Gut luminal microdialysis of glycerol as a marker of intestinal ischemic injury and recovery

OBJECTIVE: To evaluate microdialysis as a method to assess different degrees of intestinal damage and recovery during ischemia and reperfusion; to evaluate information obtained from microdialysis catheters in the peritoneum, the gut wall, and the gut lumen. DESIGN: Randomized, controlled animal experiment. SETTING: University laboratory animal center. SUBJECTS: Twenty-seven domestic pigs. INTERVENTIONS: The superior mesenteric artery was cross-clamped for 60 mins (n = 14) or 120 mins (n = 10) followed by 2 or 4 hrs of reperfusion. Three pigs served as controls. MEASUREMENTS AND MAIN RESULTS: Intestinal mucosal integrity was assessed by morphometry, adenosine triphosphate in the gut wall, and permeability of C-polyethylene glycol. Lactate, glycerol, pyruvate, and glucose were measured by microdialysis. Changes in adenosine triphosphate, permeability, or lactate did not correlate to different extents of intestinal damage caused by 60 or 120 mins of ischemia. During the reperfusion period, pigs with 60 mins of intestinal ischemia showed a faster recovery of these variables than pigs with 120 mins of intestinal ischemia. Glycerol increased with increasing duration of the ischemic insult. After 60 mins of intestinal ischemia, glycerol in the gut lumen decreased toward baseline but remained high after 120 mins of intestinal ischemia. There was a good correlation between gut luminal glycerol and recovery of mucosal damage throughout the reperfusion period. In the peritoneal cavity, both glycerol and lactate decreased to baseline relatively shortly after onset of reperfusion independent of the duration of intestinal ischemia. CONCLUSIONS: Microdialysis of glycerol provides information about the extent and severity of intestinal damage after ischemia and about the ensuing recovery. The gut lumen is to be preferred as a site for placement of microdialysis catheters.     

Myocardial ischemia in intestinal postischemic shock: the effect of hypoxemic reperfusion

OBJECTIVE: The circulatory shock following intestinal ischemia-reperfusion injury has been attributed to hypovolemia. The purpose of the current study is to clarify the pathophysiology of this type of shock and to test the hypothesis that hypoxemic compared with normoxemic reperfusion improves hemodynamics. DESIGN: Randomized animal study. SETTING: Medical school laboratory. SUBJECTS: Twenty-one pigs. INTERVENTIONS: Pigs were subjected to 120 mins of intestinal ischemia by clamping the superior mesenteric artery. Upon declamping, the animals were randomized into two groups: a group that received hypoxemic reperfusion (HR group, n = 8) with a PaO2 = 30-35 and a control group reperfused with PaO2 = 100 mm Hg (control group, n = 13). MEASUREMENTS AND MAIN RESULTS: Measurements included mean arterial pressure, cardiac index, pulmonary artery occlusion pressure, and requirements for fluids and epinephrine. Biopsies from the terminal ileal mucosa were taken for malondialdehyde measurements at baseline, at 120 mins of ischemia, and at 30 and 60 mins of reperfusion. A piece of left ventricle was obtained after 120 mins of reperfusion for histologic studies. Five of 13 animals of the control group died in intractable shock; no animal of the HR group died (p =.11). The decrease in the mean arterial pressure during reperfusion was more pronounced in the control group (p <.008) despite the larger doses of epinephrine administered, compared with the HR group (p <.02). During reperfusion, both groups exhibited a decrease in cardiac index; this was more pronounced in the control group (p =.0007). Pulmonary artery occlusion pressure increased during reperfusion in both groups and was more pronounced in the control group (p =.04 at 60 mins). Although mixed venous blood oxygen saturation of the control animals was higher at 30 mins of reperfusion (p =.005), it declined after 60 mins and became lower than that of HR animals at the end of reperfusion (p <.02). The myocardial histopathologic injury score was higher in the control group (2.0 +/- 0.69 and 3.4 +/- 0.89 for the HR and control groups, respectively; p <.03). The concentrations of intestinal mucosa malondialdehyde were significantly higher in the control group at 60 mins of reperfusion (p <.03). CONCLUSIONS: Acute myocardial ischemia and left heart failure significantly contribute to the circulatory shock that follows intestinal ischemia/reperfusion injury and are attenuated by hypoxemic reperfusion.     

