricular contractility and consistent with K+ channel activation and increased Ca2+ sensitization/transients, respectively. The sole hemodynamic effects of OR-1855 could not be delineated in the present study due to the rapid and almost complete conversion to its metabolite OR-1896, which is hemodynamically active in the rat when infused alone.
We demonstrate in the present study that infusion of OR-1896, OR-1855, and levosimendan are more potent to produce decreases in peripheral resistance (ED15 = 0.03, 0.06, and 0.17 µmol/kg, respectively) than milrinone (ED15 = 0.24 µmol/kg; no ED15 value could be calculated for dobutamine); similar potencies were noted for reductions in blood pressure by the compounds tested in the present study. It is noteworthy that reductions in both peripheral resistance and blood pressure produced by levosimendan and OR-1896 occurred at concentrations within those expected clinically in patients with heart failure and are consistent with activation of KATP/ BKCa channels (Erdei et al., 2006).
Levosimendan and OR-1896, as well as the positive inotropic agents dobutamine and milrinone, produced dose-dependent increases in left ventricular contractility in the present study. Compared on a dose-to-dose basis, dobutamine is markedly more potent than levosimendan, OR-1896, and milrinone (ED50 values = 0.03, 0.38, 0.14, and 0.09 µmol/kg, respectively) to elicit increases in dP/dt50. Although maximal increases in dP/dt50 were not different between levosimendan and OR-1896 (72 ± 8 and 52 ± 11% above baseline, respectively; p > 0.05), increases in dP/dt produced by infusion of OR-1855 (up to 18 ± 10% above baseline) were markedly attenuated versus direct infusion of OR-1896 (p < 0.05, t test) despite virtually identical plasma concentrations of OR-1896 in both groups (84 ± 2 versus 82 ± 3 ng/ml, respectively), possibly suggesting that the small amount of parent OR-1855 present in the OR-1855-infusion studies (6 ± 2 ng/ml) countered OR-1896-induced increases in dP/dt50 through an undefined mechanism. However, we are unaware of any studies reporting a negative inotropic effect of OR-1855 in preclinical models or in patients. In fact, in similar infusion studies in anesthetized dogs, OR-1855 elicited no effect on dP/dt at concentrations well above those achieved in the present study (up to 136 ± 6 ng/ml) (Banfor et al., 2007).
Whether levosimendan elicits increases in contractility through or independent of PDE3 inhibition is controversial and may be species-dependent, but it may be important when it comes to clinical efficacy (Endoh, 2001, 2002). In guinea pig heart preparations, Szilágyi et al. (2004) demonstrated that levosimendan and OR-1896 elicit increases in contractility independent of PDE inhibitory activity. However, in the rabbit, Sato et al. (1998) suggested that, in addition to the increase in sensitivity of contractile proteins to Ca2+, the accumulation of cAMP subsequent to PDE3 inhibition may contribute to the inotropic effects of the drug. Moreover, Ajiro et al. (2002) have demonstrated a differential effect of levosimendan on ICa,L current, which is regulated by cAMP-dependent phosphorylation in human versus rabbit and rat atrial cells and suggest that levosimendan may function as a PDE3 inhibitor in man. Thus, whether levosimendan elicits inotropic effects solely via Ca2+ sensitization or in combination with PDE3 inhibitory activity is unclear and warrants further investigation.
