Effects of levosimendan on cardiac remodeling and cardiomyocyte apoptosis in hypertensive Dahl/Rapp rats

BACKGROUND AND PURPOSE: Progression of heart failure in hypertensive Dahl rats is associated with cardiac remodeling and increased cardiomyocyte apoptosis. This study was conducted to study whether treatment with a novel inotropic vasodilator compound, levosimendan, could prevent hypertension-induced cardiac remodeling and cardiomyocyte apoptosis. EXPERIMENTAL APPROACH: 6-week-old salt-sensitive Dahl/Rapp rats received levosimendan (0.3 mg kg(-1) and 3 mg kg(-1) via drinking fluid) and high salt diet (NaCl 7%) for 7 weeks, Dahl/Rapp rats on low-salt diet served as controls. Blood pressure, cardiac functions by echocardiography, cardiomyocyte apoptosis by TUNEL technique, tissue morphology, myocardial expression of calcium cycling proteins, and markers of neurohumoral activation were determined. KEY RESULTS: Untreated Dahl/Rapp rats on high salt diet developed severe hypertension, cardiac hypertrophy and moderate systolic dysfunction. 38% of Dahl/Rapp rats (9/24) survived the 7-week-follow-up period. Cardiomyocyte apoptosis was increased by 6-fold during high salt diet. Levosimendan improved survival (survival rates in low- and high-dose levosimendan groups 12/12 and 9/12, p<0.001 and p=0.05, respectively), increased cardiac function, and ameliorated cardiac hypertrophy. Levosimendan dose-dependently prevented cardiomyocyte apoptosis. Levosimendan normalized salt-induced increased expression of natriuretic peptide, and decreased urinary noradrenaline excretion. Levosimendan also corrected salt-induced decreases in myocardial SERCA2a protein expression and myocardial SERCA2a/NCX-ratio. CONCLUSIONS AND IMPLICATIONS: Improved survival by the novel inotropic vasodilator levosimendan in hypertensive Dahl/Rapp rats is mediated, at least in part, by amelioration of hypertension-induced cardiac remodeling and cardiomyocyte apoptosis.     

Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels

Levosimendan, a novel calcium sensitizer developed for the treatment of acute heart failure, is an inodilator that increases coronary flow. Because it was recently shown that levosimendan stimulates potassium current through K(ATP) channels in isolated rat arterial cells, our aim was to assess whether the levosimendan-induced increase in coronary flow is due to the opening of the K(ATP) channels in coronary smooth muscle. The effect of levosimendan on the diastolic coronary flow velocity (DCFV) was measured in the Langendorff perfused spontaneously beating guinea-pig heart in the absence and presence of glibenclamide. Pinacidil was used as a reference compound, and the protein kinase C inhibitor bisindolylmaleimide was used to study the dilatory effect of levosimendan when the K(ATP) channels in smooth muscle are not inhibited by PKC-dependent phosphorylation. Levosimendan (0.01-1 microM) increased DCFV concentration-dependently and was noncompetitively antagonized by 0.1 microM glibenclamide, whereas pinacidil was inhibited competitively by glibenclamide. In the presence of glibenclamide the positive inotropic and chronotropic effects of levosimendan were unaltered. The effect of bisindolylmaleimide and levosimendan on DCFV was additive. The results indicate that levosimendan induced coronary vasodilation through the opening of the K(ATP) channels. Levosimendan and pinacidil probably have different binding sites on the K(ATP) channels. The additive effect of bisindolylmaleimide and levosimendan on the increase of DCFV suggests that the latter binds to the unphosphorylated form of the channel.     