Effects of endotoxin tolerance on liver function after hepatic ischemia/reperfusion injury in the rat

OBJECTIVE: It is known that endotoxin tolerance prevents lethality after ischemia/reperfusion injuries (e.g., myocardial infarction) in laboratory animals. We used a rat model of partial hepatic ischemia/reperfusion to investigate whether endotoxin tolerance prevents associated lethality and disorders of liver function. DESIGN: Prospective animal study. SETTING: University research facility. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Hepatic ischemia was initiated by atraumatic clipping across the portal venous and hepatic arterial blood supply to the left lateral lobe for 90 mins. The common bile duct was canalized, and in a second set of experiments the bile duct of the left lateral lobe was canalized selectively. Bile flow, bile acids, and transaminases were determined during ischemia and 300 mins of reperfusion in endotoxin-tolerant and -nontolerant rats. MEASUREMENTS AND MAIN RESULTS: Endotoxin-nontolerant animals showed a 50% lethality after hepatic ischemia/reperfusion injuries. All endotoxin-tolerant rats survived and did not react with any change in bile flow, showing a constant flow. The amount of bile acids in the common bile duct was reduced during ischemia and regained the concentrations of sham-operated animals 60 mins after reperfusion. From 180 mins after reperfusion, the difference between endotoxin-tolerant and -nontolerant animals was statistically significant. When bile acid concentration was determined in the ischemic left lateral lobe, ischemia/reperfusion was found to significantly decrease in endotoxin-nontolerant rats 60 mins after reperfusion. In contrast, endotoxin-tolerant rats produced normal amounts of bile acids 60 mins after reperfusion. At 120 mins after reperfusion, the amount of bile acids in the formerly ischemic left lateral lobe was more than normal. CONCLUSIONS: In this model of partial hepatic ischemia/reperfusion, endotoxin tolerance prevents ischemia/reperfusion injury-associated lethality and local disorders of liver function. This phenomenon induced by endotoxin tolerance may be useful in liver surgery to prevent ischemia/reperfusion injury.     

犬急性心肌梗死与再灌注的多层螺旋CT评价实验研究

目的探讨多层螺旋CT评价急性冠状动脉闭塞后心肌梗死及再灌注的能力.方法将12只杂种犬随机分成两组:①急性心肌梗死组(AMI),分别于结扎冠状动脉前、结扎后1 h和2 h进行CT平扫和增强扫描.②AMI再灌注组,分别于结扎前、结扎后1 h及再灌注30 min进行同样扫描.观察心肌梗死的病变部位及形态,测量每组正常心肌、心肌梗死部位在各个扫描时点的CT值,计算两者与左心室腔的CT值之比(M/L).结果12只犬结扎左前降支后1 h增强图像上左心室前壁或心尖区均有明显的低密度区形成.AMI组结扎后2 h图像缺血区的密度更为减低;AMI再灌注组再灌注30 min后病变的密度变化不明显.AMI组结扎后1 h与2 h的正常心肌与梗死心肌的CT值均值及两者与左心室腔的M/L均具有显著性差异(P＜0.001).AMI再灌注组结扎后1 h与再灌注后30 min正常心肌与梗死心肌的CT值均值及两者与左心室腔M/L也具有显著性差异(P＜0.001).结论急性冠脉闭塞后心肌梗死区MSCT表现为低密度,MSCT能够区分急性冠状动脉闭塞后梗死心肌与正常心肌.     

The fibrin-derived peptide Bbeta15-42 is cardioprotective in a pig model of myocardial ischemia-reperfusion injury

OBJECTIVE: The fibrin-derived peptide Bbeta15-42 has been shown to reduce infarct size in rodent models of ischemia-reperfusion injury. To increase its potential for translation into the clinic, we studied the effects of Bbeta15-42 in pigs, whose coronary anatomy is similar to that of humans. In addition, we evaluated the pharmacokinetics and safety of Bbeta15-42 in several species, including humans. DESIGN: Animal study and phase I trial. SETTING: University hospital and contract research laboratories. SUBJECTS: Pigs/healthy volunteers. INTERVENTIONS: Male farm-bred Landrace pigs were subjected to 1 hr of left anterior descending coronary artery occlusion followed by 3 hrs of reperfusion. At the time of reperfusion, Bbeta15-42 (2.4 mg/kg, n = 6) or random peptide (control; 2.4 mg/kg, n = 6) was administered as an intravenous bolus. As a positive control, pigs were subjected to ischemic preconditioning (n = 6). Cardiac damage and hemodynamics were recorded. Biodistribution and pharmacokinetics of Bbeta15-42 were determined in rats and dogs. In a phase I trial involving 30 male healthy volunteers, pharmacokinetics and safety were tested in a randomized, double-blinded, placebo-controlled, parallel-group, single ascending dose study. MEASUREMENTS AND MAIN RESULTS: Bbeta15-42 and ischemic preconditioning significantly reduced myocardial infarct size and troponin I levels. Bbeta15-42 also reduces interleukin-6 levels, underlining its anti-inflammatory properties. Furthermore, in humans, the pharmacokinetics of the peptide Bbeta15-42 were comparable to those of animals, and no serious adverse effects were observed. CONCLUSIONS: Bbeta15-42 elicits cardioprotection in pigs and is clinically safe in phase I testing of humans. This study confirms the new concept of a pathogenic role of fibrin derivatives in myocardial reperfusion injury, which can be inhibited by peptide Bbeta15-42.     