Although in the present study, the ED50 for OR-1896 to elicit increase in dP/dt is lower than that calculated for levosimendan, in vitro OR-1896 is less potent than levosimendan to elicit increases in force of contraction. Indeed, in permeabilized guinea pig left ventricular cardiomyocytes, Szilágyi et al. (2004) demonstrated that levosimendan increased isometric force production by 51 ± 7% with an EC50 of 8 ± 1 nM, whereas the EC50 for OR-1896 to elicit a similar effect on force production was 36 ± 7 nM, suggesting four to five times less potency than levosimendan. It is speculated that the apparent increased potency of OR-1896 versus levosimendan in the present study, in vivo, is due to baroreflex activation at low doses of OR-1896 (0.01 µmol/kg) in response to significant reductions in blood pressure. In contrast, levosimendan did not elicit significant decreases in blood pressure until 30-fold higher doses (0.3 µmol/kg). In addition, it is important to note that when the present results were analyzed as change in dP/dt50 and peripheral vascular resistance versus plasma concentrations was achieved, OR-1896 seemed to be more potent than levosimendan to elicit both increases in dP/dt50 and reductions in peripheral vascular resistance on a concentration-for-concentration basis. However, when taking into account the clinical Cmax values for each compound (62.6 ng/ml for levosimendan versus 5.5 ng/ml for OR-1896), it can be argued that levosimendan rather than OR-1896 accounts for the majority of the inotropic and vasodilatory effects of the compound at therapeutic levels in patients.
It is important to note that Haikala et al. (1995) demonstrated in guinea pig heart myofibrils that levosimendan elicits no effect on myosin ATPase activity, suggesting that Ca2+ sensitization is mediated through a mechanism that does not increase energy consumption by contractile proteins, results consistent with the present study whereby we demonstrate that neither levosimendan nor either of its metabolites increases myocardial oxygen consumption. However, in profound contrast to the effects of levosimendan and OR-1896, rate-pressure product was substantially and dose-dependently increased in the present study by the β1-agonist dobutamine (to 34 ± 4% above baseline during the 0.10 µmol/kg dose; vehicle =–3 ± 2% below baseline), results consistent with those previously demonstrated in patients (Akosah et al., 1999), which may explain the increase in cardiac failure in patients treated with dobutamine versus levosimendan (Mebazaa et al., 2007).
Interestingly, in this study only levosimendan elicited consistent and significant increases in peripheral cardiac output (maximal effect = 20 ± 7% above baseline), whereas neither direct infusion of OR-1896 nor OR-1896 produced through metabolic conversion from OR-1855 elicited any significant effect. These results suggest that, similar to increases in dP/dt50 produced by levosimendan, increases in cardiac output in patients administered levosimendan may be mediated by the parent rather than the OR-1896 metabolite. It is noteworthy that dobutamine, despite marked increases in dP/dt, elicited no effect on peripheral cardiac output in the present study. However, because technical limitations restricted cardiac output measurement to only the periphery without measurement of output to some vessels, it is possible that in the presence of dobutamine full cardiac output was actually enhanced despite no clear increase in this model.
In the present study, heart rate increased in response to all of the groups, with the exception of rats administered OR-1855 despite rapid conversion to OR-1896; again, why OR-1896 generated from OR-1855 elicited little to no effect on heart rate (similar to a lack of effect on dP/dt50 in the OR-1855-infusion studies) is unclear but may suggest an already unknown property of OR-1855 whereby small concentrations of the parent can mitigate the effects of the OR-1896 metabolite. Nevertheless, increases in heart rate produced by levosimendan and OR-1896 infusion probably represent a direct effect on the sinoatrial node (Haikala et al., 1997).
The same group also demonstrated in isolated rat hearts that both levosimendan and milrinone produced direct and dose-dependent increases in blood flow (Haikala et al., 1997). Indeed, the effects of levosimendan to dilate the vasculature directly has been well described; patch-clamp studies in rat cardiomyocytes have shown that levosimendan opens KATP channels, increases K+ current, and elicits hyperpolarization of the cell (Yokoshiki et al., 1997b). Levosimendan also increases KATP current in rat (Yokoshiki et al., 1997a) and human (Pataricza et al., 2000) vascular smooth muscles, an effect that would be expected to result in vasodilation as observed in the present study. The vasodilatory effects of levosimendan seem to be mediated by selective activation of KATP current because levosimendan does not activate KCa at therapeutic concentrations (Pataricza et al., 2003) (although OR-1896 has been reported to elicit activation of the BKCa in rat coronary arterioles; Erdei et al., 2006), or they seem to regulate the open state of other K+ channel currents, including inward rectifier, transient outward, and the delayed rectifier outward K+ currents as elucidated by Virág et al. (1996) using whole-cell patch clamp in rabbit ventricular myocytes. Moreover, levosimendan-induced vasodilation is endothelium-independent, an effect that may have clinical significance because coronary artery disease is often an underlying pathology in heart failure patients.
