The pathophysiology of myocardial stunning: reversibility, accumulation and continuity of the ischemic myocardial damage after reperfusion.

In order to understand the pathophysiology of myocardial stunning, reversibility, accumulation and continuity of ischemic myocardial damage after reperfusion should be studied. Then, to analyze these three factors, myocardial function, metabolism and morphology under ischemia and reperfusion were studied in anesthetized, open-chest dogs. When myocardial ischemia was induced by occlusion of the left anterior descending coronary artery, percentage regional systolic shortening (%SS) of ischemic myocardium sharply decreased and became stable 10 min after occlusion. After reperfusion, ischemic myocardium showed active shortening after within 30-min occlusion, but did not after more than 60-min occlusion. During 90-min of ischemia, extracellular K+ concentration (Ke) steeply increased for first 10 min and was almost stable for next 10 min. Then, Ke straightly increased till 90 min. Metabolic rates, calculated from myocardial tissue CO2 and pH, steeply increased for first 20 min and sharply decreased for next 10 min. After 30 min, these two variables were almost stable, near zero. By electron-microscopy with cytochemistry, distribution of Na/K ATPase to myocardial cell membrane was observed to be almost after 15-min occlusion but distinctly sparse with destruction of cell membrane after 30-min occlusion. Therefore, irreversible myocardial damage appears after about 20-min ischemia and is almost complete after 60 min. Reversibility of damage to ischemic myocardium after reperfusion may mainly occur within 60-min ischemia. Although stunned myocardium in a narrow sense is may appear after reperfusion within less than 20-min of ischemia, stunned myocardium in a broad sense may appear within less than 60-min ischemia. When reversible myocardial ischemia (4- or 15-min occlusion) was repeated after short time intervals (20-min reperfusion), %SS of ischemic myocardium was gradually decreased with each ischemic episode. Active shortening of ischemic myocardium disappeared after more than two episodes of 15-min occlusion. Fluctuation of PCO2, pH and Ke of ischemic myocardium was gradually depressed with each occlusion. Metabolic viability of ischemic myocardium was cumulatively depressed by repeated brief occlusion. Naturally, myocardial damage was more severe after repeated 15-min occlusion than after 4-min occlusion. Accumulation of ischemic myocardial damage may arise as brief ischemia, which only induces reversible damage, is repeated. At last, continuity of ischemic myocardial damage was studied. The effect of 5-min occlusion to %SS of ischemic myocardium was apparently reversed after 90-min reperfusion. Early contractile failure was advanced even after very short duration of ischemia. Thus, myocardial function will be latently damaged.(ABSTRACT TRUNCATED AT 400 WORDS)     

Temporal changes in adenylate cyclase activity in acutely ischemic dog heart: Evidence of functional subunit damage

Literature reports have indicated increased tissue levels of adenosine-3′,5′-cyclic phosphoric acid (cAMP) following ischemic insult to the myocardium. Studies were undertaken to determine possible changes in adenylate cyclase activity from ischemic and control heart tissue following complete coronary artery ligation. No changes were found in adenylate cyclase of ischemic tissue compared to controls following 10 min of occlusion. Basal adenylate cyclase velocities were slightly decreased after 20 min of ischemia and exhibited a 39% decrease after 60 min of coronary occlusion. Isoproterenol- and fluoride-stimulated activities exhibit a greater progressive decline in activity after 20 to 60 min of ischemia. The unphysiological substrate MnATP was utilized to produce a receptor-uncoupled state of the adenylate cyclase enzyme complex. Assays utilizing the substrate MnATP, revealed marked decreases in ischemic heart tissue adenylate cyclase activity following 20 min of coronary artery ligation. The data from the receptor-coupled and uncoupled states suggest initial damage in the catalytic subunit of the adenylate cyclase complex following the onset of myocardial ischemia.     

