Salutary action of nicorandil, a new antianginal drug, on myocardial metabolism during ischemia and on postischemic function in a canine preparation of brief, repetitive coronary artery occlusions: comparison with isosorbide dinitrate

The effects of two antianginal drugs, nicorandil and isosorbide dinitrate (ISDN), on metabolism and function of the ischemic myocardium were studied in a preparation of multiple coronary occlusions in barbital-anesthetized dogs. The preparation consisted of three 5 min occlusions of the left anterior descending coronary artery interspersed by 30 min of reperfusion. An equihypotensive dose of nicorandil (7.5 micrograms/kg/min) or ISDN (12.5 micrograms/kg/min) was infused 15 min before and during the second occlusion period. Hemodynamics, myocardial segment shortening (%SS), tissue blood flow, and myocardial oxygen consumption were determined throughout. Uptake of free fatty acids (FFA), glucose, and lactate were determined during control and ischemic periods. At the end of the final 30 min reperfusion period, biopsy samples of transmural tissue were taken for analysis of phosphocreatine, adenine nucleotides, and total tissue water content. No major hemodynamic changes were produced by either drug except for a 5 to 10 mm Hg decrease in mean aortic pressure. Compared with untreated and ISDN-treated hearts, hearts of dogs treated with nicorandil exhibited reversal of a significant increase in FFA uptake during recurrent ischemia. This was accompanied by an attenuation of the increase in oxygen extraction and CO2 production in the ischemic zone by nicorandil, but not by ISDN. Nicorandil, but not ISDN, improved %SS during reperfusion. Endocardial ATP and total adenine nucleotides were preserved in both nicorandil- and ISDN-treated hearts. Tissue edema was also attenuated by both compounds. Thus, nicorandil improved both function and metabolism during recurrent myocardial ischemia independent of a hemodynamic effect, whereas ISDN only attenuated the loss of adenine nucleotides and increase in tissue water.     

高密度脂蛋白抗动脉粥样硬化功能的丢失与恢复

巨噬细胞在动脉粥样硬化(As)起始、发展的全过程扮演着中心角色,从巨噬细胞脂质积聚和炎症反应入手,寻求某个作用环节进行干预有可能成为非常合适的As治疗靶点。内皮功能失调是As发生的一个重要起始事件,内皮细胞释放的粘附分子如ICAM、VCAM、ELAM及Selectin,介导单核细胞活化并向内膜下募集、分化,巨噬细胞释放的单核细胞趋化蛋白1(MCP-1)及巨噬细胞移动抑制因子(MIF)在单核细胞的移行和分化中发挥重要作用。MIF还可诱导ICAM、....     

尼可地尔后处理对急性缺血诱导的大鼠心肌细胞凋亡的影响

目的 探讨尼可地尔后处理对大鼠心肌缺血再灌注损伤的保护作用及机制.方法 SD大鼠随机分为6组:假手术组、缺血再灌注组、缺血后处理组、尼可地尔后处理2、5和10 mg/kg剂量组.采用左冠状动脉前降支结扎30 min、再灌注120 min建立大鼠心肌缺血再灌注模型.缺血后处理组在缺血后再灌注前实施5次10 s再灌注-10 s再阻断循环.尼可地尔后处理组在缺血后再灌注前分别给予三个剂量10 min.检测血清肌酸激酶和丙二醛含量,及超氧化物歧化酶活性;检测心肌细胞的凋亡率和Caspase-3蛋白的表达.结果 尼可地尔后处理能使肌酸激酶、丙二醛含量降低,超氧化物歧化酶活性增高,心肌细胞凋亡率降低, Caspase-3蛋白表达减少.结论 尼可地尔后处理对缺血再灌注损伤的心肌具有保护作用,其机制可能与提高超氧化物歧化酶活性,增强心肌抗氧化能力,减轻氧自由基损伤,稳定细胞膜,抑制细胞凋亡有关.     

Effect of nicorandil, a K+ATP -channel opener, on coronary capillary architecture and volume after early myocardial ischemia-reperfusion--a 3-dimensional confocal laser microscopic study--.