Thus, levosimendan and OR-1896 produce direct inotropic effects in the heart and also direct relaxation of the peripheral vasculature, resulting in dose-dependent vasodilation. Moreover, results from the present study demonstrate that both parent and the OR-1896 metabolite clearly differentiate themselves from dobutamine, which does not cause K+ channel activation, suggesting a more balanced effect on the cardiac-contractile state and K+ channel-mediated reductions in vascular resistance. Moreover, in the anesthetized rat, both levosimendan and OR-1896 are hemodynamically active at concentrations at and above those observed clinically. The effects of OR-1855 in the rat are thought to be predominantly mediated by rapid and almost complete conversion to OR-1896.
|
Footnotes |
|---|
ABBREVIATIONS: PDE3, phosphodiesterase 3; KATP, ATP-sensitive potassium channel; BKCa, large conductance Ca2+-activated K+ channels; OR-1896, (R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; OR-1855, (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one; MAP, mean arterial pressure; HR, heart rate; PCO, peripheral cardiac output; ANOVA, analysis of variance.
Address correspondence to: Dr. Ryan M. Fryer, Department of Integrative Pharmacology, R46R, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6119. E-mail: ryan.fryer{at}abbott.com
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Ajiro Y, Hagiwara N, Katsube Y, Sperelakis N, and Kasanuki H (2002) Levosimendan increases L-type Ca2+ current via phosphodiesterase-3 inhibition in human cardiac myocytes. Eur J Pharmacol 435: 27–33.[CrossRef][Medline]
Akosah KO, Denlinger B, and Mohanty PK (1999) Safety profile and hemodynamic responses to beta-adrenergic stimulation by dobutamine in heart transplant patients. Chest 116: 1587–1592.[CrossRef][Medline]
Antila S, Pesonen U, Lehtonen L, Tapanainen P, Nikkanen H, Vaahtera K, and Scheinin H (2004) Pharmacokinetics of levosimendan and its active metabolite OR-1896 in rapid and slow acetylators. Eur J Pharm Sci 23: 213–222.[CrossRef][Medline]
Antila S, Sundberg S, and Lehtonen LA (2007) Clinical pharmacology of levosimendan. Clin Pharmacokinet 46: 535–552.[CrossRef][Medline]
Antoniades C, Tousoulis D, Koumallos N, Marinou K, and Stefanadis C (2007) Levosimendan: beyond its simple inotropic effect in heart failure. Pharmacol Ther 114: 184–197.[CrossRef][Medline]
Banfor PN, Preusser LC, Campbell TJ, Marsh KC, Polakowski JS, Reinhart GA, Cox BF, and Fryer RM (2007) Comparative effects of levosimendan, OR-1896, OR-1855, dobutamine, and milrinone on vascular resistance, indices of cardiac function, and O2 consumption in dogs. Am J Physiol Heart Circ Physiol 294: H238–H48.[CrossRef][Medline]
Chatterjee K (1987) "Unloading" therapy for heart failure. West J Med 147: 324–325.[Medline]
De Luca L, Colucci WS, Nieminen MS, Massie BM, and Gheorghiade M (2006) Evidence-based use of levosimendan in different clinical settings. Eur Heart J 27: 1908–1920.
