Sustained protective effects of 7-monohydroxyethylrutoside in an in vivo model of cardiac ischemia-reperfusion

Earlier studies have shown that 7-monohydroxyethylrutoside (monoHER), an antioxidant flavonoid, protects against doxorubicin-induced cardiotoxicity. In this study, we investigated potential sustained cardioprotective effects of monoHER in a model of ischemia-reperfusion (I/R) in mice. Ischemia was induced for 30 min by ligating the left anterior descending coronary artery. Afterwards, the ligature was removed and reperfusion was allowed for 6 or 24 h or 2 weeks. MonoHER (500 mg/kg) was given intraperitoneally (i.p.) one hour before ischemia. Treatment with monoHER significantly attenuated myocardial neutrophil influx both at 6 and 24 h after reperfusion by 77% and 76%, respectively. Infarct size was also significantly reduced, 24 h and 2 weeks after reperfusion by 58% and 49%, respectively. Whereas ischemia-reperfusion had no influence on basal levels of cardiac contractility (+dp/dt), responses to dobutamine were blunted 24 h and 2 weeks after reperfusion. In mice treated with monoHER, cardiac contractility response was significantly restored. These results indicate that monoHER exerts a sustained cardioprotective effect on ischemia-reperfusion injury and prevents deterioration of cardiac contractility.     

Electrophysiologic effects of a calcium sensitizer inotrope levosimendan administered intravenously in patients with normal cardiac function

Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents as heart failure therapy. Calcium sensitization of the myofilaments might increase inotropy without influencing cardiac electrophysiology unless modified by ancillary properties of the drugs. Electrophysiologic effects of a calcium sensitizer inotrope levosimendan were examined in short-term intravenous administration in humans. Variables were determined in 10 patients with normal cardiac function during a preceding control phase and levosimendan infusion yielding a high therapeutic concentration of 110 (+/-22) microg/L. Levosimendan increased heart rate by 9 beats/min (p < 0.01) on average and shortened the sinus node recovery time and AH interval. At the tested cycle lengths, levosimendan shortened the effective refractory periods in the atrioventricular node by 40-63 ms (p < 0.05), in the atrium by 22-33 ms (p < 0.001), and in the ventricle by 5-9 ms (p < 0.005) on average. Levosimendan increased ventricular monophasic action potential duration by 9-17 ms at 50% (p < 0.001) and by 5-15 ms (p = 0.07) at 90% levels of repolarization on average. The QT interval during spontaneous rhythm and atrial pacing remained unchanged although increased slightly when corrected to sinus rate (p < 0.001). The observations indicate that levosimendan in short-term administration facilitates impulse formation and conduction in cardiac slow-response tissue, enhances recovery of excitability in the myocardium, and may delay ventricular repolarization. The effects on the ventricle were not substantial, and therefore the likelihood of provoking serious cardiac arrhythmias is not estimated to be high.     

Hemodynamic effects of levosimendan in patients with low-output heart failure after cardiac surgery

Following cardiac surgery, low-output syndrome is relatively common. Since this condition can lead to serious consequences, this postsurgical, low-output state should be reversed whenever possible. Patients with low-output syndrome need drug and fluid management aimed at enhancing cardiac contractility and at facilitating optimal myocardial loading. The objective of this pilot study was to evaluate whether benefits of levosimendan, a new calcium-sensitizing agent approved for treatment of patients with acute exacerbation of chronic heart failure, could be extended to patients with low-output syndrome following cardiac surgery. For this study, each patient was given levosimendan as a loading dose of 12 microg/kg over 10 minutes, followed by a continuous infusion of 0.1 microg/kg/min for 12 hours. Of 11 postsurgical patients with severely impaired cardiac output and hemodynamic compromise, 8 patients (73%) showed evidence of combined hemodynamic improvement (> 30% increase in cardiac index and PCWP corrected to < 18 mmHg) within 3 h after the start of levosimendan infusion. Specifically, cardiac index and stroke volume were significantly increased, while mean arterial pressure, indexed systemic vascular resistance, mean pulmonary pressure, right arterial pressure, and pulmonary capillary wedge pressure were all significantly lowered. Taken together, such changes showed enhanced cardiac output along with significantly decreased preload and afterload--conditions associated with recovery of cardiac function. Levosimendan is thus highly favorable for short-term treatment of patients with low cardiac output following cardiac surgery.     

