The antiarrhythmic action of phosphocreatine in acute myocardial ischemia

The mechanism of antiarrhythmic action of phosphocreatine on ischemic myocardium was studied by analyses of electrograms from normal and ischemic tissues. Ischemia induced significant changes in amplitude, duration, and conduction time of the electrograms, thereby showing depolarization of membranes and retarded conduction of excitation. Phosphocreatine administered in a single dose, 300 mg/kg iv, completely eliminated ventricular fibrillations in the ischemic hearts and significantly diminished the electrical instability occurring during reperfusion. The effects of phosphocreatine were completely reproduced by its structural analog phosphocreatine which is inactive in the creatine kinase reaction. It is concluded that the antiarrhythmic effect of both compounds is related to their specific chemical structure and that their specific effect is likely to be mediated via interaction with a sarcolemma site.     

Electrophysiological action of ethacizin in acute myocardial ischemia in dogs

The effects of ethacizin on delayed activation of the ischemic myocardium by acute left anterior descending coronary artery occlusion were studied in dogs. Ethacizin, administered intravenously at a dose of 0.5 or 1 mg/kg depressed the conduction of excitation in the ischemic myocardium and significantly increased the incidence of ventricular fibrillation. Electrophysiological effects of ethacizin in acute myocardial ischemia, as well as its antiarrhythmic activity at the advanced stages of experimental myocardial infarction might be related to an intensive influence of ethacizin on fast inward sodium current in the myocardial fibers.     

Membrane alterations in phenylhydrazine-induced reticulocytes

It is known that reticulocytes formed in animals in response to phenylhydrazine treatment have a shorter life span than those formed as a consequence of bleeding. The experiments presented illustrate that the reticulocytes formed consequent to the action of this drug exhibit membrane alterations, in the absence of intracellular oxidative changes (e.g., to hemoglobin), which might be expected to contribute to their decreased survival. These membrane alterations include the formation of flourescent chromolipids, a decrease in spectrin polypeptides, and an increase in high molecular weight membrane protein polymers. It is suggested that these effects are unique to the reticulocytes formed as a response to phenylhydrazine since they are a consequence of the peroxidation of membrane phospholipids initiated by this agent.     

硫化氢对急性心肌缺血大鼠心肌线粒体损伤的影响

目的：探讨硫化氢（H2S）对急性心肌缺血大鼠线粒体功能的影响,并探讨其改善急性心肌缺血损伤的作用机制。方法：通过结扎大鼠左冠状动脉前降支建立急性心肌缺血模型。雄性SD大鼠48只随机分为6组（n=8）：假手术组,缺血组,缺血＋硫氢化钠（NaHS）低、中、高剂量组和缺血＋炔丙基甘氨酸（PPG）组。透射电镜观察心肌组织线粒体超微结构;检测血浆中H2S含量、心肌组织CSE活性;测定心肌线粒体活力、膜肿胀度及线粒体总ATP酶、谷胱甘肽过氧化物酶（GSH-PX）、超氧化物歧化酶（SOD）的活性和丙二醛（MDA）含量。结果：与假手术组比较,缺血组大鼠血浆H2S含量和心肌组织中CSE活性降低;心肌线粒体膜肿胀,线粒体活力下降;线粒体中MDA含量明显升高,ATP酶、SOD、GSH-Px活性明显降低（P〈0.01）。与缺血组比较,缺血＋NaHS低、中、高剂量组大鼠血浆H2S含量和心组织中CSE活性均升高;缺血＋NaHS中、高剂量组大鼠心肌线粒体MDA含量明显减少,膜肿胀度减轻;缺血＋NaHS低、中、高剂量组线粒体活力有所恢复,ATP酶、SOD、GSH-Px的活性明显升高（P〈0.05或P〈0.01）。PPG可部分减弱H2S的心肌保护作用（P〈0.05或P〈0.01）。结论：H2S可增强线粒体ATP酶、SOD、GSH-Px的活性,降低线粒体脂质过氧化水平,从而起到对大鼠急性心肌缺血的保护作用。     

Some mechanisms of nonspecific antiarrhythmic action of phosphocreatine in acute myocardial ischemia