Changes of Ca2+-ATPase and cytochrome oxidase activity of myocardial cell under early and late ischemia:--comparison with ultrastructural changes

Using the histo- and cytochemical technique we assessed the Ca2+-transporting function of mitochondria (Mit) and sarcoplasmic reticulum (SR), and the ATP producing function of Mit in the ischemic myocardial cell of a dog's heart. In comparing ultrastructural ischemic changes, cytochrome oxidase (CO) and Ca2+-ATPase were cytochemically and histochemically measured when the myocardium was subjected to the ischemia of left anterior descending coronary artery occlusion for 15 min, and 60 min. After 15 min of occlusion the ischemic alterations consisted of a wide I band, decreased glycogen (G) and Mit swelling with a slight reduction of matrix density. Although CO activity was not reduced, Ca2+-ATPase had decreased mainly in Mit. Sixty min of ischemia resulted in loss of G, intermyofibrillar edema, marked Mit swelling with loss of matrix density and partial disruption of cristae, and dilatation of SR. Ca2+-ATPase activity was significantly reduced in Mit, SR and myofibrils. Although there was Mit swelling with partial disruption of cristae after 60 min of ischemia, CO activity was found to still exist in the remaining cristae. These findings suggest that intracellular organelle dysfunction progresses in the ischemic myocardial cell at different rates, and that disruption of intracellular Ca2+-homeostasis may occur early in the ischemic state.     

Degrading process of acute ischemic myocardial cells

1. Development of acute ischemic myocardial injury was studied in mongrel dogs, induced by ligation of left anterior descending coronary artery (LAD), by biochemical analysis of myocardial fractions such as sarcoplasmic reticulum (SR) and mitochondria (Mt) and by electron microscopic observation of ischemic myocardial cells with lanthanum probe method. 2. Irreversible injury of ischemic myocardium initiated in subendocardial muscle as early as 20 min after occlusion of LAD as expressed degradation of major ATPase protein and phosphatidylcholine and phosphatidylethanolamine of SR and irreversible impairment of state III respiratory and dinitrophenol (DNP)-ATPase activities of Mt, and these necrotic changes advanced to subepicardial layer at about 60 min. 3. Ultrastructural irreversible findings appeared later at about 60 min following inflow of lanthanum ions in ischemia for 30 min. 4. Activation of cathepsin B inside of SR under ischemic acidic metabolism and abnormal inflow of Ca++ into ischemic cardiac myocytes are suspective of very important factors for the initiation of myocardial ischemic injury in early myocardial ischemia.     

缺血心肌细胞钙分布变化的细胞化学研究

本文报道用细胞化学的磷酸盐—焦锑酸盐(PPA)法观察大鼠心肌缺血时心肌细胞钙分布变化。用PPA法显示正常心肌细胞钙定位在肌膜包括T管及闰盘的肌膜。钙沉淀物分布在肌膜的胞质面,沉淀物大小不超过20nm。在冠状动脉结扎30min后,肌膜的结合钙沉淀物减少甚至消失。当缺血超过60min,心肌细胞损伤严重,肌膜结合钙消失,细胞内肿胀线粒体的基质内积聚了丝团状的钙沉淀物。说明肌膜和钙结合能力是心肌细胞生存的重要特性。     

Influence of repetitive coronary occlusions on myocardial adenine nucleosides,high energy phosphates and ultrastructure