生脉注射液对离体家兔心脏缺血再灌注损伤保护作用的实验研究

目的观察生脉注射液对离体家兔心脏缺血再灌注损伤的保护作用。方法采用离体兔心Lan-gendorff灌注实验模型,离体兔心24只随机分成3组每组8只。正常对照组连续灌注Krebs-Henseleit(K-H)液60 min;缺血再灌注组关闭主动脉套管停止灌注,30 min后恢复37℃K-H液灌注60 min。生脉注射液组步骤同缺血再灌注组,但在复灌时先用生脉注射液的K-H液(浓度为每500 ml K-H液中加入生脉注射液40 mL)灌注30 min。记录血流动力学指标:冠状动脉流量、左心室舒张压(LVDP)、左心室压力时间变化率(±DP/DT);检测冠状动脉流出液中丙二醛(MDA)、超氧化物歧化酶(SOD)、肌酸激酶(CK)、乳酸脱氢酶(LDH)浓度和心肌组织中MDA、SOD含量。结果生脉注射液组可明显改善缺血再灌注后的血流动力学变化:±DP/DTmax和LVDP较缺血再灌注组显著升高,冠状动脉流量增大;冠状动脉流出液中MDA、LDH、CK以及心肌组织中MDA浓度降低,而冠状动脉流出液和心肌组织中SOD含量均升高(P<0.05),与缺血再灌注组比较,超微结构损伤较轻(P<0.05)。结论生脉注射液具有抗兔离体心脏缺血再灌注损伤的作用。     

Cardiac electrophysiological effects of levosimendan,a new calcium sensitizer

• 1.1. The conventional microelectrode and the patch-clamp techniques were used to study the electrophysiological effects of levosimendan, a new calcium-sensitizing cardiotonic drug, in cardiac ventricular muscle.
• 2.2. Levosimendan (5 W) did not change the main repolarizing currents, such as the inward rectifier potassium, transient outward and the delayed rectifier outward potassium current, in rabbit ventricular myocytes.
• 3.3. In rabbit ventricular muscle, levosimendan, at relatively low concentrations (0.1-1 μM), did not change significantly the amplitude of the inward calcium current but increased the amplitude of the twitch tension.
• 4.4. In guinea pig ventricular muscle, levosimendan, at higher concentrations (1-5 μM), significantly increased the amplitude of the inward calcium current and the slow-response action potential parameters.
• 5.5. It is concluded that levosimendan, in addition to its calcium sensitizing properties characterized by “silent electrophysiology”, exhibits cardiac electrophysiological effects similar to those of phosphodies. terase inhibitors.

     

Hemodynamic effects of anthrax toxins in the rabbit model and the cardiac pathology induced by lethal toxin

Anthrax lethal toxin (LeTx) and edema toxin (EdTx) have been shown to alter hemodynamics in the rodent model, while LeTx primarily is reported to induce extensive tissue pathology. However, the rodent model has limitations when used for comparison to higher organisms such as humans. The rabbit model, on the other hand, has gained recognition as a useful model for studying anthrax infection and its pathophysiological effects. In this study, we assessed the hemodynamic effects of lethal toxin (LeTx) and edema toxin (EdTx) in the rabbit model using physiologically relevant amounts of the toxins. Moreover, we further examine the pathological effects of LeTx on cardiac tissue. We intravenously injected Dutch-belted rabbits with either low-dose and high-dose recombinant LeTx or a single dose of EdTx. The animals' heart rate and mean arterial pressure were continuously monitored via telemetry until either 48 or 72 h post-challenge. Additional animals challenged with LeTx were used for cardiac troponin I (cTnI) quantitation, cardiac histopathology, and echocardiography. LeTx depressed heart rate at the lower dose and mean arterial pressure (MAP) at the higher dose. EdTx, on the other hand, temporarily intensified heart rate while lowering MAP. Both doses of LeTx caused cardiac pathology with the higher dose having a more profound effect. Lastly, left-ventricular dilation due to LeTx was not apparent at the given time-points. Our study demonstrates the hemodynamic effects of anthrax toxins, as well as the pathological effects of LeTx on the heart in the rabbit model, and it provides further evidence for the toxins' direct impact on the heart.     