Using isotope-labeled microspheres (diameter 15 microns) it was shown that phosphocreatine at a dose of 300 mg/kg does not affect the myocardial blood flow in the ischemic zone during acute occlusion (5 min) of the left anterior descending coronary artery (LAD) in dogs. Intravenous administration of NaCl hypertonic solution which contained the same amount of Na+ as 300 mg/kg of phosphocreatinine disodium salt prevented the development of ventricular fibrillation during acute LAD occlusion in dogs. Under these conditions excitation conduction velocity significantly increased. Experiments in isolated intraventricular rabbit septum have showed that the addition of phosphocreatine or phosphocreatinine to the perfusion medium at a concentration of 10 mmole/liter increased excitation conduction velocity in ischemic myocardium. However, when changes in perfusate Na+ and Ca2+ concentration produced by addition of phosphocreatine or phosphocreatinine were compensated, these compounds do not affect excitation conduction velocity. On the other hand, the alterations similar to those produced by the addition of phosphocreatine or phosphocreatinine led to the same increase of excitation conduction velocity. The results obtained indicate an important role of the changes of blood plasma ionic composition on intravenous administration of phosphocreatine in electrophysiological and antiarrhythmic effects of this substance during acute myocardial ischemia.     

Enkephalins and the function of the sympathetic-adrenal system in acute myocardial ischemia

It has been shown in experiments on albino rats that acute myocardial ischemia (AMI) produces a noticeable increase in excretion of adrenaline, noradrenaline, DOPA and dopamine with urine. Intraperitoneal injection of leu-enkephalin analogs (D-Ala2-Leu5-Arg6 and D-Ala2-D-Leu5-D-Arg6) to rats with AMI was accompanied by a noticeable prevention of activation of the sympathoadrenal system.     

Taxol inhibits stretch-induced electrophysiological alterations in isolated rat hearts with acute myocardial infarction

Mechanosensitive channels have been determined to work as transducers of mechanoelectric feedback in the heart, which is associated with the generation of arrhythmias. Recent studies have investigated the role of the cytoskeleton in ion channels control. This study explored the ability of taxol to inhibit stretch-induced electrophysiological alterations in the ischemic myocardium. Thirty-two Wistar rats were randomly divided into four groups: normal control group (n=9), taxol group (n=7), myocardial infarction (MI) group (n=9), and MI+taxol group (n=7). After Langendorff perfusion, the isolated hearts were stretched for 5 s by balloon inflation to 0.2 or 0.3 mL. The effects of stretching on 90% monophasic action potential duration (MAPD₉₀), premature ventricular beats (PVB), and ventricular tachycardia (VT) were observed for 30 s. Stretching increased MAPD₉₀ in both the normal control and MI groups, but MAPD₉₀ increased more in the MI group for the same degree of stretch. Taxol (5 μmol L⁻¹) had no effect on MAPD₉₀ under baseline, unstretched conditions, but MAPD₉₀ in the taxol group was slightly increased after stretching compared with the normal control group (P>0.05). However, taxol reduced MAPD₉₀ in infarcted myocardium (P<0.05 at ΔV=0.3 mL). The incidences of PVB and VT in the MI group were higher than in the normal control group (both P<0.01). Taxol had no effect on the occurrence of arrhythmias in normal myocardium, but it inhibited PVB and VT in infarcted hearts (both P<0.01). Thus changes in MAPD and the occurrence of arrhythmias caused by mechanical stretching of the myocardium could be inhibited by taxol in isolated rat hearts during AMI, indicating the involvement of tubulin in mechanoelectric feedback in AMI.     

Protective roles of cornuside in acute myocardial ischemia and reperfusion injury in rats

Cornuside is a secoiridoid glucoside isolated from the fruit of Cornus officinalis SIEB. et ZUCC. In this study, we investigated the anti-myocardial ischemia and reperfusion (I/R) injury effects of cornuside in vivo and elucidated the potential mechanism. Rat models of myocardial I/R were induced by coronary occlusion followed by reperfusion or by Isoproterenol (ISO), treatment of rats with cornuside (20 and 40 mg/kg, i.v.) protected the animals from myocardial I/R injury as indicated by a decrease in infarct volume, improvement in hemodynamics and reduction of myocardial damage severity. Treatment with cornuside also attenuated polymorphonuclear leukocytes (PMNs) infiltration, decreased myeloperoxidase (MPO) activity in the heart, lowered serum levels of pro-inflammatory factors and reduced phosphorylated IκB-α and nuclear factor kappa B (NF-κB) levels in the heart. Additionally, cornuside was shown to have remarkable antioxidant activity and inhibited ISO-induced myocardial cell necrosis. Thus, cornuside appeared to protect the rat from myocardial I/R injury by acting as an anti-inflammatory agent. These findings suggested that cornuside may be used therapeutically in the setting of myocardial I/R where inflammation and oxidant injury are prominent.     