BACKGROUND: Previous experimental and clinical studies have reported that nicorandil, an adenosine triphosphate (ATP)-sensitive K+ channel opener, exerts a beneficial effect on microvascular function and clinical outcome after myocardial ischemia. The present study assessed whether intravenous administration of nicorandil affects the 3-dimensional (3-D) architectural characteristics of capillaries and their volume after early myocardial reperfusion. METHODS AND RESULTS: Using the hearts of open-chest anesthetized rats, the left anterior descending artery was occluded for 7 min followed by reperfusion. Nicorandil or saline was infused intravenously during occlusion and reperfusion. The entire coronary microvasculature was filled with contrast medium after the hearts were arrested. Capillaries were observed 3-dimensionally by confocal laser scanning microscopy in both the control area and reperfused area of all samples. The capillary volume fraction was computed from the 3-D images. The reperfused area in both the nicorandil and saline groups showed characteristic architectural changes of the capillaries. Capillary volume fraction in the reperfused area was significantly reduced in saline group, compared with nicorandil group [12.7+/-7.2% vs 18.1 +/-5.3% (p<0.01)]. CONCLUSIONS: Intravenous nicorandil administration has a beneficial effect on capillary damage after reperfusion.     

Initial reperfusion with magnesium after cardioplegic arrest attenuates myocardial reperfusion injury

BACKGROUND: Magnesium's effect on calcium ion concentrations may attenuate myocardial reperfusion injury. The aim of this study was therefore to investigate the effects on the recovery of myocardial function of initial reperfusion with varying Mg(2+) concentrations following cardioplegic arrest. METHODS: Isolated guinea pig hearts underwent 3.5 hours of cardioplegic arrest in St. Thomas Hospital II solution (STH) or Bretschneider HTK solution (HTK) at 24 degrees C. Control hearts were reperfused with normal Krebs-Henseleit solution (KHS). In the therapy groups, hearts were initially reperfused with 5, 10, or 20 mM Mg(2+) for 15 minutes, followed by 30 minutes of perfusion with KHS. RESULTS: During initial reperfusion, elevated Mg(2+) concentrations markedly reduced rate-pressure product, dP/dt and O 2 demand. Release of LDH and CK was reduced in the therapy groups pretreated with Bretschneider HTK. After Mg(2+) washout, left ventricular function recovery and compliance was improved after HTK but not after STH cardioplegia. Following both STH and HTK cardioplegia, Mg(2+) reperfusion reduced reperfusion arrhythmias. CONCLUSIONS: The combination of HTK cardioplegia with 15 min initial Mg(2+) (5 and 10 mM, but not 20 mM) reperfusion was clearly superior to HTK followed by immediate Krebs-Henseleit reperfusion as well as STH cardioplegia with or without initial Mg(2+) reperfusion. The high Mg(2+) concentrations in the STH solution might mask beneficial effects of Mg(2+) reperfusion.     

Effects of nicorandil on coronary circulation and myocardial ischemia

The effect of the new antianginal drug, nicorandil, was studied in several models of myocardial ischemia in anesthetized dogs. In animals subjected to an acute or chronic coronary artery occlusion, nicorandil produced increases in collateral perfusion when changes in aortic pressure were minimized. In a model of irreversible ischemia, nicorandil produced a marked (50%) decrease in myocardial infarct size. In several models of reversible ischemiareperfusion injury, the “stunned myocardium,” nicorandil was shown to enhance the recovery of systolic segment shortening after a brief period (15 to 30 minutes) of coronary occlusion. Other vasodilators such as nitroglycerin or nifedipine were not as efficacious as nicorandil. In a model of multiple (n = 3) coronary occlusion (5 minutes) with intermittent (30 minutes) reperfusion, nicorandil improved the recovery of systolic segment shortening during reperfusion and prevented the loss of adenosine triphosphate and tissue edema that occurred in untreated hearts. The beneficial effects of nicorandil on functional and metabolic recovery after recurrent ischemia was shown to be partially the result of an energy-sparing effect of nicorandil to reduce free fatty acid use during the ischemic period. Cyclooxygenase blockade with indomethacin did not block the beneficial effects of nicorandil in the stunned myocardium. These results suggest that nicorandil does not promote an increase of prostacyclin. Finally, nicorandil was found to inhibit superoxide anion production by human neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine plus cytochalasin B. These results suggest that part of the beneficial actions of nicorandil may occur during reperfusion and may be the result of a reduction in oxygen free radical production. Thus, nicorandil has been found to be a highly efficacious agent in reducing ischemia and reperfusion injury in a number of animal models by several mechanisms.     

