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1.
We investigated the anti-apoptotic effect of orientin, from bamboo leaves (Phyllostachys nigra), on rat heart after treatment with ischemia/reperfusion (I/R), and on rat cardiomyocytes injured by hypoxia/reoxygenation (H/R). I/R injury was induced by occluding the left anterior descending coronary artery for 45 min and restoring perfusion for 240 min. Orientin (0.5, 1.0 and 2.0 mg kg- 1) or its vehicle was injected i.v. 10 min prior to ischemia. Cultured cardiomyocytes were subjected to hypoxia for 120 min, then reoxygenated for 60 min to induce H/R. Vehicle or orientin (3, 10, 30 μmol l- 1) was added 10 min before hypoxia and reoxygenated. TUNEL assay and DNA fragmentation assay demonstrated that myocardium apoptosis was attenuated by pretreatment with orientin (0.5, 1.0 and 2.0 mg kg- 1). Flow cytometric analysis also showed that apoptosis of cardiomyocytes was reduced by pretreatment with orientin (3, 10 and 30 μmol l- 1). In addition, results of immunohistochemistry and Western blot analysis showed that orientin increased the expression of bcl-2 and reduced Bax expression, resulting in up-regulation of the bcl-2/Bax ratio. Cytochrome c (Cyt-c) and caspase-3 expression was also reduced in myocardium and cardiomyocytes injured by I/R and H/R. These observations indicate that orientin exerts a potent cardioprotective effect on I/R- and H/R-treated myocardium and cardiomyocytes, and inhibits apoptosis by preventing activation of the mitochondrial apoptotic pathway (cytochrome c-caspase-3).  相似文献   

2.
1 Isolated rabbit hearts were perfused aerobically for 120 min, made ischaemic for 90 min, or made ischaemic for 90 min and then reperfused for 30 min. 2 Some rabbits were pretreated with 6-hydroxydopamine (6-OHDA), given as three separate intravenous doses of 30, 20 and 20 mg/kg, 20 to 48 h before they were killed; others (controls) received saline according to the same regime. 3 Mitochondria were harvested from left ventricular homogenates and their function assessed by measuring state 3O2 consumption (state 3 QO2), respiratory control index (RCI), phosphate: oxygen ratio (ADP:O), Ca2+ content, and ATP-producing activity. In other experiments peak left ventricular developed tension was recorded. 4 In hearts from saline-treated animals, mitochondrial state 3 QO2, RCI and ATP producing activities were reduced after global ischaemia, with or without reperfusion. There was a small gain in mitochondrial Ca2+ after ischaemia, and a large gain upon reperfusion. 5 6-OHDA pretreatment provided some protection against the effects of ischaemia and reperfusion on mitochondrial function and on peak developed tension. 6 It was concluded that chemical sympathectomy with 6-OHDA does not duplicate the effect of prolonged beta-adrenoceptor blockade in protecting mitochondrial function against the deleterious effects of ischaemia and reperfusion.  相似文献   

3.
猪缺血心肌嗜中性白细胞浸润及维拉帕米的保护作用   总被引:4,自引:0,他引:4  
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4.
促红细胞生成素(erythropoietin,EPO)是一种糖蛋白激素,在调节红细胞的增殖、分化、成熟的过程中起着极为重要的作用。近来有报道,EPO对心肌早期缺血/再灌注损伤有明显的保护效应。有研究发现,超过一定缺血时间后的晚期再灌注对缺血心肌也有一定的损伤作用。EPO对晚期缺血/再灌注心肌的影响如何,国内外尚无研究。本实验旨在通过兔的晚期缺血/再灌注模型,观察促红细胞生成素对此种病理生理状态下心肌的影响,并探讨其可能的机制。  相似文献   