The cardioprotective effects of levosimendan: preclinical and clinical evidence

Levosimendan, a drug used in the treatment of acute and decompensated heart failure, has positive inotropic and antistunning effects mediated by calcium sensitization of contractile proteins, and vasodilatory and antiischemic effects mediated via the opening of ATP-sensitive potassium channels in vascular smooth-muscle cells. Recently, it also has been shown to act on mitochondrial ATP-sensitive potassium (mitoKATP) channels, an action thought to protect the heart against ischemia-reperfusion damage. This finding has suggested a possible application for levosimendan in clinical situations in which preconditioning would be beneficial (eg, in pre- and perioperative settings in cardiac surgery). The demonstration that levosimendan can prevent or limit myocyte apoptosis via the activation of mitoKATP channels provides a potential mechanism whereby this agent might protect cardiac myocytes during episodes of acute heart failure. This finding may explain why short-term treatment with levosimendan may improve longer-term survival. The present article reviews the literature on the cardioprotective actions of levosimendan, with particular emphasis on its recently recognized effects on mitoKATP channels and the putative preconditioning effects of that action. A therapeutic approach to acute heart failure that includes a cardioprotective strategy could have a clinically meaningful benefit on disease progression beyond alleviation of symptoms.     

Levosimendan: from basic science to clinical trials

Levosimendan is one of the documented pharmacological agents used in the management and treatment of acute and chronic heart failure; it is a novel inodilator agent which enhanced myocardial performance without changes in oxygen consumption. The combination of positive inotropic and vasodilator effects of levosimendan relates to its Ca(2+) - sensitizing and K(+) channels opening effects. Levosimendan has been proposed, in the recent past, to be non-inferior and may have some advantages to standard inotropes; further possible indications for levosimendan have been described, in some observational studies, such as a perioperative use, cardioprotection, cardiogenic shock, sepsis and right ventricular dysfunction. The ability of levosimendan to improve myocardial function without substantially increasing oxygen consumption may appear paradoxical but is possible via improved efficacy not only with regard to the effects on the contractile apparatus of the cardiomyocytes. The aim of this review is to describe the pharmacological characteristics of levosimendan and its clinical applications. The patent review data regarding the use of levosimendan are also discussed in this review article.     

Pharmacologic Treatment of Heart Failure due to Ventricular Dysfunction by Myocardial Stunning

The treatment of heart failure continues to pose a real challenge for clinicians. This condition is sometimes reversible and therapy should therefore pursue this outcome. In the context of coronary ischemic syndromes, myocardial stunning can cause heart failure and even cardiogenic shock, with important prognostic repercussions. Myocardial stunning is mainly due to calcium overload in the cytosol of myocardial cells, the loss of myofilaments and their reduced sensitivity to calcium. Enhanced immune activation with inflammatory phenomena also plays an important role in the pathophysiology of cardiac dysfunction. Increasing evidence has shown that the myocardial ATP-dependent potassium channel (K(ATP)) plays an important role in many myocardial cell functions and that it is involved in ischemia-reperfusion injury and myocardial stunning. K(ATP) is thus considered a therapeutic target in this setting. Currently used inotropic drugs improve contractility by increasing intracellular concentrations of free calcium, but they increase myocardial consumption of energy and even produce arrhythmia; therefore, in this clinical context, they do not seem to be 'pathophysiologically correct' drugs. Levosimendan, a new calcium-sensitizing agent, increases contractility by enhancing the sensitivity of myofilaments to calcium by binding to the C cardiac troponin in cardiac muscle in a calcium-dependent way. Levosimendan also exerts a coronary and systemic vasodilatory effect through its K(ATP) channel-opening properties and may exert other cardioprotective actions through this mechanism. Levosimendan produces positive hemodynamic effects without increasing myocardial oxygen demand or causing arrhythmias. Intravenous levosimendan is generally well tolerated and has been approved by several European countries, and recently recommended in European Society of Cardiology guidelines, as inotropic therapy for the short-term treatment of acute severe decompensated heart failure in adults. Randomized, double-blind trials have shown that levosimendan is not only more clinically and hemodynamically effective but also that it significantly reduces morbidity and mortality when compared with dobutamine or placebo. Clinical trials addressing the use and efficacy of intravenous levosimendan in acute heart failure in patients with systolic dysfunction or cardiogenic shock due to myocardial stunning are scarce. Beneficial effects on myocardial contractility in patients with myocardial stunning have only been shown in small clinical trials. A positive experience with levosimendan in a small series of patients with cardiogenic shock complicating ST-elevation myocardial infarction suggests that the use of this drug in cardiogenic shock should be further evaluated.     

