依达拉奉对犬自体肾移植缺血再灌注损伤的保护作用研究

目的：探讨依达拉奉对犬自体肾移植缺血再灌注损伤的影响及机制。方法：将18 只体重匹配的健康杂种犬随机分为假手术组（S组）、依达拉奉组（ED组）、生理盐水组（PS 组）,每组各6只。S 组仅进行肾手术切除;ED组在阻断前在供体静脉内注入依达拉奉10 mg/kg,然后使用200 mL加入依达拉奉10 mg/kg 的UW液灌洗供体肾并在同样的保存液中保存供体肾8 小时,且再灌注开始时立即在受体静脉内给予依达拉奉10 mg/kg;PS 组同法使用相同体积的生理盐水。再灌注4 h 后检测MDA、MPO、SOD、iNOS、eNOS等活性;术后24 h 检测血清肌酐（Cr）、尿素氮（BUN）浓度;光镜下观察肾组织病理学改变。结果：PS 组MDA显著高于S 组及ED组（P〈0.05）,PS组MPO 含量亦低于S 组及ED组（P〈0.05）。PS组SOD、eNOS 含量显著低于于S组及ED组（P〈0.05）,PS 组iNOS含量高于S 组及ED 组（P〈0.05）,ED组的肾损伤明显减轻。结论：依达拉奉能减轻肾移植缺血再灌注损伤,其机制可能与减轻肾脂质过氧化反应有关。     

依达拉奉对犬自体肾移植缺血再灌注损伤的保护作用研究

目的:探讨依达拉奉对犬自体肾移植缺血再灌注损伤的影响及机制。方法:将18只体重匹配的健康杂种犬随机分为假手术组(S组)、依达拉奉组(ED组)、生理盐水组(PS组),每组各6只。S组仅进行肾手术切除;ED组在阻断前在供体静脉内注入依达拉奉10 mg/kg,然后使用200 mL加入依达拉奉10 mg/kg的UW液灌洗供体肾并在同样的保存液中保存供体肾8小时,且再灌注开始时立即在受体静脉内给予依达拉奉10 mg/kg;PS组同法使用相同体积的生理盐水。再灌注4 h后检测MDA、MPO、SOD、iNOS、eNOS等活性;术后24 h检测血清肌酐(Cr)、尿素氮(BUN)浓度;光镜下观察肾组织病理学改变。结果:PS组MDA显著高于S组及ED组(P0.05),PS组MPO含量亦低于S组及ED组(P0.05)。PS组SOD、eNOS含量显著低于于S组及ED组(P0.05),PS组iNOS含量高于S组及ED组(P0.05),ED组的肾损伤明显减轻。结论:依达拉奉能减轻肾移植缺血再灌注损伤,其机制可能与减轻肾脂质过氧化反应有关。     

针刺联合依达拉奉对缺血再灌注大鼠视网膜自由基代谢的影响

目的:研究针刺联合依达拉奉对大鼠视网膜缺血再灌注时自由基代谢的影响.方法:大鼠随机分为五组:假手术组、模型组、针刺组、依达拉奉组和联合(针刺+依达拉奉)组.建立缺血再灌注模型,于造模后1d,行视网膜电流图(ERG)检查,取视网膜组织,测定各组MDA含量及T-SOD、GSH-Px、CAT活性的变化.结果:①ERG a、b波振幅相对恢复率:联合组、针刺组及依达拉奉组与模型组相比,a、b波振幅相对恢复率升高,差异有显著性(P＜0.05),与针刺组和依达拉奉组相比,联合组作用更为显著(P＜0.05).②MDA含量及T-SOD、GSH-Px、CAT活性:联合组、针刺组及依达拉奉组与模型组相比,MDA显著降低,SOD、GSH-Px、CAT显著升高,差异有显著性(P＜0.05),联合组作用显著优于针剌组或依达拉奉组(P＜0.05).结论:针刺联合依达拉奉具有干预自由基代谢作用,明显减轻缺血再灌注引起的视网膜氧化应激损伤,对视网膜功能起保护作用.     