Summary We compared the effects of repeated short periods of myocardial ischemia with those of permanent occlusion (canine open-chest) with regard to tissue content of adenine nucleotides, nucleosides, creatine phosphate, and ultrastructure. Coronary occlusion for 3 min followed by a reperfusion period of 7 min was repeated up to a cumulative occlusion time of either 45 or 90 min. After cumulative occlusions of 15, 30, 45, and 90 min, transmural needle biopsies were taken from the ischemic area to be analyzed for adenine nucleotides, nucleosides, creatine phosphate, and ultrastructural changes. At the end of each experiment, tetrazolium salt staining was used for macroscopic detection of myocardial necrosis. These data were obtained with those obtained from dogs with a permanent coronary occlusion of 45 and 90 min, respectively. After repeated coronary occlusions at a cumulative occlusion time of 45 min, macroscopic detection of necrosis was negative, and after 90 min of cumulative coronary occlusion, patchy subendocardial tissue necrosis was found in only one out of 13 dogs, whereas in the group with permanent coronary occlusion, small patchy subendocardial necrosis was found in 95% after 45 min, and after 90 min permanent coronary occlusion, large subendocardial necrotic areas spreading towards the epicardial layers were found in 90% of the hearts.Ultrastructural investigations showed only slight to moderate ischemic injury after 45 and 90 min intermittent coronary occlusion, whereas permanent coronary occlusion produced moderate to severe ischemic injury after 45 min; and 90 min permanent coronary occlusion produced irreversible ischemic injury in all subendocardial tissue samples and in 80% of the subepicardial tissue samples.ATP content was decreased significantly less during intermittent coronary occlusion compared with that during permanent coronary occlusion.AMP and nucleosides did accumulate during permanent occlusion but not with repetitive brief coronary occlusions. Our results show that intermittent reperfusion significantly delays ischemic injury in comparison with permanent coronary occlusion.     

A morphometric analysis of ischemic canine myocardium with and without reperfusion

Progressive morphological changes have been quantitated in ischemic and control regions of canine hearts previously assessed biochemically and physiologically. Muscle strips removed after a 5 or 10-min occlusion of the left circumflex artery were compared to those removed after reperfusion for 20 or 60 min following 10 min occlusion and to those removed immediately from normal and sham-operated dogs. Decreased glycogen content and decreased mitochondrial matrix were observed in fibers from ischemic regions as early as 5 min after ligation. Changes in the mitochondrial volume fraction were calculated by the point counting method and changes in the number of lipid droplets per unit area were determined. Mitochondrial volume fractions in ischemic regions were not significantly higher when compared to control regions of the same hearts, and were similar to the values measured for 10 and 70-min sham-operated dogs. We conclude that in early acute ischemia considerable variability in the different control groups emerges with extensive sampling and must be considered in interpreting ultrastructural changes.     

Effects of preconditioning on myocardial interstitial levels of ATP and its catabolites during regional ischemia and reperfusion in the rat

The interstitial accumulation of adenine nucleotide breakdown products (ANBP) in the myocardium during ischemia has been shown to provide a useful index of the ischemic injury, whereas reperfusion ANBP washout rate has been regarded as an index of reperfusion damage. The purpose of this study was, using cardiac microdialysis, to examine in the rat model of regional ischemia/reperfusion the relationship between the duration of ischemia and these indices and to assess the profile of interstitial ATP concentrations and the beneficial effects of ischemic preconditioning (IP). The rats underwent 10, 20, 30 or 40 min of coronary artery occlusion and 50 min of reperfusion. Regional ischemia, with its duration, provoked a progressive increase in dialysate ANBP in the ischemic zone. The rate of purine washout during reperfusion exponentially declined with an increase in duration of the ischemic period. IP, induced by three 5-min episodes of ischemia, each separated by 5 min of reperfusion, significantly reduced the accumulation of ANBP during the 30-min period of sustained ischemia and resulted in a marked acceleration of reperfusion ANBP washout, indicating the improvement of postischemic microcirculation. These effects were suggested to be, at least in part, responsible for the infarct size limitation observed. Using the relationship between the duration of ischemia and ANBP washout rate, it could be demonstrated that IP produced similar facilitation of purine washout as shortening of the ischemic period in nonpreconditioned rats from 30 to approximately 7 min. Regional 20-min ischemia induced an early peak increase in interstitial fluid ATP which correlated with the maximal incidence of ventricular arrhythmias, whereas IP abolished both ATP release and arrhythmias during the sustained ischemia. These findings suggest that ATP may be an important mediator of ischemia-induced ventricular arrhythmias. Received: 20 April 1999, Returned for 1. revision: 11 May 1999, 1. Revision received: 23 June 1999, Returned for 2. revision:15 July 1999, 2. Revision received: 27 September 1999, Accepted: 29 September 1999     

Pathologic assessment of myocardial cell necrosis and apoptosis after ischemia and reperfusion with molecular and morphological markers