Extravascular water content of heart and lungs after acute myocardial ischemia

We measured the extravascular water content of hearts and lungs of anesthetized dogs subjected to one of the following protocols: a)sham operation, b) circumflex artery ligation, c) increased left atrial pressure (Pla), or d) increased Pla and circumflex artery ligation. After 4 h, extravascular water of the heart and lungs increased significantly in the three experimental groups when compared with values from sham-operated dogs. After circumflex artery ligation, extravascular heart water increased 29% and lung water 8%, although Pla and calculated pulmonary microvascular pressure (Pmv) did not change. Extravascular heart water also rose 30% after increasing Pla from 23 to 37 cm H2O by inflating a left atrial baloon. In these dogs, extravascular lung water increased as a hyperbolic function of Pmv. Increasing Pla to 20 cm H2O in dogs with coronary artery ligation resulted in a 16% increase in heart water. Also at each Pmv, extravascular lung water was greater in dogs with coronary artery ligation than in dogs without. These data indicate that the increased extravascular lung water after coronary artery ligation cannot be explained solely by hemodynamic mechansims. We suggest that acute myocardial ischemia contributes to an increase in vascular permeability in the heart and lungs.     

Detection of regional temporal abnormalities in left ventricular function during acute myocardial ischemia

Echocardiographic diagnosis of myocardial ischemia is based on visualizing hypokinesis, which occurs late in the ischemic cascade. We hypothesized that temporal changes in endocardial motion may constitute sensitive early markers of ischemia. Two protocols were performed in 19 anesthetized pigs. Protocol 1 included 54 intracoronary balloon occlusions. Transthoracic images were acquired at baseline and every 15 s during 5 min of occlusion and reperfusion. In protocol 2, ischemia was induced in 12 animals by use of graded dobutamine infusion, after creating significant partial occlusions without a resting wall motion abnormality. Systolic and diastolic endocardial motion was color encoded using color kinesis and analyzed using custom software. All ischemic episodes caused detectable and reversible changes. The earliest sign of ischemia was tardokinesis in 31/54 occlusions, whereas hypokinesis appeared first in 23/54 cases. Dobutamine-induced ischemia caused tardokinesis first in 9/12 and hypokinesis in 3/12 animals. Reversible ischemic changes in regional left ventricular performance can be objectively detected using analysis of echocardiographic images and will likely improve the early noninvasive diagnosis of acute ischemia.     

Effect of enkephalins on vasopressin and aldosterone levels in acute experimental myocardial ischemia

It has been demonstrated in experiments on rats that acute myocardial ischemia gives rise to a decrease in diuresis, elevation of antidiuretic activity of blood plasma and the blood concentration of immunoreactive aldosterone. Intraperitoneal injection of a synthetic enkephalin analog D-ala2-leu5-arg6-enkephalin in a dose of 1.25 nmol/kg bw resulted in partial normalization of diuresis, reduction in antidiuretic activity of blood plasma and blood aldosterone level to the control values. Naloxone eliminated the effects described. It is concluded that enkephalins have an inhibitory action on aldosterone and vasopressin secretion, with this action being mediated via opiate receptors.     

Additive beneficial effects of two inhibitors of vasoconstrictor mediators in acute myocardial ischemia

A specific inhibitor of thromboxane A2 (TxA2) synthesis, CGS-12970, a new angiotensin-converting enzyme (ACE) inhibitor, CGS-16617, and a combination of both agents were evaluated for their ability to reduce the extension of myocardial infarct size in rats. Myocardial creatine kinase (CK) loss from the left ventricular free wall (LVFW) 48 hr after left coronary artery ligation was used as an index of ischemic damage. Treatment with either CGS-12970 (4 mg/kg) or CGS-16617 (1 microgram/kg) alone did not attenuate the loss of CK from LVFW significantly, compared with animals receiving only the vehicles for these drugs. However, the combined use of both agents significantly reduced CK depletion from LFVW (P less than 0.01). These findings support the interrelated role of TxA2 and angiotensin II as mediators of myocardial ischemia and suggest that combined inhibition of their formation may be useful in the treatment of acute myocardial infarction.     

Course of acute myocardial ischemia in dogs depending on the pharmacological background]

In acute myocardial ischemia of dogs glycogen is mobilized most completely and its break down products are utilized most efficaciously after administration of izatin rather than after gamma-hydroxybutyric acid (GABA) and guthymin. Izatin potentiates a beneficial effect of GABA on myocardial energy efficiency.