The effect of intracoronary diltiazem on regional myocardial function and development of infarcts in porcine hearts

The effect of intracoronary (i.c.) pretreatment with diltiazem on regional myocardial function and the development of infarcts was investigated in regionally ischemic, reperfused porcine hearts. The left anterior descending coronary artery (LAD) was distally ligated in 16 pigs for 20-90 min followed by 24 h of reperfusion. Eight pigs were treated with increasing doses of i.c. diltiazem (0.375 mg/min, 0.75 mg/min, 1 mg/min) prior to ischemia. Eight pigs served as controls. Regional myocardial function was assessed by implanted ultrasonic crystals. Infarct size was determined as ratio of infarcted (tetrazolium stain) to ischemic myocardium (dye technique). I.c. diltiazem mainly depressed early systolic shortening (isovolumetric contraction) and lengthening during the first half of diastole. Pretreatment with this calcium antagonist significantly delayed the development of infarcts. In control experiments, a mean infarct size of 74% was found after 45-min ischemia. At that time no infarction was observed in the treated group, where infarcts started to evolve after 60-min ischemia. It is concluded that the favorable action of i.c. diltiazem can mainly be ascribed to a reduced myocardial oxygen consumption at the onset of ischemia.     

Zoniporide preserves left ventricular compliance during ventricular fibrillation and minimizes postresuscitation myocardial dysfunction through benefits on energy metabolism

OBJECTIVE: To investigate whether sodium-hydrogen exchanger isoform-1 (NHE-1) inhibition attenuates myocardial injury during resuscitation from ventricular fibrillation through effects on energy metabolism, using an open-chest pig model in which coronary perfusion was controlled by extracorporeal circulation. DESIGN: Randomized controlled animal study. SETTING: University research laboratory. SUBJECTS: Male domestic pigs. INTERVENTIONS: Ventricular fibrillation was electrically induced and left untreated for 8 mins, after which extracorporeal circulation was started and its flow adjusted to maintain a coronary perfusion pressure of 10 mm Hg. After 10 mins of extracorporeal circulation, restoration of spontaneous circulation was attempted by epicardial defibrillation and gradual reduction in extracorporeal flow. Two groups of eight pigs each were randomized to receive the NHE-1 inhibitor zoniporide (3 mg.kg-1) or vehicle control immediately before starting extracorporeal circulation. MEASUREMENTS AND MAIN RESULTS: Identical extracorporeal flows (approximately = 9% of baseline cardiac index) were required in zoniporide and control groups to attain the target coronary perfusion pressure, resulting in comparable left anterior descending coronary artery blood flow (9 +/- 1 and 10 +/- 1 mL.min-1) and resistance (0.10 +/- 0.01 and 0.10 +/- 0.01 dyne.sec.cm(-5)). Yet zoniporide prevented reductions in left ventricular volume and wall thickening while favoring higher myocardial creatine phosphate to creatine ratios (0.14 +/- 0.03 vs. 0.06 +/- 0.01, p < .05), lower myocardial adenosine (0.7 +/- 0.1 vs. 1.3 +/- 0.2, p < .05), and lower myocardial lactate (80 +/- 9 vs. 125 +/- 6 mmol.kg-1, p < .001). Postresuscitation, zoniporide-treated pigs had higher left ventricular ejection fraction (0.57 +/- 0.07 vs. 0.29 +/- 0.05, p < .05) and higher cardiac index (4.8 +/- 0.4 vs. 3.4 +/- 0.2 L.min-1.m-2, p < .05).CONCLUSIONS: Zoniporide ameliorated myocardial injury during resuscitation from ventricular fibrillation through beneficial effects on energy metabolism without effects on coronary vascular resistance and coronary blood flow.     

ATP-sensitive potassium channel blocker HMR 1883 reduces mortality and ischemia-associated electrocardiographic changes in pigs with coronary occlusion.