The present work illustrates the critical subcellular changes in the rat heart after 10-30 min of left coronary artery (LCA) occlusion and 120 min of reperfusion with a combination of several staining techniques. Triphenyltetrazolium chloride (TTC) to detect non-injured myocytes, horseradish peroxidase (HRP) and terminal deoxynucleotide nick-end labeling (TUNEL) to detect necrotic and apoptotic cells were employed and electron microscopy (EM) was used to validate these changes. After 20 min of LCA occlusion, myocytes began to undergo necrosis whilst after 10 min occlusion, no myocyte underwent irreversible cell injury in the risk area. After 30 min of LCA occlusion and 120 min reperfusion, 36.3, 26.6 and 25% cells were normal, necrotic, and reversibly injured, respectively; the remaining 12.8% cells were apoptotic. Necrotic cells were strongly positive with HRP and negative for TTC and TUNEL. TUNEL-positive or apoptotic cells were slightly HRP-positive, indicating altered cell membrane permeability. Reversibly-injured myocytes were TTC-, HRP- and TUNEL-negative. These changes were more accurately defined in the 100- microm thick sections than in the traditional slices. It is concluded that: (1) TTC-staining of 100- microm thick sections is far superior and accurate for the detection of ischemic changes with shorter period of ischemia (10 min); (2) the combination of TTC-staining, HRP reaction and TUNEL method is excellent for demarcation of early ischemic changes; (3) TTC-negativity in ischemia less than 20 min does not indicate necrosis but only represents reversible changes; (4) the apoptosis is absent in early ischemia of 20 min with or without reperfusion at a time when sufficient ATP is present, and appears only after 30 min of coronary ligation and reperfusion; and (5) the apoptotic cells lose membrane integrity accompanied by decreased glycocalyx thickness and cell swelling as opposed to commonly known characteristics of apoptotic cells.     

实验性顿抑心肌微血管结构和功能改变

目的 探讨心肌顿抑时心肌微血管结构和功能改变。方法 制备冠状动脉左前降支（LAD）不同阻断时间（15min和60min)后再灌注犬心肌顿抑模型，在不同观察时间点静脉注射含全氟丙烷声振白蛋白微泡造影剂，采用二次谐波成像和间歇发射技术行心肌声学造影。由主动脉根部分别注射乙酰胆碱（ACH）和硝酸甘油（NG）后重复心肌声学造影，并计算用药后／前二维超声上所示心肌灰阶峰值比值（PVIR）和顿抑区与正常区心肌灰阶峰值比值的比值PVIRR。心肌标本行透射电镜检查。结果 （1）LAD阻断15min组再灌注早期NG－PVIR和ACH－PVIR明显减低，但分别在再灌注60min和120min时恢复至结扎前水平；（2）LAD阻断60min组再灌注早期NG－PVIR减低，至再灌注120min时才恢复到结扎前水平，而再灌注ACH-PVIR明显减低，随着再灌注时间的延长虽有逐渐回升趋势，但至再灌注120min仍未恢复至结扎前水平；（3）两组PVIRR的变化与PVIR一致，唯恢复稍慢；（4）LAD阻断15min组心肌毛细血管和内皮细胞结构未见明显改变，而LAD阻断60min组毛细血管内皮细胞肿胀，内皮细胞间连接间隙稍增宽。结论 顿抑心肌微血管舒张功能受损，缺血时间较长则还有微血管结构改变，其受损的细胞主要是内皮细胞。     

Disruption of sarcolemmal integrity during ischemia and reperfusion of canine hearts as monitored by use of lathanum ions and a specific probe