Levosimendan

Levosimendan, a pyridazinone-dinitrile derivative, is a calcium sensitiser with additional action on adenosine triphosphate (ATP)-sensitive potassium channels. It is used intravenously (IV) for the treatment of decompensated cardiac failure. At therapeutic doses, levosimendan exhibits enhanced contractility with no increase in oxygen demands. It also produces antistunning effects without increasing myocardial intracellular calcium concentrations or prolonging myocardial relaxation. Levosimendan also causes coronary and systemic vasodilation. In patients with decompensated congestive heart failure (CHF), IV levosimendan significantly reduced the incidence of worsening CHF or death. IV levosimendan significantly increased cardiac output or cardiac index and decreased filling pressure in the acute treatment of stable or decompensated CHF in large, double-blind, randomised trials and after cardiac surgery in smaller trials. Levosimendan is well tolerated, with the most common adverse events (headache, hypotension, nausea) being secondary to vasodilation. It has not been shown to be arrhythmogenic. Levosimendan has shown no clinically important pharmacokinetic interactions with captopril, felodipine, beta-blockers, digoxin, warfarin, isosorbide-5-mononitrate, carvedilol, alcohol (ethanol) or itraconazole.     

Levosimendan for the treatment of acute heart failure syndromes

Levosimendan is a novel calcium-sensitising agent that has been shown to have beneficial inotropic, metabolic and vasodilatory effects in the treatment of acute and advanced chronic heart failure. Levosimendan binds to troponin-C in cardiomyocytes and, thereby, improves cardiac contractility without disturbing the metabolic status of the heart and increasing myocardial oxygen demand or provoking fatal cardiac arrhythmias. Levosimendan also opens ATP-sensitive potassium channels, causing peripheral arterial and venous dilatation, and increasing coronary flow reserve. When it is given as a short-term therapy, levosimendan enhances cardiac output, reduces systemic vascular resistance and lowers pulmonary capillary wedge pressure. Clinical outcomes were significantly reduced in decompensated or postmyocardial infarction heart failure patients who received levosimendan, compared with those on dobutamine or placebo. Recent investigations focusing on the anti-inflammatory and antiapoptotic actions of levosimendan in the failing heart indicate that improvement of cardiac contractile performance is closely related with the drug-induced reduction of circulating pro-inflammatory cytokines and apoptosis inducers. The most common adverse effects of levosimendan treatment are hypotension and headache. Overall, levosimendan represents an effective and safe option for the treatment of decompensated heart failure patients.     

Levosimendan for the treatment of acute heart failure syndromes

Levosimendan is a novel calcium-sensitising agent that has been shown to have beneficial inotropic, metabolic and vasodilatory effects in the treatment of acute and advanced chronic heart failure. Levosimendan binds to troponin-C in cardiomyocytes and, thereby, improves cardiac contractility without disturbing the metabolic status of the heart and increasing myocardial oxygen demand or provoking fatal cardiac arrhythmias. Levosimendan also opens ATP-sensitive potassium channels, causing peripheral arterial and venous dilatation, and increasing coronary flow reserve. When it is given as a short-term therapy, levosimendan enhances cardiac output, reduces systemic vascular resistance and lowers pulmonary capillary wedge pressure. Clinical outcomes were significantly reduced in decompensated or postmyocardial infarction heart failure patients who received levosimendan, compared with those on dobutamine or placebo. Recent investigations focusing on the anti-inflammatory and antiapoptotic actions of levosimendan in the failing heart indicate that improvement of cardiac contractile performance is closely related with the drug-induced reduction of circulating pro-inflammatory cytokines and apoptosis inducers. The most common adverse effects of levosimendan treatment are hypotension and headache. Overall, levosimendan represents an effective and safe option for the treatment of decompensated heart failure patients.     