Endoh M (2001) Mechanism of action of Ca2+ sensitizers–update 2001. Cardiovasc Drugs Ther 15: 397–403.[CrossRef]
Endoh M (2002) Mechanisms of action of novel cardiotonic agents. J Cardiovasc Pharmacol 40: 323–338.[CrossRef][Medline]
Endoh M and Hori M (2006) Acute heart failure: inotropic agents and their clinical uses. Expert Opin Pharmacother 7: 2179–2202.[CrossRef][Medline]
Erdei N, Papp Z, Pollesello P, Edes I, and Bagi Z (2006) The levosimendan metabolite OR-1896 elicits vasodilation by activating the KATP and BKCa channels in rat isolated arterioles. Br J Pharmacol 148: 696–702.[CrossRef][Medline]
Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, Harjola VP, Mitrovic V, Abdalla M, Sandell EP, et al. (2002) Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 360: 196–202.[CrossRef][Medline]
Fryer RM, Hsu AK, and Gross GJ (2001) Mitochondrial KATP channel opening is important during index ischemia and following myocardial reperfusion in ischemic preconditioned rat hearts. J Mol Cell Cardiol 33: 831–834.[CrossRef][Medline]
Gross GJ and Fryer RM (1999) Sarcolemmal versus mitochondrial ATP-sensitive K+ channels and myocardial preconditioning. Circ Res 84: 973–979.
Gross GJ and Fryer RM (2000) Mitochondrial KATP channels: triggers or distal effectors of ischemic or pharmacological preconditioning? Circ Res 87: 431–433.
Haikala H, Kaheinen P, Levijoki J, and Linden IB (1997) The role of cAMP- and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan. Cardiovasc Res 34: 536–546.
Haikala H, Nissinen E, Etemadzadeh E, Levijoki J, and Linden IB (1995) Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation. J Cardiovasc Pharmacol 25: 794–801.[Medline]
Kaheinen P, Pollesello P, Levijoki J, and Haikala H (2001) Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels. J Cardiovasc Pharmacol 37: 367–374.[CrossRef][Medline]
Kivikko M, Antila S, Eha J, Lehtonen L, and Pentikainen PJ (2002) Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure. Int J Clin Pharmacol Ther 40: 465–471.[Medline]
Kivikko M and Lehtonen L (2005) Levosimendan: a new inodilatory drug for the treatment of decompensated heart failure. Curr Pharm Des 11: 435–455.[CrossRef][Medline]
Kopustinskiene DM, Pollesello P, and Saris NE (2001) Levosimendan is a mitochondrial KATP channel opener. Eur J Pharmacol 428: 311–314.[CrossRef][Medline]
Kopustinskiene DM, Pollesello P, and Saris NE (2004) Potassium-specific effects of levosimendan on heart mitochondria. Biochem Pharmacol 68: 807–812.[CrossRef][Medline]
Lehmann A, Boldt J, and Kirchner J (2003) The role of Ca++-sensitizers for the treatment of heart failure. Curr Opin Crit Care 9: 337–344.[CrossRef][Medline]
Lilleberg J, Sundberg S, and Nieminen MS (1995) Dose-range study of a new calcium sensitizer, levosimendan, in patients with left ventricular dysfunction. J Cardiovasc Pharmacol 26 (Suppl 1): S63–S69.[CrossRef]
Liu G, Zhao H, Liu B, Xin Z, Liu M, Serby MD, Lubbers NL, Widomski DL, Polakowski JS, Beno DW, et al. (2007) Hemodynamic effects of potent and selective JNK inhibitors in anesthetized rats: implication for targeting protein kinases in metabolic diseases. Bioorg Med Chem Lett 17: 495–500.[CrossRef][Medline]
Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, Thakkar R, Padley RJ, Poder P, and Kivikko M (2007) Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. J Am Med Assoc 297: 1883–1891.
Moiseyev VS, Poder P, Andrejevs N, Ruda MY, Golikov AP, Lazebnik LB, Kobalava ZD, Lehtonen LA, Laine T, Nieminen MS, et al. (2002) Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J 23: 1422–1432.