利多氟嗪的心肌保护作用机制－腺苷转运抑制

用１８只狗研究了利多　嗪（Ｌｉｄｏｆｌａｚｉｎｅ）的心肌保护作用机制。实验分三组：对照组（Ｃ）、利多　嗪组（Ｌ）及利多　嗪加氨茶硷组（ＬＡ）。在体外循环（ＥＣＣ）开始前１５分钟内给予实验药物及安慰剂。然后施行四次间断升主动脉阻断１５分钟间隔以１０分钟再灌注。ＥＣＣ结束后监测６０分钟心功能恢复情况。结果发现在最后一次主动脉阻断未Ｌ组心肌腺苷含量是Ｃ组的３．５倍；每次再灌注时Ｌ组心肌腺苷释放量远较Ｃ组高：Ｌ组心肌摄取乳酸盐量每次再灌注时都恢复到正常水平，而Ｃ组则没有恢复正常；Ｌ组心功能各项指标的恢复均明显优于Ｃ组。当用了腺苷受体阻滞剂氨茶硷后再用利多嗪时，其心肌保护作用明显下降，而心肌腺苷的含量及释放量在Ｌ组与ＬＡ组间无明显差异。     

Experimental studies on ischemic injury and reperfusion injury to the cardiac sarcoplasmic reticulum--the myocardial protective effect of nicorandil

Ischemic and reperfusion injuries to the myocardium were evaluated by measuring cardiac function and the calcium binding capacity of the sarcoplasmic reticulum (SR) and by studying the myocardial protective effect of nicorandil. While undergoing cardiopulmonary bypass, dogs were subjected to 120-min global myocardial ischemia and then to 120-min reperfusion. Group I hearts were arrested with untreated potassium cardioplegic solution; Group II with the same solution containing 2 mg/L and Group III with the same plus 10 mg/L of nicorandil. Group III exhibited better recovery from ischemic and reperfusion injuries than Group I with recovery rates of LV dp/dt max (95.0 +/- 28.9% vs 61.1 +/- 30.4, p less than 0.05) and LV negative dp/dt max (69.0 +/- 12.5% vs 46.8 +/- 21.7, p less than 0.05). The 3 groups showed a marked decrease in the max calcium binding capacity during ischemia compared with the Control Group but exhibited no further decrease after reperfusion. After ischemia and reperfusion, Group III (30.4 +/- 9.13 nmol Ca/mg protein, 30.0 +/- 8.50) demonstrated a significantly higher binding capacity than Group I (17.0 +/- 2.41 and 18.3 +/- 1.01, p less than 0.05), while Group II did not. These results suggest that ischemia is more injurious to the calcium binding capacity of SR than reperfusion and that 10 mg/L of nicorandil added to the cardioplegic solution preserves SR function and enhances the recovery of cardiac function.     

Tolerance of the hypertrophic heart to ischemia. Studies in compensated and failing dog hearts with pressure overload hypertrophy