大鼠脑缺血-再灌注损伤后Beclin-1和LC3的表达及依达拉奉的干预作用

目的:检测大鼠脑缺血-再灌注损伤模型中自噬相关蛋白Beclin-1和LC3在皮层和海马区表达以及依达拉奉的干预。方法:将SD大鼠(雄性)随机分为以下几组:假手术组、模型组、依达拉奉组。采用Zea Longa线栓法通过大脑中动脉阻塞2 h再灌注24 h制备脑缺血-再灌注模型,其中假手术组仅分离左侧颈总动脉。剂量为10 mg/kg的依达拉奉于再灌注前15 mim经腹腔注射。采用神经行为学评分评估大鼠脑神经损伤表现;TTC染色判断模型是否成功和脑部损伤程度;对大鼠神经元细胞进行HE染色,观察其在皮层和海马区的变化;免疫组化检测Beclin-1和LC3的表达。结果:脑缺血-再灌注24 h后,依达拉奉组神经行为学评分为(2.00±0.67),显著低于模型组的(2.50±0.53)(P0.05)。模型组大鼠脑部观察到梗死灶出现,皮层和海马区神经元受损伤,依达拉奉组上述症状减轻。皮层区假手术组、模型组、依达拉奉组的Beclin-1阳性表达率分别为(11.08±0.85)%、(33.42±1.57)%和(25.61±1.39)%,模型组与假手术组和依达拉奉组比较差异都有统计学意义(P0.05);海马区假手术组、模型组、依达拉奉组的Beclin-1阳性表达率分别为(10.34±0.21)%、(31.82±1.73)%和(22.74±1.26)%,模型组与假手术组和依达拉奉组比较差异都有统计学意义(P0.05)。皮层区LC3的阳性表达率分别为(15.33±0.47)%、(39.72±1.73)%和(28.53±1.61)%,模型组与假手术组和依达拉奉组比较差异都有统计学意义(P0.05);海马区LC3的阳性表达率分别为(13.74±0.37)%、(32.53±1.43)%和(25.38±1.23)%,模型组与假手术组和依达拉奉组比较差异都有统计学意义(P0.05)。结论:脑缺血-再灌注后Beclin-1和LC3表达水平增加,而依达拉奉可能通过下调它们的表达减少自噬发生,减轻脑损伤。     

雷米普利与BQ-123合用对大鼠在体心肌缺血／再灌注损伤的保护作用

目的：研究雷米普利与BQ-123合用对大鼠在体心肌缺血／再灌注损伤的影响。方法：健康雄性Wistar大鼠随机分为5组,制备缺血30min再灌注120min模型,采用雷米普利、BQ-123单用及两药联合应用的方式处理实验动物。观察两药合用对大鼠在体心肌缺血／再灌注损伤的保护作用。观察动物心率、血压、心电图ST-段变化,记录缺血期室性心律失常;检测血浆CK及LDH活力;心肌HE染色和TIC染色,定性和定量检测心肌梗死情况。结果：与I／R组比较,各给药组ST-段均明显降低;缺血期室性心律失常（VA）出现时间明显推迟且持续时间明显缩短,联合给药组作用更为显著;心律失常发生率明显降低;血浆CK及LDH活力显著降低且联合给药组降低更为显著;梗死面积明显缩小,心肌损伤程度明显减轻,其中联合给药组变化更为显著。结论：雷米普利、BQ-123单用及联合应用均对大鼠在体心肌缺血／再灌注损伤有保护作用,且两药合用在推迟缺血期VA的出现时间,缩短其持续时间,减少CK及LDH漏出,缩小心肌梗死面积方面优于两药各自单用。     

竹叶提取物对心肌缺血再灌注损伤的保护作用

本文通过两种不同的模型来探讨竹叶提取物对心肌缺血再灌注(缺氧/复氧)损伤的保护作用。在体内模型中不同剂量的竹叶提取物均提高了模型组室内压最大上升和下降速率,降低了左室末期舒张期压力,提高了心输出量。同时降低了模型组肌酸磷酸激酶及乳酸脱氢酶的活性,减少了丙二醛的含量,增加了超氧化物歧化酶的活性,通过电压依赖性钙通道及受体依赖性钙通道降低了钙的含量。说明竹叶提取物对心肌缺血再灌注(缺氧复氧)损伤具有保护作用,其作用是通过电压依赖性钙通道及受体依赖性钙通道降低了钙的含量而对心肌缺血再灌注(缺氧复氧)损伤产生保护作用。     

细胞因子在心肌缺血再灌注损伤中的作用机制

心肌缺血再灌注损伤(Myocardial Ischemic/Reperfusion Injury,MI/RI)已成为临床心肌梗塞病人血管再通后重要的死亡因素之一,对于这一过程中因细胞因子诱导炎症反应的的作用机制仍是目前研究的热点。本文综述了与MI/RI相关的细胞因子的作用及其机制,并就其相互作用进行探讨。     