5.
The role of iron-catalysed hydroxyl radical production in development of myocardial injury was examined in an in vivo rabbit heart with regional ischaemia (45 min) and reperfusion (3 h). Open-chest anaesthetised rabbits were assigned to control (saline) or desferrioxamine-treated [30 mg/kg subcutaneously (s.c.) plus 1, 10, 20, or 100 mg/kg/h intravenously (i.v.) starting 15 min before ischaemia] groups. Haemodynamics and ECG were monitored throughout. Following reperfusion, hearts were excised and perfused in vitro with buffer. The artery was religated, and fluorescent particles were injected to delineate the ischaemic zone. Tetrazolium staining was used to define necrosis. Planimetry was performed on photographed heart slices for calculation of the size of the hearts and of the ischaemic and infarcted zones. Infarct size (as a percentage of ischaemic zone size) in control hearts was 51.2 +/- 5.8% (n = 10) and in the groups treated with desferrioxamine 1, 10, 20, and 100 mg/kg/h it was 53.1 +/- 11.7% (n = 8), 45.3 +/- 6.3% (n = 9), 65.1 +/- 10.1% (n = 6), and 52.5 +/- 9.4% (n = 7), respectively (p = NS vs. control in each instance). In addition, no antiarrhythmic effects were observed at any dose. Thus, iron-catalysed hydroxyl radical damage may not play a role in the pathogenesis of tissue injury under these conditions.  相似文献   

6.
In the present study, interaction of the ATP-sensitive K+-channel blocker glibenclamide with enantiomers of the antihypertensive drug, cicletanine, was studied on ischaemic myocardial function, lactate-dehydrogenase (LDH) release, and early reperfusion-induced ventricular fibrillation (VF). Isolated working rat hearts subjected to 10-min coronary artery occlusion followed by 2-min reperfusion were perfused with 1.5x10(-5)-6.0x10(-5)M D-cicletanine[+] (BN50417) and L-cicletanine[-] (BN50418), respectively. Their interaction with 10(-7) M glibenclamide was also studied. The most effective concentration of BN50418 (3x10(-5) M) increased ischaemic aortic flow (AF) from its non-treated control value of 20.3+/-1.16 to 30.3+/-2.6 ml min-1(P<0.01), decreased left ventricular end-diastolic pressure (LVEDP) from 1.81+/-0.05 to 0.97+/-0.08 kPa (P<0.001), attenuated ischaemia-induced increase in LDH leakage from 164+/-41 to 14.8+/-20 mU min-1g-1 wet wt. (P<0.01) at the 10th-min of coronary occlusion, and reduced VF upon reperfusion. Glibenclamide did not considerably affect cardiac performance, however, it inhibited the anti-ischaemic but not the antiarrhythmic effect of BN50418. BN50417 (3x10(-5) M) tended to improve ischaemic AF to 24.2+/-1.1 ml min-1, and significantly attenuated ischaemia-induced increase in LVEDP to 1.3+/-0.08 kPa (P<0.01), relative increase in LDH release to 29.4+/-44 mU min-1g-1(P<0.05), and alleviated reperfusion-induced VF. Glibenclamide abolished the anti-ischaemic and antiarrhythmic effect of BN50417. The cardioprotective effect of both enantiomers of cicletanine involves a glibenclamide-sensitive mechanism, however, the antiarrhythmic effect of BN50418 is not glibenclamide sensitive. BN50418 is the more potent enantiomer of cicletanine in terms of its cardioprotective effect.  相似文献   