Myocellular injury induced by acute ischemia and subsequent reperfusion was studied in 38 dogs, with special reference to sarcolemmal permeability as determined by the vital ionic lanthanum (La³⁺) probe technique and electron microscopy. The left anterior descending coronary artery (LAD) was occluded in 14 dogs for 10 to 60 min, and the ischemic zone was perfused slowly for 7 min with a La³⁺-containing solution. In 21 dogs, the LAD was released for 10 min after occlusion and was then reperfused for 7 min with arterial blood plus the La³⁺-containing solution. Subsequently, in both groups of animals, the ischemic myocardium was subjected to perfusion fixation in preparation for electron microscopy. In normal cardiac myocytes, La³⁺ was localized exclusively in the extracellular space. After 10 to 20 min of ischemia, more than 80% of myocytes appeared normal or were damaged only slightly, and the majority continued to exclude La³⁺. After 10 min of ischemia, deposits of lanthanum were detected in 1 and 6 % of myocytes in the absence or presence of reperfusion, respectively. The number of cells with such deposits was markedly increased after 30 min of ischemia (19%), as well as after 20 min of ischemia followed by reperfusion (17%), prior to the development of irreversible myocardial damage. After 60 min of ischemia with or without reperfusion, about 30% of myocytes showed severe injury with particulate deposits of lanthanum throughout the entire cell.These results indicate that sarcolemmal permeability increases during the early stage of myocardial injury due to ischemia or ischemiareperfusion and contributes to the development of myocardial damage.     

Study on reperfusion injury on sarcoplasmic reticulum in acute myocardial ischemia.

Reperfusion injury in early myocardial ischemia was studied in the dog with special reference to sarcoplasmic reticulum (SR) and contraction bands. Acute myocardial ischemia (I) was induced by occlusion of the left anterior descending coronary artery (LAD) for 10, 20 and 30 min followed by reperfusion for 15 min (R). Ca(++)-ATPase activity of SR in 10-min-R-Group was significantly reduced to 60% of control activity, but activity of 10-min-I-Group remained near the control level in subendomyocardium (Endo). ATPase activity in 30-min-I-Group diminished to 60% of control activity in Endo and it was similar for 30-min-R-Group. In ischemic myocardium, composition of major ATPase protein decreased significantly in 30-min-I-Group and similar reduction was observed in 20-min-R-Group in Endo. In morphology proportion of appearance of contraction bands in Endo was significantly increased in 20-min or longer-R-Groups. These results suggest that reperfusion injury is likely to occur when coronary artery is reflowed after 10 min of ischemia. This may be caused by increased intracellular Ca++ at a very early stage of reperfusion period, and reperfusion injury may be induced due to acceleration in the necrotic process of the membrane system in the myocytes during ischemia.     

Detection of mitochondrial membrane damages in myocardial ischemia with ESR spin labeling technique

The ultrastructure and membrane fluidity were examined in two fractions of myocardial mitochondria isolated from the ischemic region following occlusion of the circumflex coronary artery of the dog. Transmission electron microscopy revealed that 60 min of ischemia produced more structural change in the subsarcolemmal mitochondria than in the intermyofibrillar mitochondria. Changes in the dynamic properties of the mitochondrial membranes were examined using the spin labeling technique with electron spin resonance (ESR). From the ESR spectra, the membrane fluidity of the subsarcolemmal mitochondria was found to decrease significantly after ischemic injury, whereas no difference was observed in intermyofibrillar mitochondria. In addition, a negative correlation between the increase of order parameter S and dysfunction of respiratory responses of subsarcolemmal mitochondria was found. These results suggest that the two fractions of mitochondria in the myocardium showed different responses to acute ischemic injury. The damage to mitochondrial membranes occurred during the period of ischemia.     

Protective effect of verapamil in ischemic porcine hearts: analysis of ultrastructural and metabolic changes using in vivo 31P-NMR spectroscopy