缺血预处理对缺血/再灌注离体心脏的保护作用

目的：探讨连续多次短暂缺血预处理对缺血/再灌注损伤心肌的保护作用及机制。方法：采用大鼠离体心脏Lan-gendorff灌流模型,观察缺血预处理对心肌缺血/再灌注后不同时间点冠脉流出液中AST、CPK、UDH及冠脉流量,心肌组织中SOD、LPO以及再灌注性心律失常的影响。结果：缺血预处理可以减少缺血/再灌注损伤的心肌冠脉流出液中AST、CPK、LDH的含量,提高心肌SOD活性,降低LPO水平,并且抑制再灌注性心律失常的发生,提高再灌注期间的冠脉流量。结论：缺血预处理对心肌缺血/再灌注损伤具有一定保护作用。     

雌激素对去卵巢大鼠离体心脏缺血／再灌注损伤的保护作用

目的：探讨雌激素对去卵巢大鼠离体心脏缺血／再灌注损伤的保护作用。方法：成年SD雌鼠,随机分为假手术组（Sham）,双侧卵巢切除组（Ovx）和双侧卵巢切除后补充17β-雌二醇组（Ovx＋E2）。各组离体心脏再随机分为不同时间的缺血再灌注亚组。测量的指标包括冠脉流出液中LDH及CK含量、心室肌细胞存活率及产率、基础状态和异丙肾上腺素（ISO）刺激状态下收缩幅度。结果：30min缺血及其各复灌纽均显著增加冠脉流出液中LDH、CK的释放量。Ovx组LDH、CK漏出在30min缺血及再灌注条件下,显著高于正常灌注组,而Ovx＋E2组可减轻心肌损伤,减少LDH、CK的释放。10min和20min缺血对心肌细胞存活率、产率及冠脉流出液中LDH、CK含量影响均不明显。Sham、Ovx、Ovx＋E2各组心肌细胞基础收缩幅度在正常和10minⅠ＋30minR灌注条件下无显著差异。Ovx显著增加其他各组心肌细胞基础收缩和ISO刺激收缩幅度,Ovx＋E2可使其降至Sham水平。结论：雌激素对去卵巢大鼠心肌缺血／再灌注损伤具有保护作用。     

依达拉奉对毒死蜱所致大鼠脑损伤的保护作用及其机制

目的:探讨依达拉奉在毒死蜱诱导的神经元凋亡中的保护作用及其线粒体机制。方法:在随机双盲的原则下,将大鼠分为对照组、毒死蜱组、依达拉奉组(n=6);以毒死蜱(18 mg/0.7 ml/kg, sc.)造模,在注射毒死蜱1 h后用依达拉奉(10 mg/1.6 ml/kg, ip.)治疗。连续注射毒死蜱及依达拉奉28 d后,通过旷场和水迷宫试验测试大鼠学习记忆能力。在心脏灌流后取大鼠脑组织,通过HE染色检测大脑海马区的神经元损伤情况以及透射电子显微镜观察线粒体和细胞核损伤情况。测定Na⁺-K⁺-ATP酶、ATP含量判断线粒体损伤情况。用免疫组织化学和免疫印迹法测定线粒体分裂蛋白DRP1及DRP1的Ser 637位点磷酸化的表达。结果:与对照组相比,毒死蜱组大鼠在旷场实验的3 min内的总运动距离和平均速度明显减小(P<0.01),在水迷宫试验中的1 min内的逃避潜伏期明显延长、平台穿越次数明显减少(P<0.01),脑组织的ATP酶活性明显降低(P<0.01)且ATP含量下降(P<0.05)、线粒体DRP1的Ser637位点...     

大鼠肢体预缺血减小心肌缺血-再灌注后的梗塞范围

在氨基甲酸乙酯麻醉大鼠上观察肢体预缺血(limb ischemic preconditioning,LIP)对缺血-再灌注(ischemia—reperfusion,IR)心肌的影响,旨在探讨LIP对IR心肌有无保护效应,并明确腺苷和神经通路是否参与此效应。所得结果如下:(1)在心脏缺血30 min和再灌注120 min过程中,梗塞心肌占缺血心肌的51.48±0.82％。(2)LIP时心肌梗塞范围为35.14±0.88％,较单纯心肌缺血-再灌注时显著减小(P<0.01),表明LIP对心肌有保护作用。(3)事先切断股神经可取消LIP的保护效应。(4)股动脉内局部给予腺苷(10nmol/kg),可模拟LIP对心肌的保护作用;心肌梗塞范围是37.28±1.68％,而股静脉内注射同等剂量腺苷则无保护作用。(5)股动脉内预先应用腺苷A.受体拈抗剂8-环戊-1,3-二丙基嘌呤(DPCPX)(32 nmol/kg)可部分阻断LIP诱发的心肌保护效应。以上结果表明,肢体短暂预缺血可减小心肌缺血-再灌注后的梗塞范围,而局部释放的腺苷和由此所激活的相关的神经通路在LIP的心肌保护中起重要作用。     