ATP-sensitive potassium (K(ATP)) channels are activated during myocardial ischemia. The ensuing potassium efflux leads to a shortening of the action potential duration and depolarization of the membrane by accumulation of extracellular potassium favoring the development of reentrant arrhythmias, including ventricular fibrillation. The sulfonylthiourea HMR 1883 was designed as a cardioselective blocker of myocardial K(ATP) channels for the prevention of arrhythmic sudden death in patients with ischemic heart disease. We investigated the effect of HMR 1883 on sudden cardiac arrhythmic death and electrocardiography (ECG) changes induced by 20 min of left anterior descending coronary artery occlusion in pentobarbital-anesthetized pigs. HMR 1883 (3 mg/kg i.v.) protected pigs from arrhythmic death (91% survival rate versus 33% in control animals; n = 12; p<.05). Ischemic areas were of a similar size. The compound had no effect on hemodynamics and ECG, including Q-T interval, under baseline conditions and no effect on hemodynamics during occlusion. In control animals, left anterior descending coronary artery occlusion lead to a prompt and significant depression of the S-T segment (-0.35 mV) and a prolongation of the Q-J time (+46 ms), the former reflecting heterogeneity in the plateau phase of the action potentials and the latter reflecting irregular impulse propagation and delayed ventricular activation. Both ischemic ECG changes were significantly attenuated by HMR 1883 (S-T segment, -0.14 mV; Q-J time, +15 ms), indicating the importance of K(ATP) channels in the genesis of these changes. In conclusion, the K(ATP) channel blocker HMR 1883, which had no effect on hemodynamics and ECG under baseline conditions, reduced the extent of ischemic ECG changes and sudden death due to ventricular fibrillation during coronary occlusion.     

Left ventricular myocardial adenosine triphosphate changes during reperfusion of ventricular fibrillation: the influence of flow and epinephrine

OBJECTIVE: To determine whether epinephrine in combination with high flow worsens left ventricular (LV) myocardial high-energy phosphate stores during reperfusion of ischemic ventricular fibrillation (VF). DESIGN: Blinded, prospective block randomized, placebo controlled study. SETTING: University medical center research laboratory. SUBJECTS: A total of 22 mixed breed swine weighing 22.0+/-3.3 kg (SD). INTERVENTIONS: Open-chest swine, anesthetized with alpha-chloralose, underwent 10 mins of nonperfused VF followed by reperfusion with cardiopulmonary bypass for 90 mins and then defibrillation. Animals were block randomized to four groups for reperfusion: Group 1 (n = 5), high flow (100 mL/kg/min) and epinephrine (2.5 microg/kg/min); Group 2 (n = 5), high flow and placebo; Group 3 (n = 6), low flow (30 mL/kg/min) and epinephrine; and Group 4 (n = 6), low flow and placebo. MEASUREMENTS AND MAIN RESULTS: In vivo LV creatine phosphate (CP) and adenosine triphosphate (ATP) were determined using whole wall and spatially localized 31P NMR spectroscopy at 4.7 Tesla. During perfusion of the fibrillating myocardium, epinephrine significantly increased aortic pressure (p < .05) and improved defibrillation rates (p < .01). ATP levels during reperfusion were significantly decreased within all groups compared with baseline. There were no differences in ATP levels between groups. High flow, independent of epinephrine, was associated with increased preservation of ATP (p < .05), increased CP/ATP ratios (p < .02) in all layers of the LV wall, and decreased aortic and cardiac vein lactates (p < .001). CONCLUSIONS: Epinephrine, in combination with flow higher than standard cardiopulmonary resuscitation flows, increased perfusion pressure and defibrillation rates, but did not significantly alter myocardial ATP during VF reperfusion in the in vivo heart Reperfusion flow, independent of epinephrine, is a critical determinant of myocardial ATP preservation.     

Nicotinic acid, free fatty acids and myocardial function during coronary occlusion and reperfusion in the dog

The effect of nicotinic acid on regional myocardial blood flow, percentage of segment shortening and myocardial uptake of free-fatty acids during a 15-min occlusion of the left anterior descending coronary artery and 3-hr reperfusion period was compared to a saline-treated control group. Nicotinic acid (2.4 mumol/kg/min i.v.) was infused 30 min before and throughout the occlusion period. Heart rate, arterial blood pressure and left ventricular systolic and end diastolic pressures were not different during occlusion and reperfusion in the nicotinic acid or saline-treated groups. However, left ventricular dP/dt, an index of global myocardial function and percentage of segment shortening in the ischemic region were greater during occlusion and reperfusion after nicotinic acid. Even though myocardial blood flow was unaltered in the normal or ischemic region during nicotinic acid infusion, subendocardial blood flow during reperfusion was enhanced significantly when compared to the control group. Nicotinic acid also decreased free-fatty acid uptake by the heart during occlusion which returned gradually to the pretreatment control during 3 hr of reperfusion. Thus, the improvement in percentage of segment shortening, dP/dt and subendocardial blood flow during reperfusion may be related to the ability of nicotinic acid to reduce free-fatty acid uptake by the heart during coronary occlusion.     