左西孟旦与米力农在心脏瓣膜置换术围术期的心肌保护作用研究

目的分析比较左西孟旦与米力农在心脏瓣膜置换术围术期的心肌保护作用。方法 60例需要在体外循环辅助下进行心脏瓣膜置换的患者随机分为左西孟旦组、米力农组及对照组,每组20例。左西孟旦组使用左西孟旦注射液,米力农组使用米力农注射液。分别在麻醉诱导后,升主动脉开放后1、8 h,术后24、48 h检测患者血浆心肌肌钙蛋白I(cTnI)、乳酸脱氢酶(LDH)及磷酸肌酸激酶同工酶(CK-MB)含量,观察各组患者术后心脏自动复跳率,并记录三组患者术后监护时间。结果与对照组比较,左西孟旦组和米力农组主动脉开放1 h至术后48 h,患者cTnI、LDH与CK-M B明显降低,且左西孟旦组明显低于米力农组,差异有统计学意义(P <0. 05);左西孟旦组和米力农组患者自动复跳率明显高于对照组,且左西孟旦组明显高于米力农组,差异有统计学意义(P <0. 05)。左西孟旦组和米力农组患者术后拔管时间、ICU监护时间均短于对照组,且左西孟旦组短于米力农组,差异有统计学意义(P <0. 05);三组患者术后住院时间比较差异无统计学意义(P> 0. 05)。结论左西孟旦与米力农对心脏瓣膜置换术患者围术期的心肌缺血再灌注损伤均有明显的保护作用,可增强患者术后心肌收缩力,缩短患者康复时间,左西孟旦较米力农效果更为明显。     

重复无创肢体缺血预适应对大鼠心肌缺血再灌注损伤的保护作用

目的研究重复多次无创肢体缺血预适应对大鼠心肌缺血再灌注损伤的保护作用。方法 SD大鼠24只随机分为对照组、单次无创肢体预适应(LPC)组、反复无创后肢缺血预适应(RLPC)组各8只,观察重复无创性肢体缺血预适应对大鼠心脏缺血再灌注损伤的作用。通过颈动脉插管法测定大鼠的平均动脉压(MAP),肢体Ⅱ导联记录心电图以分析心率、心律失常情况。实验结束后采血测定血清中的丙二醛(MDA)含量、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)的活性,留取心脏染色测定各组梗死面积。结果与对照组相比,LPC组和RLPC组可以减小梗死面积,减轻心律失常情况,血清MDA浓度降低,SOD,GSH-PX的活性增加。但LPC组和RLPC组差异无统计学意义。结论 RLPC对大鼠缺血再灌注损伤的保护作用与LPC相似。     

左西孟旦对瓣膜置换术后心功能影响的临床研究

目的观察左西孟旦对瓣膜置换术后患者心功能的影响。方法选取2013年12月1日至2017年12月1日在湖南中医药大学第一附属医院心胸外科行心脏瓣膜置换手术的患者67例,随机分为对照组(35例,术后接受常规治疗)和左西孟旦组(32例,在常规治疗基础上给予左西孟旦治疗24 h)。所有患者术中留置Swan-Ganz导管,记录术毕、术后24 h、术后72 h肺毛细血管楔压(Pulmonary capillary wedge pressure,PCWP)、肺动脉平均压(Pulmonary average mean pressure,PAMP)、心输出量(Cardiac output,CO),同时抽取静脉血,检测氨基末端脑利钠肽前体(NT-proBNP)水平;术毕、术后7 d行超声心动图检查,记录左心室射血分数(LVEF)、短轴收缩率(FS);记录术后呼吸机辅助时间、ICU治疗时间及不良事件发生情况。结果术毕时,两组患者PCWP、PAMP、CO、NT-proBNP比较差异无统计学意义(P>0.05);术后24、72 h时,两组患者PCWP、PAMP、NT-proBNP较术毕时降低,CO较术毕时升高,且左西孟旦组PCWP、PAMP、NT-proBNP低于对照组,CO高于对照组,差异有统计学意义(P<0.05)。术毕时,两组患者LVEF、FS比较差异无统计学意义(P>0.05);术后7 d时,两组患者LVEF、FS显著高于术毕时,且左西孟旦组高于对照组,差异有统计学意义(P<0.05)。左西孟旦组术后呼吸机辅助时间、ICU治疗时间均较对照组显著减少(P<0.05),两组患者不良事件发生例数比较差异无统计学意义(P>0.05)。结论左西孟旦有助于改善心脏瓣膜置换术后患者的心功能,耐受性和安全性好。     