A3 adenosine receptor agonist IB-MECA reduces myocardial ischemia-reperfusion injury in dogs

We examined the effect of the A3 adenosine receptor (AR) agonist IB-MECA on infarct size in an open-chest anesthetized dog model of myocardial ischemia-reperfusion injury. Dogs were subjected to 60 min of left anterior descending (LAD) coronary artery occlusion and 3 h of reperfusion. Infarct size and regional myocardial blood flow were assessed by macrohistochemical staining with triphenyltetrazolium chloride and radioactive microspheres, respectively. Four experimental groups were studied: vehicle control (50% DMSO in normal saline), IB-MECA (100 microg/kg iv bolus) given 10 min before the coronary occlusion, IB-MECA (100 microg/kg iv bolus) given 5 min before initiation of reperfusion, and IB-MECA (100 microg/kg iv bolus) given 10 min before coronary occlusion in dogs pretreated 15 min earlier with the ATP-dependent potassium channel antagonist glibenclamide (0.3 mg/kg iv bolus). Administration of IB-MECA had no effect on any hemodynamic parameter measured including heart rate, first derivative of left ventricular pressure, aortic pressure, LAD coronary blood flow, or coronary collateral blood flow. Nevertheless, pretreatment with IB-MECA before coronary occlusion produced a marked reduction in infarct size ( approximately 40% reduction) compared with the control group (13.0 +/- 3.2% vs. 25.2 +/- 3.7% of the area at risk, respectively). This effect of IB-MECA was blocked completely in dogs pretreated with glibenclamide. An equivalent reduction in infarct size was observed when IB-MECA was administered immediately before reperfusion (13.1 +/- 3.9%). These results are the first to demonstrate efficacy of an A3AR agonist in a large animal model of myocardial infarction by mechanisms that are unrelated to changes in hemodynamic parameters and coronary blood flow. These data also demonstrate in an in vivo model that IB-MECA is effective as a cardioprotective agent when administered at the time of reperfusion.     

钙敏感受体通过JNK途径参与内毒素心肌损伤*

目的: 观察内毒素所致的心肌损伤中,钙敏感受体(CaSR)对c-Jun氨基末端激酶 (JNK)途径的影响。方法: 腹腔注射内毒素(5 mg/kg)制作新生大鼠内毒素心肌损伤模型,Wistar新生大鼠随机分为6组:对照组、内毒素组、CaSR激动剂组、CaSR抑制剂组、JNK抑制剂组、CaSR抑制剂+JNK抑制剂组。HE染色观察心肌形态, 测定血清乳酸脱氢酶(LDH)含量,PCR检测IL-6的mRNA表达,Western blot检测CaSR及JNK的蛋白表达。结果: 与对照组相比,内毒素组心肌损伤加重,LDH含量、IL-6的mRNA表达、CaSR和JNK的蛋白表达均明显增加(P＜0.05)。与内毒素组比较,CaSR激动剂组心肌损伤加重,LDH含量、IL-6的mRNA表达、CaSR和JNK的蛋白表达增加(P＜0.05); CaSR抑制剂组心肌损伤减轻,LDH含量、CaSR和JNK的蛋白表达减少(P＜0.05);JNK抑制剂组心肌损伤进一步减轻,LDH含量、IL-6的mRNA表达、CaSR和JNK的蛋白表达均减少(P＜0.05);CaSR抑制剂+JNK抑制剂组心肌损伤明显减轻,LDH含量、IL-6的mRNA表达、CaSR和JNK的蛋白表达进一步减少(P＜0.05)。结论: CaSR可能通过JNK途径参与内毒素所致的心肌损伤。     

Effect of aminoguanidine on ischemia-reperfusion induced myocardial injury in rats