Levosimendan, a new calcium-sensitizing inotrope for heart failure

Calcium sensitizers are a new class of inotropes that share the in vitro properties of calcium sensitization and phosphodiesterase inhibition. Levosimendan is a distinct calcium sensitizer, as it stabilizes the interaction between calcium and troponin C by binding to troponin C in a calcium-dependent manner, improving inotropy without adversely affecting lusitropy. It does not exhibit clinically relevant phosphodiesterase inhibition at therapeutic concentrations. It also exerts vasodilatory effects, possibly through activation of several potassium channels and other less well characterized mechanisms. The pharmacokinetics of levosimendan are similar in healthy subjects and patients with heart failure and remain relatively unaltered by age, sex, and organ dysfunction. In preclinical and clinical studies, levosimendan exerted potent dose-dependent positive inotropic and vasodilatory activity. Unlike conventional inotropes, levosimendan is not associated with significant increases in myocardial oxygen consumption, proarrhythmia, or neurohormonal activation. The most common adverse effects are attributable to the vasodilation. Two large, double-blind, randomized trials demonstrated favorable hemodynamic effects, improved tolerability, and a possible mortality benefit over dobutamine and placebo in patients who had acute symptoms of failure and required inotropic therapy. The long-term effect on patient outcomes is being confirmed in ongoing placebo- and inotrope-controlled trials. Levosimendan appears to be an effective inodilator devoid of the detrimental effects of conventional inotropes. In the future, levosimendan may provide a promising alternative to conventional inotropes for patients with acutely decompensated heart failure.     

Levosimendan modulates programmed forms of cell death through K(ATP) channels and nitric oxide

Levosimendan exerts cardioprotection through mitochondrial K(ATP) (mitoK(ATP)) channels opening. In addition, intracoronary levosimendan was found to modulate programmed forms of cell death by nitric oxide (NO) involvement. The aim of this study was to examine the role of mitoK(ATP) channels and NO in the effects of levosimendan on apoptosis/autophagy. In H9c2 cells treated with hydrogen peroxide apoptosis/autophagy, survival signaling, cell viability, mitochondrial membrane potential, and permeability transition pore opening were analyzed through Western blot and colorimetric and fluorescence assays. Pretreatment of H9c2 cells with levosimendan was able to counteract the oxidative injuries caused by hydrogen peroxide. The effects of levosimendan were potentiated by diazoxide and were similar to those elicited by the autophagic activator rapamycin. The autophagic inhibitor 3-methyladenine reduced the effects of levosimendan, whereas after the pan-caspases inhibitor N-Acetyl-Asp-Glu-Val-Asp-al (Z-VAD.FMK), cell survival and autophagy in response to levosimendan increased. Both the mitoK(ATP) channels inhibition and the NO synthase blocking attenuated the cardioprotection elicited by levosimendan. The results have shown that levosimendan protects H9c2 cells against oxidative injuries through the modulation of the interplay between autophagy and apoptosis and the activation of survival signaling. The mitoK(ATP) channels and NO may be involved in such cardioprotection through interference with mitochondrial functioning.     

Multiple signalling pathways underlie the protective effect of levosimendan in cardiac myocytes

Levosimendan is a cardiovascular drug for the treatment of acute and decompensated heart failure. The current weight of evidence on the cardioprotective effects of levosimendan originates from whole heart models and there is no information on the mechanism whereby signalling pathways are activated. In the present study, we investigated the effect of levosimendan on ischaemia/reperfusion injury and the underlying mechanism in cardiac myocytes. Pretreatment with levosimendan reversed the effects of ischaemia and ischaemia/reperfusion on cell viability and enhanced phosphorylation of Akt, p38-mitogen activated protein kinase (MAPK) and extracellular signal-regulated kinases 1/2 (ERK1/2). Inhibitors of these kinases and the blocker of the mitochondrial K(ATP) channels, 5-hydroxydecanoate, completely abolished the protection afforded by levosimendan. Levosimendan stimulated the phosphorylation of Akt, ERK1/2 and p38-MAPK with different kinetics and the activation of these pathways was dependent on the opening of the mitochondrial K(ATP) channels and the production of oxygen free radicals. The levosimendan-induced phosphorylation of ERK1/2 and Akt was reduced by inhibitors of epidermal growth factor receptor and Src. On the other hand, inhibition of the protein kinase A (PKA) pathway reduced phosphorylation of p38-MAPK. Furthermore, p38-MAPK was activated when a phosphodiesterase inhibitor or a selective PKA activator was used. Overall, our results suggest that levosimendan regulates the wiring of the natural salvaging pathways to execute the prosurvival signals. This network includes Akt, ERK1/2 and p38-MAPK. Opening of mitochondrial K(ATP) channels and the subsequent production of oxygen free radicals, the epidermal growth factor receptor/Src, and the cAMP/PKA pathways seem to mediate this response.     