Tolerance of the canine heart to prolonged ischemic arrest was studied in 10 hearts from normal control dogs and 15 hearts from dogs with left ventricular hypertrophy (LVH); experiments were performed 1 year after banding the aorta in 8-week-old puppies. At 1 year, hemodynamic studies revealed decreased left ventricular (LV) fiber shortening and elevated end-diastolic pressure (EDP) in five dogs (group with LVH failure); 10 dogs exhibited normal shortening and normal EDP (group with LVH compensation). The left ventricle-to-body weight ratio (g/kg) was 4.4 +/- 0.8 in the control group of dogs, 7.7 +/- 1.0 in the group with LVH compensation, and 10 +/- 2.5 in the group with LVH failure. The tolerance to 60 minutes of global ischemia (37 degrees C) followed by 90 minutes of reperfusion was studied in an isolated blood-perfused heart apparatus (isovolumic left ventricle, coronary perfusion pressure of 100 mm Hg). In the baseline (preischemic) state, coronary blood flow, myocardial oxygen consumption, lactate extraction, and myocardial high-energy phosphate content were essentially equal in the three groups; with LV volume adjusted to produce a systolic pressure of 100 mm Hg, there were no significant differences in LVEDP among the three groups. During ischemia, the diastolic (asystolic) pressure increased from 11 +/- 3 to 28 +/- 16 mm Hg (p less than 0.05) in the group with LVH failure; however, it did not increase in the control or the LVH compensation groups. Myocardial ATP levels declined equally in all three groups. During early reperfusion, lactate washout was lowest in the group with LVH failure. By 90 minutes of reperfusion, there were no significant differences in coronary blood flow, myocardial oxygen consumption, lactate extraction, or high-energy phosphate levels. High diastolic pressure persisted at 90 minutes of reperfusion in the LVH failure group (EDP was 34 +/- 19 mm Hg); however, there was no significant change in EDP during reperfusion in the control or with LVH compensation groups. After 90 minutes of reperfusion, developed pressures in the control (54 +/- 9 mm Hg), the LVH compensation (49 +/- 18 mm Hg), and the LVH failure (67 +/- 17 mm Hg) groups were not significantly different. These data indicate that hearts with compensated LVH do not exhibit an impaired tolerance to ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)     

钾通道开放剂对离体兔心缺血再灌注损伤的保护作用

目的观察非选择性三磷酸腺苷敏感性钾(KATP)通道开放剂Pinacidil和线粒体型KATP(mitoKATP)通道开放剂Diazoxide预处理对高钾停跳离体兔心缺血再灌注损伤的保护作用,以及mitoKATP通道阻断剂5-hydroxydecanoic acid sodiumsalt(5HD)应用后其心肌保护作用的变化。方法采用离体兔心Langendorff灌注实验模型。离体兔心40只随机等分成5组(n=8):对照组(C组)、Pinacidil组(P组)、Diazoxide组(D组)、5HD Pinacidil组(HP组)和5HD Diazoxide组(HD组)。离体兔心用标准Thomas停搏液(4℃,K 16mmol/L)至心停跳,45min后再灌注20min,于心脏停跳前灌注药物15min,对比观察Pinacidil、Diazoxide及其与5HD合用时对再灌注后心功能及冠状动脉血流的影响以及再灌注末心肌超微结构、蛋白含量、脂质过氧化物丙二醛(MDA)以及腺苷酸含量的变化。结果再灌注后P组、D组、HP组心功能的恢复率均明显高于C组,心肌MDA的含量、蛋白的漏出量明显低于C组,超微结构观察损伤较轻;但HP组心功能的恢复要差于P组,心肌MDA的含量、蛋白的漏出量明显高于P组;HD组与C组各检测指标比较差异无统计学意义。结论Pinacidil(10μmol/L)和Diazoxide(30μmol/L)预处理对离体兔心缺血/再灌注心肌具有保护效果,且其保护效果可以部分被5HD所阻断,提示心肌mitoKATP通道可能是产生心肌保护作用的靶点之一。     

Enhanced thrombolytic efficacy and reduction of infarct size by simultaneous infusion of streptokinase and heparin