Early albumin infusion improves global and local hemodynamics and reduces inflammatory response in hemorrhagic shock

OBJECTIVE: To evaluate the effects of an early, short-term albumin infusion on mesenteric microcirculation and global hemodynamics in hemorrhagic shock. DESIGN: A prospective, randomized study. SETTING: Animal laboratory at a university medical clinic. SUBJECTS: Seventeen Sprague-Dawley rats weighing 250-400 g. INTERVENTIONS: The rats underwent median laparotomy and exteriorization of an ileal loop for intravital microscopy of the mesenteric microcirculation. Volume-controlled hemorrhagic shock was provoked by arterial blood withdrawal (2.5 mL/100 g body weight for 60 mins), followed by a 4-hr reperfusion period. Albumin (20%) or 0.9% NaCl was administered intravenously as a continuous infusion for 30 mins at the beginning of reperfusion. Reperfusion time mimicked a "prehospital" phase of 30 mins followed by a quasi "in-hospital" phase of 3.5 hrs. The "in-hospital" phase in both groups was initiated by substitution of blood followed by reperfusion with normal saline. MEASUREMENTS AND MAIN RESULTS: Central hemodynamics, mesenteric microcirculation, and arterial blood gas parameters were monitored before, during, and 60 mins after hemorrhagic shock, and for a 240-min follow-up period after initiation of reperfusion. Application of albumin markedly reduced rolling and adherent leukocytes, maximum velocity, and shear rate in the mesenteric microcirculation. Later, after improvement of mesenteric microcirculation, an intermittent increase of central venous pressure and abdominal blood flow and decrease of hematocrit was observed. CONCLUSIONS: Albumin treatment of hemorrhagic shock improves microcirculation and global hemodynamics and attenuates the inflammatory response to reperfusion. It may provide clinical benefit when applied at an early stage of reperfusion during hemorrhagic shock.     

Low flow after global ischemia to improve postischemic myocardial function and bioenergetics

OBJECTIVE: In this study, we test the hypothesis that a period of low flow perfusion before full reperfusion improves ventricular function and bioenergetics. DESIGN: Prospective, randomized, controlled animal study. SETTING: Research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Hearts were perfused with Krebs-Henseleit buffer at 85 mm Hg. The protocol consisted of 10 mins of baseline flow, 15 mins of global ischemia, 5 mins of low flow ischemia, and 30 mins of reperfusion. Groups received 10% or 1% of baseline flow during the low flow period. A control group received 0% low flow (20 mins of global ischemia). MEASUREMENTS AND MAIN RESULTS: Left ventricular function was continuously measured. Hearts were freeze-clamped at various time points, and metabolites were measured. At 10% flow, following global ischemia, both left ventricular function and bioenergetics improved compared with 0% flow and 1% flow. At 1% flow, no changes in function were seen and adenosine 5'-triphosphate concentrations decreased during reperfusion, compared with no flow (9.4 +/- 1.0 vs. 13.2 +/- 1.0 micromol/g of dry weight, p <.01). CONCLUSIONS: Following global ischemia but before full reperfusion, a period of low flow improves postischemic myocardial function and energetic recovery, only if a certain level of low flow is met. Very low flow may further reduce bioenergetic recovery without improvement in postischemic function, compared with continuous global ischemia.     

A1-receptor blockade: a novel approach for assessing myocardial viability in chronic ischemic cardiomyopathy.