7.
Myocardial ischaemia and reperfusion lead to myocardial cell death due, at least in part, to apoptotic mechanisms. Although cysteinyl aspartate-specific proteinase (caspase) activation is a major event and the most-cited culprit in the development of apoptosis, its potential contribution to ischaemic myocardial cell death is largely unknown. To study the role of caspase activation, isolated rat hearts (n=6 per group) were subjected to 30 min coronary artery occlusion followed by 120 min reperfusion. A non-selective [0.1 or 0.5 microM acetyl-Tyr-Val-Ala-Asp chloromethylketone (YVAD-cmk)] or selective caspase inhibitors [0.07 or 0.2 microM acetyl-Asp-Glu-Val-Asp-cmk (Ac-DEVD-cmk, caspase-3 inhibitor); 0.07 or 0.2 microM benzoxycarbonyl-Leu-Glu-OMe-His-Asp(OMe)-fluoromethylketone (z-LEHD-fmk, caspase-9 inhibitor)] were added to the perfusate at the start of reperfusion. Non-selective caspase inhibition with 0.1 or 0.5 microM YVAD-cmk limited infarct size: (21 +/- 4%, P<0.05; 17 +/- 3%, P<0.05, respectively) compared with the ischaemic/reperfused control (32 +/- 5%). In hearts treated with 0.1 or 0.5 microM caspase II non-selective inhibitor, the fraction of terminal-deoxynucleotidyl-transferase deoxyuridine nick end labelling (TUNEL)-positive myocyte nuclei in the infarcted zone was reduced from the ischaemic/reperfused non-treated control of 11.2 +/- 2.1% to 6.2 +/- 1.6% (P<0.05) and 1.2 +/- 0.2% (P<0.05), respectively. The recovery of post-ischaemic cardiac function (coronary flow, aortic flow and left-ventricular developed pressure) improved significantly with the application of the non-selective caspase inhibitor as well. In hearts perfused with specific caspase inhibitors (caspase-3 and caspase-9) there was no significant reduction in the infarct size, no improvement in post-ischaemic cardiac function and no reduction of apoptotic cell death. We conclude that non-specific inhibition of caspases may be therapeutically beneficial in myocardial ischaemia/reperfusion-induced damage, while selective caspase inhibitors may fail to prevent such reperfusion-induced injury in our model system.  相似文献   

8.
Effects of neferine on the isolated rabbit myocardium   总被引:2,自引:0,他引:2  
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9.
Initiation of 60 min ischaemia to rat isolated hearts produced a depression in developed tension and heart rate. Subsequent reperfusion caused a greatly exacerbated creatine phosphokinase (CPK) efflux and limited functional recovery. Sulphinpyrazone (100 ng ml-1 and 1 microgram ml-1) significantly reduced CPK release, particularly after reperfusion, the lower concentration being more effective. A reduction in the mechanical depression during ischaemia and enhanced recovery after reperfusion were seen only with 100 ng ml-1 sulphinpyrazone. Heart rate and coronary perfusion pressure were unaffected by drug treatment. The reduction in reperfusion-induced CPK efflux by 100 ng ml-1 sulphinpyrazone was maximal when the drug was present throughout the perfusion period although some protection was evident when sulphinpyrazone was present either during ischaemia or reperfusion only. An enhanced recovery in contractility was seen only when the drug was present throughout all phases of perfusion. It is suggested that sulphinpyrazone exerts a direct protective effect on the heart particularly during reperfusion. The degree of protection is critically dependent on the concentration of sulphinpyrazone.  相似文献   

10.
BACKGROUND AND PURPOSE:Ischaemia damages to the cardiac mitochondria by increasing generation of reactive oxygen species (ROS) and peroxidation of cardiolipin. The inhibited mitochondrial function leads to the cardiac injury during reperfusion. Propofol (2, 6-diisopropylphenol), an intravenous anaesthetic, has been shown to decrease cardiac ischaemia and reperfusion injury. In the present study, we propose that propofol protects mitochondrial function and decreases cardiac injury by prevention of cardiolipin peroxidation during ischaemia and reperfusion. EXPERIMENTAL APPROACH:After isolation of mitochondria from isolated rat heart perfused on a Langendorff model, various mitochondrial bioenergetic parameters were evaluated such as rates of mitochondrial oxygen consumption, H(2)O(2) production, complex I and III activity as well as the degree of lipid peroxidation and cardiolipin content. The action of propofol was also explored in isolated mitochondria. And the effect of cardiolipin was evaluated by fusing cardiolipin liposome with mitochondria. KEY RESULTS:Propofol treatment had strong dose-dependent protection attenuating these parameters alterations in reperfused rat heart and isolated mitochondria. Additionally, cardiolipin treatment had the same protective effect, compared with propofol treatment at high concentration. CONCLUSIONS AND IMPLICATIONS:The protective effect of propofol appears to be due, at least in part, as a chemical uncoupler, to the interruption of the vicious circle of ROS-cardiolipin-complexes of the respiratory chain-ROS through preserving the content and integrity of cardiolipin molecules by ROS attack. These findings may provide an explanation for some of the factors responsible for cardioprotection and one approach exploring an available antioxidant.  相似文献   