Because paradoxical increase in thrombin activity was reported after the administration of streptokinase in patients with acute myocardial infarction the velocity of reperfusion and degree of myocardial damage were studied when heparin was infused during rather than after streptokinase infusion. Thirty seven consecutive patients with acute myocardial infarction were randomised to receive intravenous heparin during (group 1, n = 18) or after (group 2, n = 19) streptokinase (1.5 megaunits over 60 minutes). Markers of reperfusion were monitored every 15 minutes for 3 hours. The serum concentration of creatine kinase was measured every 2 hours. The two groups were similar in terms of age and sex distribution, infarct site, time to treatment, and baseline myocardial ischaemia. Patients in group 1 had a significantly shorter mean (SD) reperfusion time (57 (35) minutes v 101 (47)). From 60 to 120 minutes after randomisation there were significant differences in ST segment elevation between the groups. Serum creatine kinase MB peaked earlier (8 (2) hours) in group 1 than in group 2 (10 (4) hours). The peak concentration was significantly lower in group 1 (87 (47) mU/ml) than in group 2 (134 (96) mU/ml) and infarcts were smaller (25.2 (9.8) gram equivalents/m2) in group 1 than in group 2 (35.1 (10.2) gram equivalents/m2). Simultaneous infusion of heparin and streptokinase speeds up the appearance of signs of reperfusion and reduces infarct size.     

Enhanced thrombolytic efficacy and reduction of infarct size by simultaneous infusion of streptokinase and heparin.

Because paradoxical increase in thrombin activity was reported after the administration of streptokinase in patients with acute myocardial infarction the velocity of reperfusion and degree of myocardial damage were studied when heparin was infused during rather than after streptokinase infusion. Thirty seven consecutive patients with acute myocardial infarction were randomised to receive intravenous heparin during (group 1, n = 18) or after (group 2, n = 19) streptokinase (1.5 megaunits over 60 minutes). Markers of reperfusion were monitored every 15 minutes for 3 hours. The serum concentration of creatine kinase was measured every 2 hours. The two groups were similar in terms of age and sex distribution, infarct site, time to treatment, and baseline myocardial ischaemia. Patients in group 1 had a significantly shorter mean (SD) reperfusion time (57 (35) minutes v 101 (47)). From 60 to 120 minutes after randomisation there were significant differences in ST segment elevation between the groups. Serum creatine kinase MB peaked earlier (8 (2) hours) in group 1 than in group 2 (10 (4) hours). The peak concentration was significantly lower in group 1 (87 (47) mU/ml) than in group 2 (134 (96) mU/ml) and infarcts were smaller (25.2 (9.8) gram equivalents/m2) in group 1 than in group 2 (35.1 (10.2) gram equivalents/m2). Simultaneous infusion of heparin and streptokinase speeds up the appearance of signs of reperfusion and reduces infarct size.     

Sustained protection by acadesine against ischemia- and reperfusion-induced injury. Studies in the transplanted rat heart.

BACKGROUND. We have shown that acadesine (AICAr: 5-amino-4-imidazole carboxamide riboside) improves the early recovery of function of the ischemic and reperfused rat heart. In the present studies we used the transplanted rat heart, with reperfusion for up to 24 hours, to assess whether the beneficial effect of acadesine is a transient or a sustained phenomenon (i.e., to determine whether the drug improves the extent of recovery or only the rate). METHODS AND RESULTS. Hearts (n = 8 per group) were excised and immediately arrested with an infusion (2 minutes at 20 degrees C) of the St. Thomas' Hospital cardioplegic solution with or without the addition of acadesine (20 mumol/l). They were then subjected to 4 hours of global ischemia (20 degrees C), and the cardioplegic solution (with or without acadesine) was infused for 2 minutes every 30 minutes. The hearts then were transplanted (1 hour additional ischemic time) into the abdomens of recipient rats, which had been given acadesine (100 mg/kg i.v.) or saline. They were reperfused in situ for 30 minutes or 24 hours and then excised and perfused aerobically for 20 minutes. Contractile function was assessed, and the hearts were taken for metabolite analysis. Two sets of four groups (n = 8 per group) were studied (one set with 30 minutes and the other with 24 hours of reperfusion): group A, acadesine-free control; group B, acadesine during cardioplegia alone; group C, acadesine during reperfusion alone; and group D, acadesine during both cardioplegia and reperfusion. With 30 minutes of reperfusion, a significant improvement in functional recovery was seen in the two groups (groups B and D) in which acadesine had been added to the cardioplegic solution. Left ventricular developed pressure (LVDP) at 12 mm Hg of left ventricular end-diastolic pressure (LVEDP) was 104 +/- 3 mm Hg in both groups versus 88 +/- 3 mm Hg in the acadesine-free controls (p less than 0.05). No protection was observed after 30 minutes of reperfusion when acadesine had been added during reperfusion alone (89 +/- 4 mm Hg). In contrast, after 24 hours of reperfusion there was a significant improvement in postischemic LVDP in all acadesine-treated groups (group B, 104 +/- 6 mm Hg; group C, 106 +/- 7 mm Hg; and group D, 117 +/- 3 mm Hg versus only 73 +/- 6 mm Hg in the acadesine-free controls; p less than 0.05 in each case). Metabolite analysis indicated that at the end of ischemia ATP was less depleted and levels of tissue adenosine were higher in the acadesine group. During early (30 minutes) reperfusion, acadesine produced higher mean ATP contents, although this achieved a level of statistical significance only when the drug was administered during both cardioplegia and reperfusion. After 24 hours of reperfusion, the adenine nucleotide pools were similar in all groups. CONCLUSIONS. Acadesine can afford sustained functional protection against injury during extended periods of ischemia and reperfusion. We present evidence that the beneficial effect of acadesine may be mediated by two different components, with one operative during ischemia and early reperfusion and the other acting later in the reperfusion period.     