Myocardial ischemia-reperfusion (MI/R) has been implicated in the induction of inducible nitric oxide synthase (iNOS) that leads to increase production of nitric oxide (NO). Recently, excessive production of NO has been involved in causing myocardial injury. In our in vivo model, we examined the effects of aminoguanidine (AMG), a known iNOS inhibitor, on percentage infarct size in anaesthetized rats. A total of 14 rats were equally divided into two groups (n = 7 in each group). To produce myocardial necrosis, the left main coronary artery was occluded for 30 min, followed by 120 min of reperfusion, in anesthetized rats. AMG (200 mg kg⁻¹) was given intravenously 10 min before occlusion. The volume of infarct size and the risk zone were determined by planimentry of each tracing and multiplying by the slice thickness. Infarct size was normalized by expressing it as a percentage of the area at risk. Hemodynamic parameters were measured via the left carotid artery. Compared to MI/R group, whereas AMG administration elevated mean arterial blood pressure, statistically reduced the myocardial infarct size (21± 1 and 14± 4%, respectively) and infract size/risk zone (53± 3 and 37± 5%, respectively) in rat model of ischemia-reperfusion. In conclusion, this study indicates that iNOS inhibitor, AMG, show reduction in NO’s side effect in I/R injury.     

Lipocortin 1 reduces myocardial ischemia-reperfusion injury by affecting local leukocyte recruitment.

We assessed here the effect of the glucocorticoid-regulated protein lipocortin 1 (LC1) in a model of rat myocardial ischemia reperfusion. Treatment of animals with human recombinant LC1 at the end of a 25-min ischemic period significantly reduced the extent of infarct size in the area at risk as measured 2 h later, with approximately 50% inhibition at the highest dose tested of 50 microg per rat (equivalent to 5.4 nmol/kg). The protective effect of LC1 was abolished by protein denaturation and not mimicked by the structurally related protein annexin V. A combination of electron and light microscopy techniques demonstrated the occurrence of the myocardial damage at the end of the reperfusion period, with loss of fiber organization. LC1 provided a partial and visible protection. The dose-dependent protection afforded by LC1 was paralleled by lower values of myeloperoxidase activity, tumor necrosis factor a, and macrophage inflammatory protein-1a. The functional link between migrated leukocytes and the myocardial damage was confirmed by electron and light microscopy, and a significantly lower number of extravasated leukocytes was counted in the group of rats treated with LC1 (50 microg). In conclusion, we demonstrate for the first time that LC1 reduces the leukocyte-dependent myocardial damage associated with an ischemia-reperfusion procedure.     

The protective effect of ApolipoproteinA-I on myocardial ischemia-reperfusion injury in rats

It is well established that reperfusion of heart is the optimal method for salvaging ischemic myocardium, however, the success of this therapy could be limited by reperfusion injury, which is involved in inflammatory responses. High density lipoprotein (HDL) has an anti-inflammatory function and can protect the heart from ischemia-reperfusion (I/R) injury. In this study, we investigated the cardioprotective role of apolipoprotein A-I (ApoA-I), the major apolipoprotein of HDL, in I/R injury. Using rats subjected to myocardial I/R by ligation of left anterior descending coronary artery (LAD), we found that administration of ApoA-I (20 mg/kg, iv) before the onset of reperfusion of myocardial infarction can significantly reduce serum creatine kinase (CK) levels (62.1+/-13.8%, p<0.01) and heart TNF-alpha as well as IL-6 levels, compared with saline controls (40.4+/-14.7%, 44+/-9.8%, p<0.01 respectively). Moreover, ApoA-I treatment suppresses the expression of ICAM-1 on endothelium, thus diminishing neutrophil adherence, transendothelial migration, and the subsequent myocyte injury. We concluded that ApoA-I could effectively protect rat heart from I/R injury.     

Effect of estrogen on global myocardial ischemia-reperfusion injury in female rats

We investigated the effects of estrogen on global myocardial ischemia-reperfusion injury in rats that were ovariectomized (Ovx), sham-operated, or ovariectomized and then given 17beta-estradiol (E(2)beta) supplementation (Ovx+E(2)beta). Hearts were excised, cannulated, perfused with and then immersed in chilled (4 degrees C) cardioplegia solution for 30 min, and then retrogradely perfused with warm (37 degrees C), oxygenated Krebs-Henseleit bicarbonate buffer for 120 min. The coronary flow rate, first derivative of left ventricular pressure, and nitrite production were all significantly lower in Ovx than in sham-operated or Ovx+E(2)beta hearts. However, coronary flow rates or nitrate production were not consistently different throughout the entire reperfusion period. Ca(2+) accumulated more in Ovx rat hearts than in sham-operated or Ovx+E(2)beta hearts, and mitochondrial respiratory function was lower in Ovx hearts than in hearts from the other two groups. Marked interstitial edema and contraction bands were seen in hematoxylin-eosin-stained sections of Ovx rat hearts but not in hearts from either of the other groups. Hematoxylin-basic fuchsin-picric acid-stained sections revealed fewer viable myocytes in hearts from the Ovx group than from the sham or Ovx+E(2)beta group. Transmission electron microscopy demonstrated more severely damaged mitochondria and ultrastructural damage to myocytes in Ovx rat hearts. Our results indicate that estrogen plays a cardioprotective role in global myocardial ischemia-reperfusion injury in female rats.     