Diminished myocardial function can be seen in chronic coronary stenosis (CS) even in the presence of normal resting myocardial blood flow. We hypothesized that adenosine contributes to myocardial depression in this setting, predominantly through activation of the A(1) adenosine receptor. To test this hypothesis we used aminophylline, a nonselective adenosine receptor antagonist, and 8-cyclopentyl 1,3 dipropylxanthine, a selective A(1) adenosine receptor antagonist, in a canine model of chronic CS. Chronic CS was produced by placement of ameroid constrictors on the left anterior descending and left circumflex coronary arteries in 17 adult mongrel dogs, which resulted in severe left ventricular dysfunction 6 weeks later. Eight dogs without ameroid placement were used as controls (C). Closed-chest echocardiographic short-axis images at the low midpapillary level, hemodynamics, and radiolabeled microsphere-derived myocardial blood flow were obtained before and immediately after injection of either 5 mg/kg(-1) of aminophylline (7 left ventricular dysfunction and 4 C dogs) or 1 mg/kg(-1) of 8-cyclopentyl 1,3-dipropylxanthine (10 left ventricular dysfunction and 4 C dogs). Both 8-cyclopentyl 1,3-dipropylxanthine and aminophylline had no effect in C animals but resulted in a significant transient increase in regional percent wall thickening (P <.05) with a concomitant decrease in end-systolic wall stress (P <.05) in CS animals. There was no change in transmural myocardial blood flow or systemic hemodynamics to explain these results. Thus, adenosine plays a significant role in myocardial dysfunction in chronic ischemia by activation of the A(1) receptor. Aminophylline or a selective A(1) adenosine receptor antagonist can be used to detect viable myocardium and may be safer than dobutamine in severe chronic ischemic heart disease.     

以球囊封堵法建立猪心肌梗死模型的可行性研究

背景:国外20世纪90年代开始采用球囊封堵建立闭胸式心肌梗死动物模型,但术中室颤及血栓形成等因素降低了制作心肌梗死动物模型的成功率.目前国内建立球囊封堵闭胸式心肌梗死大动物模型的报道较少.目的:应用球囊封堵法建立闭胸式猪心肌梗死模型,探索提高建模成功率的方法.设计、时间及地点:随机对照动物实验,病理观察,于2008-07/2009-05在昆明医学院第一附属医院心内科及昆明医学院病理教研室完成.材料:8～11月龄健康滇南小耳猪15只,体质量19～25kg,随机数字表分为3组:假手术组、缺血再灌注组、缺血后处理组,每组5只.方法:冠脉封堵后和再灌注期预防性静滴利多卡因1.0～2.0mg/kg,以减少恶性心律失常的发生率,使用肝索防治血栓形成,在X射线监控下将球囊导管送至冠状动脉左前降支第一对角支的远端,假手术组只放置球囊至冠状动脉左前降支,不封堵;缺血再灌注组行球囊充气堵闭冠状动脉左前降支60min后撤除球囊:缺血后处理组行球囊充气堵闭冠状动脉左前降支60min后,球囊放气30s,充气30s(循环8次)后撤除球囊.主要观察指标:行冠脉造影、心电图及心肌酶检测评价心肌梗死模型的建立情况.3d后行心肌三氯四氮唑染色及病理学检查验证心肌梗死.结果:假手术组猪全部存活;缺血再灌注组4只成功建立心肌梗死模型,1只死于顽固性室颤;缺血后处理组全部成功建立心肌梗死模型.堵闭左前降支远端后,心电图V1～3导联上ST段抬高,有病理性Q波形成:心肌酶谱演变过程与人体心肌梗死过程基本一致.心肌梗死部位分别位于心尖、左心室前壁、前间隔部.三氯四氮唑染色后正常心肌呈砖红色,梗死区心肌颜色暗淡,呈灰白色;病理学检查显示,梗死区心肌正常结构破坏,胞浆浓缩,染色加深,横纹消失,核浓缩、溶解、碎裂,梗死区内有较多的红细胞,梗死区周围有较多肉芽组织增生及大量炎性细胞浸润.结论:球囊封堵冠脉建立猪闭胸式心肌梗死模型对动物创伤性小,且最为接近临床实际的过程,术中使用利多卡因及肝素防治心律失常及血栓形成是成功建立该模型的有效方法,缺血后处理可能是提高建模成功率的因素之一.     