Effects of Magnesium and its Mechanism on the Incidence of Reperfusion Arrhythmias Following Severe Ischemia in Isolated Rat Hearts

Magnesium sulfate (Mg) has been widely used for the treatment of ventricular arrhythmias (VF) in patients with coronary artery disease. However, the mechanisms of prevention on the incidence of VF have not been defined. The aim of study was to investigate the role of Mg in the prevention of VF and the mechanism of those effects. Series 1 studied antiarrhythmic effects on VF. Isolated rat hearts were perfused in the working heart mode with Krebs'-Henseleit bicarbonate buffer (KHB). Whole heart ischemia was induced by a one-way ball valve with 300 beats/min electrical pacing for 10 minutes followed by 20 minutes of aerobic reperfusion. After control perfusion, Mg was added from 5 minutes before ischemia and was continued to the end of ischemia (1.2 mM for the control group and 2.4, 3.6, 4.8, and 9.6 mM for the study animals) or during reperfusion (3.6 mM). Left ventricular pressure, aortic flow, and ECG were monitored. Series 2 studied the effect of Mg on [Ca²⁺]i. Hearts were perfused by the Langendorff mode and were loaded with 4 M of Fura 2/AM as a [Ca²⁺]i indicator. Ca²⁺ was monitored using the ratio of Fura-2 fluorescence intensity at excitation wavelengths of 340 and 380 nm. The hearts were subjected to a 20 minutes of low-flow ischemia followed by 20 minutes of aerobic reperfusion. Then 3.6 mM Mg was added to the KHB medium during ischemia. The duration of VF was significantly suppressed in the 2.4, 3.6, and 4.8 mM/L Mg-added groups (472 ± 173, 779 ± 159, and 525 ± 202 second, respectively) when compared with the control group (1200 seconds). Magnesium sulfate suppressed the fluorescence ratio of the diastolic Ca²⁺ level at the end of 20 minutes of ischemia from 40.5 ± 3.6% to 9.0 ± 1.0% (P 0.05 vs. control hearts). These results suggested that Mg had a beneficial effect on VF and that the optimal Mg concentration was between 2.4 and 4.8 mM. The mechanism of the prevention of VF by Mg could be through the inhibition of [Ca²⁺]i retention during ischemia.     