Ng TM and Akhter MW (2005) Levosimendan: dual mechanisms for acute heart failure and beyond? Minerva Cardioangiol 53: 565–584.[Medline]
Pataricza J, Hohn J, Petri A, Balogh A, and Papp JG (2000) Comparison of the vasorelaxing effect of cromakalim and the new inodilator, levosimendan, in human isolated portal vein. J Pharm Pharmacol 52: 213–217.[CrossRef][Medline]
Pataricza J, Krassoi I, Hohn J, Kun A, and Papp JG (2003) Functional role of potassium channels in the vasodilating mechanism of levosimendan in porcine isolated coronary artery. Cardiovasc Drugs Ther 17: 115–121.[CrossRef][Medline]
Pollesello P, Ovaska M, Kaivola J, Tilgmann C, Lundstrom K, Kalkkinen N, Ulmanen I, Nissinen E, and Taskinen J (1994) Binding of a new Ca2+ sensitizer, levosimendan, to recombinant human cardiac troponin C. A molecular modelling, fluorescence probe, and proton nuclear magnetic resonance study. J Biol Chem 269: 28584–28590.
Sato S, Talukder MA, Sugawara H, Sawada H, and Endoh M (1998) Effects of levosimendan on myocardial contractility and Ca2+ transients in aequorin-loaded right-ventricular papillary muscles and indo-1-loaded single ventricular cardiomyocytes of the rabbit. J Mol Cell Cardiol 30: 1115–1128.[CrossRef][Medline]
Shin DD, Brandimarte F, De Luca L, Sabbah HN, Fonarow GC, Filippatos G, Komajda M, and Gheorghiade M (2007) Review of current and investigational pharmacologic agents for acute heart failure syndromes. Am J Cardiol 99: 4A–23A.[Medline]
Sorsa T, Heikkinen S, Abbott MB, Abusamhadneh E, Laakso T, Tilgmann C, Serimaa R, Annila A, Rosevear PR, Drakenberg T, et al. (2001) Binding of levosimendan, a calcium sensitizer, to cardiac troponin C. J Biol Chem 276: 9337–9343.
Szilágyi S, Pollesello P, Levijoki J, Kaheinen P, Haikala H, Edes I, and Papp Z (2004) The effects of levosimendan and OR-1896 on isolated hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea pig. Eur J Pharmacol 486: 67–74.[CrossRef][Medline]
Takahashi R and Endoh M (2002) Effects of OR-1896, a metabolite of levosimendan, on force of contraction and Ca2+ transients under acidotic condition in aequorin-loaded canine ventricular myocardium. Naunyn Schmiedebergs Arch Pharmacol 366: 440–448.[CrossRef][Medline]
Virág L, Hala O, Marton A, Varro A, and Papp JG (1996) Cardiac electrophysiological effects of levosimendan, a new calcium sensitizer. Gen Pharmacol 27: 551–556.[Medline]
Yokoshiki H, Katsube Y, Sunagawa M, and Sperelakis N (1997a) Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. Eur J Pharmacol 333: 249–259.[CrossRef][Medline]
Yokoshiki H, Katsube Y, Sunagawa M, and Sperelakis N (1997b) The novel calcium sensitizer levosimendan activates the ATP-sensitive K+ channel in rat ventricular cells. J Pharmacol Exp Ther 283: 375–383.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
), OR-1896 (
), and OR-1855 (
).
), and milrinone (
); statistical significance is indicated by filled symbols (p < 0.05), change from baseline at each post-treatment time point, one-way ANOVA with repeated measures, and Dunnett's post-test. B, the efficacious dose for each compound to produce a 15% reduction in peripheral resistance (ED15) was calculated, and values are shown in the figure as decrease in peripheral resistance as a function of dose (log transformed from micromoles per kilogram); based on potency for reductions in blood pressure, compounds can be rank-ordered as OR-1896 > OR-1855 > levosimendan > milrinone; dobutamine elicited no significant change in peripheral resistance, and thus an ED15 value could not be accurately calculated.
), its metabolite OR-1896 (