L-肉碱预处理对离体家兔心肌缺血再灌注损伤的保护作用

目的:观察L-肉碱预处理对离体家兔心肌缺血再灌注损伤的保护作用.方法:采用离体兔心Langendorff灌注实验模型,离体兔心24只,随机等分成3组(n=8).正常对照组:连续灌注K-H液 90 min;缺血再灌注损伤组:灌注 30 min,关闭主动脉套管停止灌注,30 min后恢复37 ℃ K-H液灌注 60 min;L-肉碱组:步骤同缺血再灌注组,但在停灌前先用含10 mmolL-1 L-肉碱的K-H液灌注 30min.记录血流动力学指标:冠脉流量(CF)、左心室舒张压(LVDP)、左心室压力时间变化率(±dp/dt);检测冠脉流出液中丙二醛(MDA)、超氧化物歧化酶(SOD)、肌酸激酶(CK)、乳酸脱氢酶(LDH)浓度和心肌组织中MDA、SOD及L-肉碱的含量.结果:L-肉碱组能显著促进再灌注时心功能恢复:±dp/dtmax和LVDP显著升高;CF增大;冠脉流出液中MDA、LDH、CK以及心肌组织中MDA浓度降低;而冠脉流出液和心肌组织中SOD含量均升高(P<0.05);心肌中L-肉碱含量明显增高(P<0.01);超微结构观察结构损伤较轻(P<0.05).结论:L-肉碱预处理具有抗兔离体心肌缺血再灌注损伤的作用.     

Potassium-specific effects of levosimendan on heart mitochondria

In this study, we evaluated levosimendan, a new drug developed for the treatment of acute and decompensated heart failure, as a potential activator of ATP-sensitive potassium flux to the matrix of cardiac mitochondria. We estimated the KATP channel openers-induced increase in mitochondrial inner membrane permeability for potassium by registering changes in membrane potential of heart mitochondria, oxidizing endogenous substrates. We compared the effect of levosimendan with the effects of the known KATP channel openers diazoxide and pinacidil. Levosimendan (1 microM) accelerated potassium-specific DeltaPsi decrease by 0.15%/s, whereas 50 microM diazoxide by 0.10%/s, and 50 microM pinacidil by 0.08%/s, respectively. These results were confirmed by swelling experiments of non-respiring mitochondria in potassium nitrate medium. We found that levosimendan with an EC50 of 0.83 +/- 0.24 microM activates potassium flux to the mitochondrial matrix. This effect is discussed as a possible explanation of the anti-ischemic action of levosimendan.     

Vasodilator effects of nebivolol in a rat model of hypertension and a rabbit model of congestive heart failure

Both hypertension and congestive heart failure are characterized by a reduced vasodilatory capacity. In both conditions, the impairment of endothelial function is mainly the result of a reduced nitric oxide availability. The highly beta1-selective third-generation adrenoceptor blocker nebivolol displays additional endothelium-dependent vasodilating actions in humans as well as in animal models. In this study, we investigated whether these vasodilating properties of nebivolol are preserved in conditions with endothelial dysfunction. The vasodilatory effects of nebivolol were compared with those of the muscarinic agonist methacholine in isolated aortic rings obtained from spontaneous hypertensive rats and rabbits with experimental heart failure. The methacholine-induced responses were attenuated in aortic rings from both spontaneous hypertensive rats and congestive heart failture rabbits (42+/-6% and 25+/-3% vs. 89+/-3% and 54+/-7% for controls, respectively; P<0.05, n=6-13), indicating an endothelial dysfunction in these preparations. In contrast, nebivolol-induced vasorelaxation remained unaffected in both preparations when compared to control preparations (40+/-12% and 43+/-6% vs. 52+/-8% and 50+/-13% for controls, respectively; P>0.05, n=6-13). These results implicate that the favorable hemodynamic profile of nebivolol may be preserved in patients with hypertension or congestive heart failure despite an impaired endothelial function.     

Protective effects of m-nisoldipine and nisoldipine on myocardial damage in working rabbit hearts after ischemia-reperfusion

m-Nisoldipine 4, 8, 16 nmol/L, nisoldipine 1, 4 nmol/L and nifedipine 4, 8, 16, 50 nmol/L enhanced the recoveries of functional parameters of working rabbit hearts after ischemia-reperfusion, as well as prevented the development of contracture and the release of CPK from the reperfused hearts. m-Nisoldipine 8 nmol/L, nisoldipine 1 nmol/L and nifedipine 8 nmol/L attenuated the reduction of myocardial Na+-K+-ATPase and 5'-nucleotidase activity induced by ischemia-reperfusion. The breakdown of membrane phospholipids and elevation of the myocardial Ca2+-ATPase activity and the free fatty acids level were also prevented.     