Mechanism of cardiac arrhythmias induced by epinephrine in dogs with hypokalemia

To investigate the mechanism of ventricular arrhythmias induced by epinephrine in dogs with hypokalemia, 30 adult mongrel dogs were separated into a control group (n = 13) and a hypokalemia group (n = 17). In the hypokalemia group, sodium polystyrene sulfonate (5 g/kg body weight) was infused into the colon. In both groups, the serum concentrations of sodium, potassium and calcium were measured every 15 minutes for 60 minutes. The mean (+/- standard deviation) serum potassium level of the hypokalemia group decreased significantly from 3.81 +/- 0.21 to 2.92 +/- 0.36 mEq/liter; there were no significant changes in other electrolytes. After 60 minutes, epinephrine (10 micrograms/kg) was injected intravenously in the hypokalemia and control groups, and the arrhythmia ratio (the number of ventricular ectopic beats divided by the total heart rate) was calculated for 5 minutes. Each group was further classified into subgroups of dogs with an arrhythmia ratio higher or lower than 10%. An arrhythmia ratio over 10% was observed in 7.7% of the control group and 53% of the hypokalemia group. Immediately after 5 minutes of epinephrine injection, myocardial mitochondria and plasma membrane fraction were prepared from each group. Mitochondrial calcium content and phospholipase activity of plasma membrane fraction were determined. Significant increases in both mitochondrial calcium content and phospholipase activity were observed in the dogs with hypokalemia and an arrhythmia ratio greater than 10%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Magnetic resonance imaging of acute myocardial infarction: gadolinium diethylenetriamine pentaacetic acid as a marker of reperfusion

We examined the effects of a paramagnetic contrast agent, gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) on magnetic resonance images of acute myocardial infarction with and without reperfusion. Twenty-two dogs underwent occlusion of the left anterior descending coronary artery (LAD). In 10 dogs (group I) the LAD remained occluded for 3 hr and in the other 12 (group II) for 2 hr followed by 1 hr of reperfusion. Gd-DTPA (0.34 mM/kg) was administered to five dogs in group I at 2 hr and 5 min after occlusion and to seven dogs in group II 5 min after reperfusion. At 3 hr after ligation, the hearts were excised and imaged with spin echo and inversion recovery pulse sequences on a 0.35 Tesla magnetic resonance imager. Reperfused hearts given Gd-DTPA demonstrated a significant increase in contrast between normal and reperfused myocardium as compared with nonreperfused hearts and reperfused hearts not given Gd-DTPA. This enhancement was particularly prominent in the inversion recovery images. Studies performed in vivo in two additional dogs demonstrated similar enhancement with reperfusion with Gd-DTPA in gated spin echo images. Contrast-enhanced magnetic resonance imaging allows the detection of reperfusion early in the course of acute infarction.     

Role of the Na+/H+ pump in heart ischemia-reperfusion lesions in the neonatal period

OBJECTIVE: Amiloride 5-(N,N-dimethyl)(AMD), an Na+/H+ pump inhibitor, was used to evaluate the maturity and sensitivity of the Na+/H+ pump in neonatal myocardial cells. METHOD: Using the isolated contraction isometric heart model, the hearts of neonatal rabbits (10-12 days) were stopped by cardioplegia with and without AMD (20 mumoles/l), then submitted to 40 minutes of ischaemia at 37 degrees C or 120 minutes of ischaemia at 20 degrees C before being reperfused for 30 minutes at 37 degrees C. When AMD was added to the cardioplegic solution, it was also added (20 mumoles/l) to the Krebs solution for the first five minutes of reperfusion. Functional assessment of myocardial contractility and relaxation was performed before aortic clamping and after 30 minutes of reperfusion. Coronary venous drainage during reperfusion was collected to evaluate CPK levels. RESULTS: To 37 degrees C or 20 degrees C, Na+/H+ pump inhibition was marked by improvement of all myocardial contractility and relaxation parameters at the end of the reperfusion period. A significantly reduced CPK release wase also observed during reperfusion associated with Na+/H+ pump inhibition. CONCLUSION: This study demonstrates maturation of the Na+/H+ pump in neonatal myocardial cells and confirms the role of this ion exchange pump in the pathogenesis of ischaemia-reperfusion lesions. The study at 20 degrees C demonstrated the sensitivity of the Na+/H+ pump to a low transmembrane proton gradient.     