11.
The contribution of alpha-melanocyte-stimulating hormone (alpha-MSH) treatment, an active fragment of adrenocorticotropic hormone (ACTH), to the recovery of postischemic cardiac function, infarct size, the incidence of reperfusion-induced ventricular fibrillation and apoptotic cell death was studied in ischemic/reperfused isolated rat hearts. Rats were subcutaneously injected with 40, 200 and 400 microg/kg of alpha-MSH, and 12 h later, hearts were isolated, perfused and subjected to 30 min of ischemia followed by 120 min of reperfusion. Thus, after 120 min of reperfusion, with the concentration of 200 microg/kg alpha-MSH, coronary flow, aortic flow and left ventricular developed pressure were significantly improved from their control values of 14.6+/-0.6 ml/min, 7.5+/-0.5 ml/min and 9.1+/-0.4 kPa to 20.2+/-0.4 ml/min (p<0.05), 31.5+/-0.9 ml/min (p<0.05) and 15.9+/-0.6 (p<0.05) kPa, respectively. With the doses of 40, 200 and 400 microg/kg of alpha-MSH, infarct size was reduced from its control value of 38+/-5% to 33+/-6% (NS), 17+/-3% (p<0.05) and 19+/-4% (p<0.05), respectively. The reduction in the incidence of reperfusion-induced ventricular fibrillation followed the same pattern. It is reasonable to assume that a reduction in infarct size, in the alpha-MSH-treated myocardium, resulted in a reduction as well in apoptotic cell death. Although we did not specifically study the exact mechanism(s) of alpha-MSH-afforded postischemic protection, we assume that this protection may be related to alpha-MSH-induced corticosterone release and corticosterone-induced de novo protein synthesis, which reflected in the recovery of postischemic cardiac function in isolated hearts. Thus, interventions that are able to increase plasma corticosterone or glucocorticoid release may prevent the development of ischemia/reperfusion-induced damage.  相似文献   

12.
13.
1. Ischaemia/reperfusion causes intracellular calcium overloading in cardiac cells. Administration of calcium antagonists reduces myocardial infarct size. Recent in vitro studies have demonstrated that calcium plays a critical role in the signal transduction pathway leading to apoptosis. However, whether or not calcium antagonists may reduce myocardial apoptosis induced by ischaemia-reperfusion, and thus decrease myocardial infarction, has not been directly investigated. 2. The present study investigated the effects of benidipine, an L-type calcium channel blocker, on myocardial infarct size, apoptosis, necrosis and cardiac functional recovery in rabbits subjected to myocardial ischaemia/reperfusion (MI/R, 45 min/240 min). Ten minutes prior to coronary occlusion, rabbits were treated with vehicle or benidipine (10 microg x kg(-1) or 3 microg x kg(-1), i.v.). 3. In the vehicle-treated group, MI/R caused cardiomyocyte apoptosis as evidenced by DNA ladder formation and TUNEL positive nuclear staining (12.2+/-1.1%). Treatment with 10 microg x kg(-1) benidipine lowered blood pressure, decreased myocardial apoptosis (6.2+/-0.8%, P<0.01 vs vehicle) and necrosis, reduced infarct size (20+/-2.3% vs 49+/-2.6%, P<0.01), and improved cardiac functional recovery after reperfusion. Administering benidipine at 3 microg x kg(-1), a dose at which no haemodynamic effect was observed, also exerted significant anti-apoptosis effects, which were not significantly different from those observed with higher dose benidipine treatment. However, treatment with this low dose benidipine failed to reduce myocardial necrosis. 4. These results demonstrate that benidipine, a calcium antagonist, exerts significant anti-apoptosis effects, which are independent of haemodynamic changes. Administration of benidipine at a higher dose produced favourable haemodynamic effects and provided additional protection against myocardial necrotic injury and further improved cardiac functional recovery.  相似文献   