To assess the protective effect of verapamil on ischemic myocardium, the changes in high energy phosphates, inorganic phosphate, and intracellular pH were serially and quantitatively measured in ischemic porcine hearts without collateral circulation using 31P-NMR spectroscopy, together with ultrastructural examination. Twenty-six farm pigs weighing 11 to 14 kg were anesthetized with fluothane and were divided into control (C) group and verapamil pretreatment (V) group. In V group 0.2 mg/kg of verapamil was administered for 20 mins before occlusion of the anterior descending coronary artery. 31P-NMR spectra were serially obtained throughout the experiment, and ultrastructural examination was done at 20-min occlusion and at 120-minute occlusion in each group. At 10-min ischemia, creatine phosphate was significantly preserved in V group (C/V = 11 +/- 4%/16 +/- 5% P less than 0.05). At 20 min ischemia, ATP was significantly preserved (C/V = 60 +/- 9%/73 +/- 8% P less than 0.05), and intracellular pH was significantly higher in V group (C/V = 6.4 +/- 0.2/6.6 +/- 0.1 P less than 0.05). Morphologically, clumping of the nuclear chromatin, mitochondrial swelling and decrease in glycogen were milder in V group at 20 min ischemia. However, these beneficial effects disappeared at 120 min ischemia. Thus pretreatment with verapamil attenuated depletion of high energy phosphates, progression of acidosis, and ultrastructural changes. There was no significant difference of rate pressure product and regional blood flow between hearts with and without pretreatment of verapamil. Therefore, this protective effect may be due to the energy sparing effect or other direct subcellular effect of verapamil on ischemic myocyte.     

曲美他嗪对心肌缺血时细胞骨架损伤的作用

目的　探讨心肌缺血时细胞骨架改变并观察曲美他嗪对心肌缺血时细胞骨架损伤的影响 ,为临床应用提供理论依据。方法　将大白鼠随机分为对照组和用药组并制成缺血模型 ,分别于缺血 30 m in、6 0 min、12 0 min时取心肌组织用免疫组化的方法观察肌动蛋白、波形蛋白、肌球蛋白、结蛋白等心肌细胞骨架蛋白的改变 ,并用计算机图象模拟分析系统计算骨架蛋白量的变化。结果　心肌缺血 30 min即有肌动蛋白、肌球蛋白损伤 ,12 0 min时有结蛋白损伤 (P<0 .0 5 )。曲美他嗪干预后 ,心肌缺血 6 0 min、12 0 min时肌动蛋白、肌球蛋白损伤明显减少 (P<0 .0 5 )。结论　心肌缺血时可以导致细胞骨架损伤 ,曲美他嗪对心肌缺血时细胞骨架损伤有保护作用     

Effects of nicardipine on ischemic mechanical failure and tissue injury in isolated perfused rat heart

Using a Langendorff rat heart preparation, we examined effects of nicardipine, a calcium channel blocker, on different stages of ischemic damage, characterized by a development of contracture and leakage of intracellular enzymes. Maximum recoveries of heart rate (HR) and peak left ventricular pressure-HR product after 20 min ischemia were attenuated by about 25% compared with those before ischemia. When nicardipine (0.1 mumol) was added to the perfusate 5 min prior to ischemia, this mechanical failure recovered completely to the pre-ischemic level. Although a significant increase in left ventricular end-diastolic pressure was observed in hearts exposed to 30 min ischemia, the amount of creatine kinase (CK) released during re-flow after 30 min ischemia was not enhanced by contracture but was proportional to the duration of ischemia (compared with that of 20 min ischemia). Nicardipine reduced CK leakage by 25% after 30 min ischemia but did not alter either ATP levels or coronary flow. The beneficial effects of nicardipine on ischemic damage are probably related to inhibition of calcium influx (Terai et al: Biochem Pharmacol 30: 375, 1981), which may accompany reperfusion of ischemic myocardium.     

Histochemical, ultrastructural and cytochemical study of reperfusion effect on ischemic myocardial injury