兔心脏缺血再灌注损伤后重组水蛭素的保护作用及其机制

背景重组水蛭素能否通过抑制白细胞浸润来拮抗心肌缺血/再灌注(ischemia/reperfusion,IR)损伤,从而起到对心肌的保护作用?目的观察重组水蛭素对缺血心肌内白细胞浸润的影响,进一步探讨重组水蛭素对心肌保护的作用机制.设计随机对照的实验研究.地点、材料和干预本实验在第四军医大学唐都医院心血管病实验室完成.选取24只日本大耳白兔随机分为2组,每组12只.IR组;心脏左冠状动脉前降支IR动物模型,缺血45 min、再灌注120 min,再灌注前后静脉应用生理盐水;重组水蛭素组缺血45 min、再灌注120 min,再灌注前15 min静注重组水蛭素(1 mg/kg),再灌注时继以持续静滴重组水蛭素[1 mg/(kg·h)]120 min.主要观察指标心肌梗死范围及缺血心肌内白细胞浸润的变化.结果重组水蛭素组的心肌梗死范围为(11.7±2.4)%,与缺血再灌注组的(21.2±5.3)%比较,梗死范围明显缩小(t=7.436,P＜0.01).缺血再灌注组的髓过氧化物酶(myeloperoxidase,MPO)活性为(56.01±3.83)nkat/g,重组水蛭素组(35.51±1.67)nkat/g.重组水蛭素组缺血心肌内白细胞聚集较缺血再灌注组显著减少(t=3.935,P＜0.05).结论重组水蛭素能够抑制再灌注期缺血心肌内白细胞浸润,拮抗心肌IR损伤.     

Inhalation of NO during myocardial ischemia reduces infarct size and improves cardiac function

Purpose

Bioactive NO carriers in circulating blood formed during NO inhalation selectively distribute blood flow to areas in need, and may thus improve collateral perfusion to the area-at-risk in acute myocardial infarction (AMI). Here, we tested the hypothesis that NO inhalation during the ischemic phase of AMI may improve left ventricular function and reduce infarct size in rats.

Methods

Following left anterior descending coronary artery (LAD) occlusion, rats received 50?ppm NO for 2?h of ischemia, during subsequent 3?h of reperfusion, or for 5?h of ischemia and reperfusion. Effects of inhaled NO were compared to those of intravenous nitrite as a putative carrier formed during NO inhalation. Downstream signaling via soluble guanylate cyclase was tested by inhibition with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ).

Results

NO inhalation during myocardial ischemia increased left ventricular systolic pressure, contractility, relaxation, and cardiac output, and reduced myocardial infarction size and area-at-risk as compared to untreated controls. NO inhalation during the reperfusion phase caused a comparable protective effect. Combined inhalation during ischemia and reperfusion did not further improve left ventricular hemodynamics, but had an additive protective effect on the myocardial area-at-risk. NO inhalation increased circulating nitrite levels, and mimicking of this effect by intravenous nitrite infusion achieved similar protection as NO inhalation during myocardial ischemia, while ODQ blocked the protective NO effect.

Conclusions

Inhalation of NO during myocardial ischemia improves left ventricular function and reduces infarct size by mechanisms that increase levels of circulating nitrite and involve soluble guanylate cyclase. NO inhalation may represent a promising early intervention in AMI.     

Positive end-expiratory pressure does not compromise myocardial contractility in myocardial ischemia/reperfusion

Therapy for severe myocardial ischemia/reperfusion sometimes necessitates intermittent positive pressure ventilation, which may impair left ventricular function by reduction of ventricular loading. It is unknown today whether positive airway pressure also affects contractile force after myocardial ischemia/reperfusion. The authors tested whether positive end-expiratory pressure (PEEP) impairs myocardial contractility in acute ischemic heart failure. In 11 anesthetized mechanically ventilated pigs (28 +/- 3 kg), cardiac output (CO, aortic flow probe), load-independent parameters of left ventricular contractility (conductance method: preload recruitable stroke work [PRSW] and end-systolic elastance [E(es)]) and preload (end-diastolic volume [EDV] conductance) were assessed before and after myocardial ischemia and reperfusion (left anterior descending artery occlusion, 60 min). Data were taken during PEEP 0, 5, and 10 cm H2O. Before myocardial ischemia, both PEEP 5 and 10 cm H2O reduced CO (P < 0.05) because of a reduction of EDV (P < 0.05, PEEP 10 cm H2O). The PRSW remained unchanged (not significant [NS]) and E(es) increased (P < 0.05, PEEP 10 cm H2O). After myocardial ischemia/reperfusion, CO and PRSW, but not E(es) (NS), deteriorated markedly. At the same time, PEEP 10 cm H2O reduced CO (P < 0.05) and, slightly, EDV (NS). Now, both PRSW (P < 0.05, PEEP 5 cm H2O) and E(es) (P < 0.05, PEEP 10 cm H2O) improved upon ventilation with PEEP. In our model, the administration of PEEP impaired global left ventricular function before and after myocardial ischemia/reperfusion. The observed impairment is not attributable to compromised contractility.     