Cardiopulmonary bypass in a model of acute myocardial infarction and cardiac arrest

Cardiopulmonary bypass (CPB) reperfusion has demonstrated improved resuscitation rates in ventricular fibrillation cardiac arrest models. To investigate the effectiveness of CPB reperfusion in an ischemic cardiac arrest setting, simulating the clinical scenario of myocardial ischemia preceding sudden cardiac death, we developed a canine model of acute myocardial infarction followed by ventricular fibrillation. Sixteen dogs were randomly assigned to two groups. Group 1 (eight) had ventricular fibrillation induced without left anterior descending coronary artery occlusion. Group 2 (eight) had a thrombogenic copper coil placed in the left anterior descending artery and showed ECG evidence of acute myocardial infarction before induction of ventricular fibrillation. CPR commenced after eight minutes of ventricular fibrillation. Epinephrine 0.05 mg/kg and NaHCO3 1.0 mEq/kg were administered at ten minutes. CPB was begun at 12 minutes and continued for one hour. Myocardial ischemic and necrotic areas were determined in four-hour survivors by dual histochemical staining. All animals were resuscitated; all eight group 1 and six of eight group 2 animals survived to four hours. With the onset of CPB, coronary perfusion pressures increased significantly by 68.6 +/- 31.8 (SD) mm Hg in group 1 and 56.2 +/- 34.6 mm Hg in group 2 over those obtained with CPR (P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Beneficial effect of HEPES buffer in repeated coronary reperfusion

BACKGROUND: We have demonstrated previously that, when repeated reperfusion is performed after reocclusion, there is a decrease in the amount of myocardial salvage, despite early reperfusion. Treatment with nisoldipine induced a beneficial effect by reduction of infarct size in this experimental model. OBJECTIVE: To study the effect of HEPES buffer on infarct size, using a repeated-reperfusion model. METHODS: The left anterior descending coronary artery was occluded in anesthetized dogs. Thirty minutes after the occlusion, dogs were allocated randomly to either the treatment group (n = 7; HEPES 0.64 mmol/l infused intravenously throughout the experiment) or the control group (n = 8; saline). Occlusion was maintained for 2 h, followed by 1 h of reperfusion, then 1 h of reocclusion and 2 h of second reperfusion. An in-vivo area at risk was determined by gentian violet staining, and infarct size was defined and quantitated by triphenyl-tetrazolium chloride staining. RESULTS: Hemodynamic measurements were similar in both groups. Mass of necrosis/mass at risk was significantly smaller in the HEPES group (30.7 +/- 1.6%, mean +/- SEM) compared with controls (50.6 +/- 3.8%, P < 0.001). CONCLUSION: Treatment with HEPES induces a beneficial effect by reduction of infarct size in repeated coronary reperfusion.     

Protective effects of ginsenosides in myocardial ischemia and reperfusion injury

To verify whether ginsenosides will attenuate the myocardial ischemia and reperfusion injury, the left anterior descending coronary artery (LAD) was snared for 2 hours in 23 dogs and then the ischemic myocardium was reperfused. 45 minutes after ischemia, the animals were randomly divided into a ginsenosides group (n = 11, receiving a slow IV bolus of ginsenosides 10 mg/kg and then a continuous infusion of 80 micrograms/kg/min) and a saline solution group (n = 12 receiving equal amount of glucose in saline). The treatment was started 45 minutes after coronary occlusion and stopped one hour after reperfusion. 24 hours later, the dogs were killed and the extent of myocardial necrosis was determined histologically. The LVEDP, arterial pressure and heart rate were markedly lower in the ginsenosides group. Electrocardiographic findings of myocardial ischemia were significantly improved in the ginsenosides group. 8 controls developed malignant arrhythmia after reperfusion, but none in ginsenosides group. The myocardial ultrastructure can be protected by ginsenosides during the period of ischemia and reperfusion. The infarct size in saline group was 22.7 +/- 3.2% while in the ginsenosides group it was 5.2 +/- 1.3% (P less than 0.05). These results show that ginsenosides can protect the ischemic myocardium and reperfusion injury of myocardium.