We assessed the histochemical, ultrastructural and cytochemical effects of reperfusion on ischemic myocardial cells during the early and late reperfusion phases in two groups of dogs. Group A were 8 dogs undergoing 1 hour occlusion of LAD, and Group B were 14 dogs undergoing 1 hour occlusion of LAD followed by 2 hour reperfusion period. The results of the histochemical study (PAS stain) demonstrated that in Group A, a patchy distribution of glycogen occurred primarily in the subepicardial region. Three-dimensional analysis of this distribution revealed peninsulas of glycogen running parallel with a vessel. The cells in Group B, mainly subepicardium, showed a moderate glycogen content which was more extensive than those in Group A. The ultrastructural changes were assessed after a 60-minute ischemia and subsequent recovery (after 5 minutes and 120 minutes of reflow) using transmural biopsy specimens. Each myocardial cell was graded from 0-4 according to the degree of ischemic injury and recovery. The degree of ischemic damage varied in intensity from slight to severe, in both the subepicardium and the subendocardium. Ca++-ATPase activity was examined cytochemically in myocardial cells of Group B. After 60-minute occlusion, the moderately ischemic cells (especially in the subepicardium) that were without amorphous dense bodies or marked sarcolemmal lifting-off made significantly greater ultrastructural recovery (p less than 0.05) with restoration of Ca++-ATPase activity on sarcoplasmic reticulum and mitochondria after 120 minutes of reflow. This occurred even though after 5 minutes of reflow the cell showed temporary deterioration such as contraction bands, vacuoles and severe destruction of some mitochondria.     

Maximal rate of the left ventricular pressure fall (peak negative dP/dt) in early stage of myocardial ischemia following experimental coronary occlusion.

Short-term, repeated myocardial ischemia was produced in 20 opened-chest anesthetized dogs by left anterior descending (LAD) branch occlusion. Left ventricular pressure (LVP) and its dP/dt were recorded by Satham SF-1 transducer, and isometric local force (F) was measured by a Walton-Brodie strain gauge arch sewn onto LV free wall. In all experiments, within a few beats after LAD occlusion, peak negative dP/dt started to diminish its amplitude, reaching a nadir after 20-30 sec (63 +/- 5% of control, 9 dogs). It recovered to 83 +/- 3% of control level in 45 sec and remained essentially unchanged thereafter. This change preceded those of LVP and max dP/dt, which showed only minor falls. In 6 dogs, changes by occluding root of LAD were compared with those by its branch occlusion. The greater the extent of ischemia, the more marked and prolonged were the changes. While F in the ischemic center (Fc) rapidly lost its contractile activity following LAD occlusion, F in marginal zone between infarcted and non-infarcted region (Fm) showed variable extent and different time-course of its diminution. Thus, it was concluded that the change in peak negative dP/dt following LAD occlusion was one of the sensitive signs of early ischemic changes, and was attributed at least in part to characteristic changes in contractile activity of myocardium surrounding the ischemic injury.     

高钾保护心肌缺血再灌注损伤的机理研究

心肌缺血时肌原纤维过度收缩可致心肌细胞膜机械性撕裂。缺血时,甚至缺血停既后,给予少量高钾液可抑制心肌过度收缩,防止毛细血管内皮细胞肿胀,明显减轻再灌注损伤。     

Usefulness of defibrotide in protecting ischemic myocardium from early reperfusion damage

Defibrotide, a partially depolymerized polydeoxyribonucleotide obtained from mammalian lungs, was found to stimulate prostacyclin (PGI2) production and to possess significant antithrombotic and fibrinolytic activities. The present study was designed to evaluate the actions of defibrotide on feline myocardial ischemia, produced by 3 hours of occlusion of the left anterior descending coronary artery (LAD) and followed by 2 hours of reperfusion. Intravenous administration of defibrotide (32 mg/kg/hour subsequent to a 32 mg/kg bolus injection), beginning 30 minutes after LAD occlusion, resulted in a 60% reduction in loss of CK specific activity from ischemic myocardium at 5 hours, while the nonischemic myocardium remained unaffected. Defibrotide largely antagonized the increase in ST segment during LAD occlusion and prevented the appearance of a Q wave during early reperfusion, which was found in all vehicle-treated cats. Although 2 of 8 vehicle-treated cats died from ventricular fibrillation and another had severe ventricular tachyarrhythmia, none of the defibrotide-treated cats had similar severe changes in the electrocardiogram and all 7 cats survived the 5-hour observation period. Defibrotide had no direct action on general hemodynamic functions. In a separate set of experiments, defibrotide (0.1 mg/ml) produced an 8- to 10-fold stimulation of PGI2 release. The data suggest a remarkable protective potential of defibrotide on reperfusion damage of the ischemic myocardium, which may be associated with a PGI2-related mechanism.