实时心肌造影评价犬腺苷预适应的心肌保护作用

目的 探讨腺苷预适应对犬心肌缺血再灌注后收缩功能及危险区心肌血流量的保护作用。 方法 健康犬13只,随机分为2组:腺苷预适应组(n=7):缺血前静脉滴注腺苷0.3 mg/min,30 ml;对照组(n=6):缺血前静脉滴注生理盐水30 ml作为平衡对照。阻断左冠状动脉前降支,制作心肌缺血再灌注模型(缺血3 h,再灌注1 h),于阻断前基础状态、缺血3 h、再灌注1 h各时间点经股静脉注入造影剂声诺维,分别采集左心室乳头肌水平短轴图像。同步记录左心室压力曲线。 结果 腺苷预适应组再灌注1 h的左心室内压峰值(LVSP)高于对照组(P＜0.05);缺血3 h、再灌注1 h的左心室内压最大上升速率高于对照组(P均＜0.05);心肌缺血再灌注后,坏死区、危险区心肌血流量低于正常区,其中坏死区最低(P均＜0.05),腺苷预适应组危险区心肌血流量较对照组增加(P＜0.05)。 结论 腺苷预适应能够有效改善犬心肌缺血再灌注后收缩功能,增加危险区心肌血流灌注,改善心肌微循环。     

Cardioprotective effects of acute isovolemic hemodilution in a rat model of transient coronary occlusion

OBJECTIVES: Following isovolemic hemodilution (AIH), lowering blood viscosity induces acceleration of erythrocyte velocity resulting in improved tissue oxygen delivery. Using a rat model of myocardial infarct, we tested the hypothesis that AIH would attenuate myocardial damage due to transient coronary occlusion. DESIGN: Prospective, randomized, and controlled animal study. SETTING: Animal research laboratory in a university hospital. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: All rats were subjected to 30 mins of left coronary artery occlusion followed by 48 hrs of reperfusion. Before the ischemic period, the anesthetized rats were randomly allocated to undergo either 15 mins of waiting (controls) or AIH to achieve a hematocrit of 30% (AIH-CO) by stepwise blood withdrawal and isovolemic compensation with 6% hydroxyethylstarch 200-0.5. MEASUREMENTS AND MAIN RESULTS: Hemodynamic variables were comparable in the two groups, except for higher indexes of stroke volume in the AIH-CO group. During coronary occlusion and the reperfusion period, AIH resulted in a lower incidence of fatal ventricular tachyarrhythmia (17% vs. 50% in control group, p < .05) and higher survival at 48 hrs of postreperfusion (83% vs. 42%, p < .05).Preischemic hemodilution significantly attenuated myocardial damage as shown by lower release of cardiac troponin I and reduction in myocardial infarct size as measured by tetrazolin staining. Histologic examination revealed no difference regarding peri-ischemic infiltration with neutrophil granulocytes. CONCLUSIONS: Our data provide the first experimental demonstration that preischemic moderate AIH confers cardioprotection and improves survival in a rat model of myocardial infarct.     

Direct protective effects of dexmedetomidine against myocardial ischemia-reperfusion injury in anesthetized pigs

Systemic administration of α2-adrenergic agonists has been shown to protect ischemic myocardium, but the direct effects on ischemia-reperfused myocardium have not yet been clarified. This study was carried out to determine the effects of intracoronary dexmedetomidine (DEX) on the myocardial ischemia-reperfusion injury in anesthetized pigs. In open-chest pigs, the left anterior descending coronary artery was perfused through an extracorporeal circuit from the carotid artery. They received intracoronary infusion of DEX at a rate of 1 ng · mL(-1) (group LD, n = 9), 10 ng · mL(-1) (group MD, n = 9), or 100 ng · mL(-1) (group HD, n = 9) of coronary blood flow or vehicle (group C, n = 12) for 30 min before ischemia. Myocardial stunning was produced by 12-min ischemia of the perfused area of left anterior descending coronary artery and 90-min reperfusion. The effect on reperfusion-induced arrhythmias was evaluated using the incidence of ventricular tachycardia or fibrillation after reperfusion. Regional myocardial contractility was evaluated with segment shortening (%SS). Dexmedetomidine significantly reduced the incidence of reperfusion-induced ventricular arrhythmias. Dexmedetomidine significantly improved the recovery of percentage segment shortening at 90 min after reperfusion (32.6% ± 3.1% in group C, 58.2% ± 2.1% in group LD, 61.1% ± 1.8% in group MD, and 72.0% ± 2.0% in group HD). Dexmedetomidine suppressed the increase in plasma norepinephrine concentration after reperfusion. The results indicate that DEX would exert the protective effect against ischemia-reperfusion injury by the direct action on the myocardium, which is not mediated through the central nervous system.