Levosimendan: a parenteral calcium-sensitising drug with additional vasodilatory properties

Levosimendan (Simdax) is a new inodilator developed specifically for the treatment of decompensated heart failure. Its inotropic mechanism is based on calcium sensitisation of myofilaments and its vasodilator actions are related to the opening of ATP-dependent K-channels in the vasculature. Since the inotropic action of levosimendan does not require an increase in cytosolic free calcium, it is less arrhythmogenic than the conventional parenteral beta-agonist inotropes or PDE III inhibiting drugs. Due to the calcium-dependent binding of the drug to troponin C, levosimendan, unlike some other calcium-sensitising drugs, does not prolong diastolic relaxation of the myocytes but acts in synergy with the intramyocellular calcium levels. Furthermore, due to the anti-ischaemic effects of the K-channel opening in myocytes, levosimendan can be used during myocardial ischaemia. In clinical trials, levosimendan has dose-dependently increased cardiac output and decreased pulmonary capillary wedge pressure in patients with heart failure. On the other hand, it also increases heart rate and decreases blood pressure in these patients. In major clinical trials, where patients with decompensated heart failure have been treated with levosimendan, a reduction of overall mortality in comparison to placebo or dobutamine has been seen. This interesting finding should be verified in prospective outcome trials. In any case, the safety of levosimendan during myocardial ischaemia makes this drug valuable in the short-term treatment of decompensated heart failure.     

The use of levosimendan in comparison and in combination with dobutamine in the treatment of decompensated heart failure

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 β-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.     

Levosimendan: implications for clinicians

Levosimendan is a novel calcium sensitizing agent in development for the treatment of acute and chronic heart failure. The agent increases myocardial force without increasing myocyte calcium concentrations, thus reducing the possibility for myocardial necrosis. In addition, the agent also causes vasodilation of coronary and peripheral vessels to improve coronary blood flow and reduce afterload. The short half-life is a benefit for intravenous administration but could be problematic for the drug's use in chronic heart failure. The risk of the development of arrhythmias from levosimendan appears small secondary to an increase in the QTc interval of 15 msec but needs to be evaluated in light of the ability of levosimendan to open adenosine triphosphate (ATP)-sensitive potassium channels. In addition, the agent has not been studied in patients with additional risks for torsades de pointes. Levosimendan has been shown to have beneficial survival effects in several populations; its use improves patient outcomes relative to the standard of care and has the potential to reduce hospital costs associated with heart failure.     

The use of levosimendan in comparison and in combination with dobutamine in the treatment of decompensated heart failure

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.     

An emerging role for calcium sensitisation in the treatment of heart failure

Heart failure occurs in 2 - 3% of the adult population in the developed world. With decompensation of cardiac function, haemodynamic stability can be achieved by using intravenous vasodilators, diuretics and inotropes. Unlike traditional inotropes, Ca2+ sensitisers enhance cardiac function without significantly increasing cardiac oxygen consumption, promoting arrhythmia or impairing lusitropy. The most promising drug in this new class is levosimendan, which has a unique dual mechanism; it enhances cardiac output through a Ca(2+)-dependent stabilisation of cardiac myofilaments and exhibits vasodilatory effects by opening ATP-dependent K(+) channels. Clinical trials have demonstrated the beneficial haemodynamic effects of levosimendan, and prospective trials are currently underway to confirm its potential benefits on long-term prognosis. Updated guidelines from the European Society of Cardiology advise on how to incorporate levosimendan into care for patients who have acute heart failure.     