14.
为了研究多柔比星 (Dox)心脏损伤机理和牛磺酸 (Tau)的保护作用 ,将实验兔随机分成Dox组 ,对照组 (即生理盐水组 ,NS组 )和Dox +Tau组 .兔均于第12周 ,测量心输出量 (CO) ,颈动脉收缩压 (SP)和舒张压 (DP) ,颈动脉平均压 (MAP) ,左心室收缩压(LVSP)和左心室舒张末压 (LVEDP) .取左心室心肌细胞检测细胞内游离钙离子浓度 ([Ca2 +]i) ;用血清检测一氧化氮 (NO)的含量 .结果表明 ,Dox组CO ,SP ,DP ,MAP ,LVSP均明显低于NS组 ,LVEDP显著高于NS组 ,Dox +Tau组SP ,DP ,MAP ,LVSP均显著低于NS组 ,LVEDP明显低于Dox组 ,但明显高于NS组 .Dox组和Dox +Tau组血清NO含量均明显高于NS组 .Dox组左心室心肌细胞 [Ca2 +]i 明显高于NS组 ,Dox +Tau组心肌细胞 [Ca2 +]i 明显低于Dox组 .本文提示 ,Tau对Dox损伤心脏具有一定的保护作用  相似文献   

15.
心肌缺血时 ,由于细胞内 pH值下降 ,激活了Na+/H+交换泵 (NHE) ,细胞内Na+浓度升高 ,促进Na+ Ca2 +交换 ,最终导致细胞内Ca2 +超负荷 ,造成细胞损伤。NHE1抑制剂可通过抑制Na+/H+交换 ,防止细胞内Ca2 +超负荷及其他相关作用 ,对缺血再灌注心脏起保护作用 ,改善心肌功能。目前部分NHE1抑制剂已进行临床研究。  相似文献   

16.
We investigated whether nitroglycerin (NTG) was able to produce an anti-ischaemic effect in isolated working hearts of rats with vascular tolerance to NTG. Hearts isolated from tolerant and non-tolerant rats were subjected to 10 min coronary occlusion in the presence of 10(-7) M NTG and/or its solvent. NTG alleviated ischaemia-induced deterioration of cardiac function and decreased lactate dehydrogenase release whilst having no effect on coronary flow nor the area of the ischaemic zone both in hearts isolated from NTG-tolerant and non-tolerant rats. The magnitude of the effect was similar in the two groups. These results suggest that the anti-ischaemic effect of NTG involves direct myocardial mechanisms independent of its vascular action and that vascular tolerance to NTG does not affect this direct protective action.  相似文献   