Management of acute cardiac failure by intracoronary administration of levosimendan

Acute cardiac failure caused by myocardial infarction or inadequate cardioprotection during heart surgery is associated with increased mortality and morbidity. Levosimendan is a new drug used in heart failure though it is limited by the systemic hypotension, which develops with intravenous administration. Intracoronary (IC) administration however should affect systemic circulation less while maintaining the beneficial cardiac effects of the drug. We herewith report the results from the first such clinical series. Levosimendan was administered IC in 33 consecutive patients who developed cardiogenic shock during heart surgery and were unable to wean off cardiopulmonary bypass despite maximal support. Preadministration/postadministration coronary graft flows, hemodynamic parameters, left ventricular function, and metabolic requirements were measured and compared. Levosimendan significantly increased graft flows and improved hemodynamic parameters. Systolic blood pressure (93 ± 26.4 vs. 106 ± 18.2 mm Hg, P < 0.05) and cardiac index (2.0 ± 0.5 vs. 3.1 ± 0.2, P < 0.001) were increased, whereas systemic vascular resistance (1470.7 ± 114 vs. 1195.8 ± 112, P < 0.01) was reduced. Better myocardial perfusion improved metabolic requirements, with myocardial oxygen extraction and glucose uptake increasing by 72% and 74%, respectively, whereas lactate production was reduced by 64%. Echocardiography demonstrated additional ventricular segment recruitment. Therefore, IC Levosimendan administration in acute heart failure is safe and efficacious producing improved cardiac function without significant detrimental hypotension.     

Lipo-PEG1注射液对无心跳兔肺缺血再灌注损伤的保护作用

目的:研究Lipo-PGE1注射液对无心跳兔肺缺血再灌注损伤的保护作用,并探讨其可能的作用机制。方法:将16只健康新西兰大白兔随机平均分为2组:对照组以低钾右旋糖酐(LPD)液进行肺灌洗及保存;试验组采用Lipo-PGE1注射液(20μg.L-1)加LPD液灌注(进行肺灌洗及保存)。两组都在4℃保存2 h后再灌注1 h,测定经肺氧合后动脉血氧分压值(PaO2)和肺气道峰压值(PawP)。于再灌注结束后取右上肺组织,测其湿重(Wr)与干重(Wd)、计算湿/干重比(Wr/Wd);ELISA法检测超氧化物歧化酶(SOD)、丙二醛(MDA)含量;免疫组化法检测NF-κB的表达;并用光学显微镜和透射电子显微镜观察再灌注后肺组织结构的病理变化。结果:再灌注30 m in后,两组的PaO2逐渐降低,PawP逐渐升高,实验组PaO2降低程度及PawP的升高程度均低于对照组(P<0.01);实验组的SOD明显高于对照组,MDA及肺组织的NF-κB的表达低于对照组(P<0.01),肺组织的病理变化较对照组轻。结论:Lipo-PGE1注射液能减轻无心跳兔肺缺血/再灌注损伤,改善肺功能,具有肺保护功能。     

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.     

Effect of trapidil in myocardial ischemia-reperfusion injury in rabbit

Objectives:

To evaluate the cardioprotective effects of trapidil on myocardial ischemia-reperfusion injury (MIRI) in rabbits.

Materials and Methods:

Rabbits were subjected to 40 min of myocardial ischemia followed by 120 min of reperfusion. Blood for superoxide dismutase (SOD) and malondialdehyde (MDA) were estimated. At the end of reperfusion, the rabbits were sacrificed and the hearts were isolated for histological examination. An apoptotic index (AI) was determined using the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end-labeling (TUNEL) method. The expression of apoptosis-related proteins Bax and Bcl-2 was analyzed using immunohistochemistry. Statistical analyses were performed by one-way analysis of variance (ANOVA), P < 0.05 considered statistically significant

Results:

Trapidil caused a significant (P < 0.05) increase in SOD activity, as decreased MDA levels and significantly (P < 0.05) reduced the expression of Bax as compared with the ischemia-reperfusion (IR) control group.

Conclusion:

Trapidil may attenuate the myocardial damage produced by IR injury and offer potential cardioprotective action.KEY WORDS: Apoptosis index, ischemia-reperfusion, myocardial ischemia-reperfusion injury, trapidil