Effects of tamoxifen on myocardial ischemia-reperfusion injury model in ovariectomized rats

The purpose of this study is to examine the antiarrhythmic and antioxidant effects of tamoxifen, one of the selective estrogen modulators, in ovariectomized rats subjected to myocardial ischemia-reperfusion (I/R) injury. A month after ovariectomy, rats were divided into four groups: (I) ovariectomized controls without any treatment, (II) ovariectomized rats treated with vehicle dimethylsulfoxide (DMSO), (III)–(IV) ovariectomized rats treated with tamoxifen 1 or 10 mg/kg,sc daily for 14 days. To produce arrhythmia, the left main coronary artery was occluded for 7 min, followed by 7 min of reperfusion. The blood pressure (BP), heart rate (HR), electrocardiography (ECG) was recorded before and during the ischemia-reperfusion period. The blood levels of malondialdehyde (MDA), creatine kinase (CK), glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione reductase (GR), and catalase (CAT) were measured after the rats were killed. Tamoxifen reduced the incidence of ventricular tachycardia (VT) on ischemia and reperfusion as well as the incidence and duration of reversible ventricular fibrillation (VF) on reperfusion. I/R injury caused a significant fall in GSH, GSH-Px as well as an increase in MDA and CK levels in the control group when compared to tamoxifen treated groups. The changes in levels of CAT and GR were however, not significant. In conclusion, our findings suggest that tamoxifen has cardioprotective effects against I/R injury in rats, likely its antioxidant properties.     

Resveratrol protects myocardial ischemia-reperfusion injury through both NO-dependent and NO-independent mechanisms

We previously showed that resveratrol (3,4',5-trihydroxystilbene) stimulates NO production and is cardioprotective in rat heart subjected to ischemia-reperfusion (I/R rat heart). We now show that in I/R rat heart, inducible nitric oxide synthase (iNOS) expression is markedly induced, while expression of endothelial nitric oxide synthase (eNOS) and nueronal nitric oxide synthase (nNOS) is unchanged. In animals preconditioned with resveratrol (0.5 to 1 mg/kg body wt), I/R-induced iNOS induction is abrogated; however, expression of eNOS and nNOS is greatly upregulated. The protective effects of resveratrol on I/R rat heart include reduced rhythm disturbances, reduced cardiac infarct size, and decreased plasma levels of lactate dehydrogenase (LDH) and creatine kinase (CK). Among these, the reductions in LDH/CK levels and infarct size are NO-dependent as the coadministration of N(omega)-nitro-L-arginine methyl ester (L-NAME, 1 mg/kg body wt) with resveratrol abolishes the resveratrol effect. In contrast, the reductions in the severity of ventricular arrhythmia and mortality rate are not affected by L-NAME coadministration, suggesting that a NO-independent mechanism is involved.     

Sphingolipid therapy in myocardial ischemia-reperfusion injury

Sphingolipids are known to play a significant physiological role in cell growth, cell differentiation, and critical signal transduction pathways. Recent studies have demonstrated a significant role of sphingolipids and their metabolites in the pathogenesis of myocardial ischemia-reperfusion injury. Our laboratory has investigated the cytoprotective effects of N,N,N-trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analogue on myocardial and hepatic ischemia-reperfusion injury in clinically relevant in vivo murine models of ischemia-reperfusion injury. TMS administered intravenously at the onset of ischemia reduced myocardial infarct size in the wild-type and obese (ob/ob) mice. Following myocardial I/R, there was an improvement in cardiac function in the wild-type mice. Additionally, TMS also decreased serum liver enzymes following hepatic I/R in wild-type mice. The cytoprotective effects did not extend to the ob/ob mice following hepatic I/R or to the db/db mice following both myocardial and hepatic I/R. Our data suggest that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals which may be due to altered signaling mechanisms in these animal models. Here we review the therapeutic role of TMS and other sphingolipids in the pathogenesis of myocardial ischemia-reperfusion injury and their possible mechanisms of cardioprotection.