17.
We examined phosphatidylcholine (PC) effects on the isolated rat heart subjected to low- or zero-flow ischemia followed by reperfusion. Untreated hearts subjected to 30 min of low-flow ischemia recovered 15% contractility following reperfusion compared to time-control hearts. Phosphatidylcholine (0.005%) addition either 10 or 20 min before ischemia significantly enhanced recovery to approximately 61% and reduced the incidence of arrhythmias during ischemia and reperfusion. Contracture during ischemia and reperfusion was significantly reduced when PC was added 20 min before ischemia. Phosphatidylcholine was ineffective when administered at the time of reperfusion except for a moderate reduction in arrhythmia development. Phosphatidylcholine also produced a salutary effect when added 20 min prior to zero-flow ischemia. Subsarcolemmal mitochondria (SLM) and, to a much lesser degree, interfibrillar mitochondria (IFM) of untreated hearts subjected to low-flow ischemia and reperfusion exhibited depressed oxidative phosphorylation which was prevented by PC. Both mitochondrial populations exhibited a marked depression in ADP/ATP translocase activity; however, this was generally unaffected by PC. Subsarcolemmal mitochondria but not IFM of zero-flow ischemic reperfused hearts also exhibited significantly depressed oxidative phosphorylation, which was unaffected by PC. Zero-flow ischemia produced a rapid and total cessation of contractility. Both populations exhibited a substantial PC-insensitive reduction in translocase activity. Our results demonstrate, for the first time, a protection by PC on the reperfused ischemic heart. The PC-induced protection following low-flow but not zero-flow ischemia is associated with improved SLM oxidative phosphorylation suggesting dissimilar contribution of mitochondria to reperfusion-associated myocardial injury.  相似文献   

18.
Glycerol formal (CAS 5464-28-8), an organic solvent used to vehicle drugs to target cells, has been shown to possess its own toxicopharmacological properties. The present work was undertaken to study its direct effect on the isolated rabbit heart. At 2.3 and 4.6 mmol/l (bolus) glycerol formal exerted a positive inotropic effect. Upon a perfusion of 4.5 mmol/l/h, the left ventricular pressure and the coronary flow were increased, while at 11 mmol/l/h these two parameters showed a tendency to decrease. Glycerol formal upon a perfusion at 11 mmol/l/h decreased mildly the positive inotropic effect of noradrenaline, and strongly that produced by acetylcholine at a nicotinic dose, while it accentuated the bradycardia induced by acetylcholine at a muscarinic dose. On the contrary it potentiated the stimulant effect of nicotine. The positive inotropic effects of tyramine, dimethylphenylpiperazinium and potassium chloride were decreased showing an inhibition of noradrenaline liberation induced by glycerol formal at the doses used. The action of glycerol formal on agents inducing a positive inotropic effect, except nicotine, and its cardiodepressant effect are probably partly due to its action on the Ca2+ ion.  相似文献   

19.
In the isolated rabbit sinus node and right atrial myocardium, the effects of bepridil (1-6 x 10(-6) M) on impulse formation, impulse conduction, and tissue refractoriness were examined. In the sinus node, drug concentrations between 1 and 3 x 10(-6) M were tested. In the border zone of the sinus node, bepridil (3 x 10(-6) M) reduced impulse conduction velocity by 65% and prolonged the effective refractory period by 81% (n = 11). In the center of the sinus node, bepridil in a concentration of 2.5 x 10(-6) M decreased impulse conduction velocity by 78% and prolonged effective refractory period by 77% (n = 9), whereas a drug concentration of 3 x 10(-6) M blocked impulse conduction systematically. Despite these marked effects on nodal conduction properties, only limited effects on sinus rate were found. Conduction properties in the atrium were affected by bepridil as well, but higher concentrations (4-6 x 10(-6) M) were needed. Impulse conduction velocity was decreased by 57%, and the effective refractory period was prolonged by 73% (6 x 10(-6) M; n = 8). At these higher drug concentrations, sinus automaticity decelerated and ceased abruptly, after which only subthreshold oscillations were detectable. From these findings, we concluded that (a) bepridil reduces impulse conduction velocity and prolongs refractoriness in the sinus node, less markedly in the atrial myocardium; (b) bepridil affects nodal impulse conduction prior to nodal impulse formation; and (c) bepridil possesses both "fast channel" and "slow channel" inhibitory properties.  相似文献   

20.
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