Levosimendan: a parenteral calcium-sensitising drug with additional vasodilatory properties

Levosimendan (Simdax^®) is a new inodilator developed specifically for the treatment of decompensated heart failure. Its inotropic mechanism is based on calcium sensitisation of myofilaments and its vasodilator actions are related to the opening of ATP-dependent K-channels in the vasculature. Since the inotropic action of levosimendan does not require an increase in cytosolic free calcium, it is less arrhythmogenic than the conventional parenteral β-agonist inotropes or PDE III inhibiting drugs. Due to the calcium-dependent binding of the drug to troponin C, levosimendan, unlike some other calcium-sensitising drugs, does not prolong diastolic relaxation of the myocytes but acts in synergy with the intramyocellular calcium levels. Furthermore, due to the anti-ischaemic effects of the K-channel opening in myocytes, levosimendan can be used during myocardial ischaemia. In clinical trials, levosimendan has dose-dependently increased cardiac output and decreased pulmonary capillary wedge pressure in patients with heart failure. On the other hand, it also increases heart rate and decreases blood pressure in these patients. In major clinical trials, where patients with decompensated heart failure have been treated with levosimendan, a reduction of overall mortality in comparison to placebo or dobutamine has been seen. This interesting finding should be verified in prospective outcome trials. In any case, the safety of levosimendan during myocardial ischaemia makes this drug valuable in the short-term treatment of decompensated heart failure.     

左西孟旦在临床麻醉和重症监护病房中的应用及前景

左西孟旦是一种新型钙增敏剂,在增强心肌收缩力的同时不增加细胞内钙负荷,能激活ATP敏感性钾通道(K_(ATP)通道),具有抗心力衰竭、抗心肌顿抑、降低周围血管阻力、舒张冠状动脉及肺血管等作用。本文综述左西孟旦在临床麻醉和重症监护病房(ICU)中的应用。     

Luteolin inhibits apoptosis and improves cardiomyocyte contractile function through the PI3K/Akt pathway in simulated ischemia/reperfusion

Luteolin, a naturally occurring polyphenol flavonoid, has demonstrated to exert myocardial protection effects. However, the mechanisms have not been fully elucidated. In the present study, we investigated whether luteolin pretreatment was associated with cardioprotection in a rat ischemia/reperfusion (I/R) model. Luteolin significantly not only restored contractility of the left ventricle, but also reduced the infarct size and lactate dehydrogenase leakage during I/R. In addition, luteolin pretreatment significantly improved cardiomyocyte shortening amplitude, decreased the apoptotic rate, upregulated Bcl-2 expression, downregulated Bax expression and raised the Bcl-2/Bax ratio under a simulated ischemia/reperfusion (SI/R) condition. Moreover, luteolin pretreatment increased protein kinase B (Akt) phosphorylation, phospholamban phosphorylation and the expression of sarcoplasmic reticulum calcium ATPase following SI/R. The phosphoinositide 3-kinase (PI3K)/Akt pathway is one of the most important intracellular survival signal pathways. To determine whether luteolin-induced cardioprotection was mediated by the PI3K/Akt pathway, we utilized the PI3K inhibitor LY294002. Inhibition of Akt activity markedly abolished luteolin-induced positive contraction and inhibition of apoptosis in SI/R cardiomyocytes. These results showed that luteolin inhibits apoptosis and improves cardiomyocyte contractile function at least partly through the PI3K/Akt pathway in SI/R.     

新型钙增敏剂左西孟旦和盐酸椒苯酮胺研究进展

新型钙增敏剂左西孟旦对长期服用β受体阻滞剂等药物的心力衰竭患者疗效较好;单用或与地高辛合用对心力衰竭都有一定疗效,口服没有静脉给药疗效明显;用于心脏手术患者可以缩短术后康复时间、降低术后心房颤动发生率,对缺血及再灌注损伤心肌也有保护作用。钙增敏剂盐酸椒苯酮胺也有心肌保护作用,已经完成127例Ⅰ期临床试验,结果显示有良好的耐受性,但疗效及安全性有待进一步确定。本文综述了近年来左西孟旦及盐酸椒苯酮胺的研究进展。