Alterations of the bioenergetics systems of the cell in acute and chronic myocardial ischemia

The aim of the works presented here is to analyze the alterations induced by acute ischemia-reperfusion and chronic ischemia on mitochondrial function, in relation to alterations on heart function. Parameters of mitochondrial function were assessed on skinned fibers coming from isolated perfused rat hearts. The effects of chronic ischemia were studied on a rat model of left descending coronary artery stenosis. Two key events observed after acute ischemia-reperfusion and chronic ischemia are the decrease (or the loss) of the stimulatory effect of creatine and the alteration of outer mitochondrial permeability to cytochrome c and ADP. Taken together, these effects indicate the alteration of the intermembrane space architecture leading to the loss of intracellular adenine nucleotides compartmentation and possibly of functional coupling of mitochondrial creatine kinase and adenine nucleotide translocase. These alterations result in the impairment of intracellular energy transfer (channeling) from mitochondria to ATP-utilizing sites located in the cytosol. This may play a significant role in ischemic injury and alterations in heart function. We show that these effects were prevented by effective cardioprotective strategies like ischemic preconditioning or pharmacological preconditioning by perfusion of mitochondrial ATP-sensitive potassium channel openers. We hypothesize that an open mitochondrial ATP-sensitive potassium channel during ischemia maintains the tight structure of the intermembrane space that is required to preserve the normal low outer membrane permeability to ADP and ATP.     

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.     

Role of the locus coeruleus in the development of cerebrovascular disorders in acute myocardial ischemia

Experiments on rats were made to examine the total cerebral blood flow during locus coeruleus (LC) stimulation, acute myocardial ischemia and in the presence of acute myocardial ischemia after LC precoagulation . LC electric stimulation caused a decrease in the cerebral blood flow. The most profound cerebrovascular disorders were observed in animals with acute myocardial ischemia without LC precoagulation and were followed by cardiac arrhythmias. Cerebrovascular hemodynamic disorders occurring in acute myocardial ischemia were prevented by LC coagulation. It is suggested that the cerebrovascular disorders are consequent on the formation in the LC of the hyperactive determinant structure and play a role of a secondary pathogenetic factor in heart regulation disorders.     

诺迪康对急性心肌缺血和心衰大鼠血流动力学的影响

目的：研究诺迪康（rhodiola）对急性心肌缺血和心力衰竭大鼠血流动力学的影响,探讨该药的血流动力学作用机制。方法：采用垂体后叶素（Pit）诱发大鼠急性心肌缺血,20min后用戊巴比妥钠（PS）致急性心力衰竭,经Powerlab／4SP和BL-420E多道生物信号分析系统监测血流动力学。结果：①Rhodiola明显对抗Pit诱导的急性心肌缺血大鼠心电图ST段的偏移、HR的降低厦LVEDP的升高;＋dP／dtmax．dP／dtmax均高于NS组．该作用具有剂量依赖性。②和对照组相比,rhodiola能通过改善血流动力学对抗PS导致的急性心衰。结论：rhodiola能改善心肌缺血和心力衰竭大鼠的血流动力学。     

Membrane alterations in acute myocardial ischemia

The molecular consequences of acute myocardial ischemia induced in rabbit hearts by ligation of the left circumflex branch of the coronary artery were assessed in terms of the biochemical properties of subcellular organelles. Mitochondrial alteration, as reflected in progressive decrease in the activity of azide-sensitive ATPase, was apparent as early as 5 min postligation, but the activity of another mitochondrial enzyme, cytochrome c oxidase, was unchanged, even following 60 min of coronary ligation. Sarcolemmal Na+K+-ATPase exhibited a time course of inactivation similar to that of the mitochondrial ATPase, but differed from the latter in that the impairment was not reversed on reperfusion. Cellular levels of ATP, which decreased in parallel with the loss of ATPase activities, also remained depressed following reperfusion. Decreases in lysosomal enzyme latency were noted, but these occurred somewhat later than the sarcolemmal and mitochondrial alterations. Attempts to demonstrate the production of a population of labile lysosomal structures during ischemia were unsuccessful. Similarly, no alterations in the gel electrophoretic profiles of proteins or in the P phosphatidylcholine/P phosphatidylethanolamine ratio of isolated mitochondrial or sarcolemmal membranes from hearts subjected to ischemia and (or) subsequent reperfusion could be found. It is suggested that sarcolemmal Na+,K+-ATPase may serve as a sensitive and readily quantifiable index of irreversible cellular necrosis and, therefore, be of value in assessing the possible beneficial effects of pharmacological interventions.     

Effect of electrostimulation of the dorsolateral funiculus of the spinal cord on changes in the cardiac rhythm in acute myocardial ischemia

The experiments were carried out on inbred white male rats. Cardiac rhythm changes revealed in acute myocardial ischemia under conditions of electrostimulation (ES) of descending sympathicoinhibitory pathways, constituting part of spinal dorsolateral funiculi (DLF) were studied. 10-min stimulation of DLF, started immediately after ligation of the left coronary artery, checked the development of severe cardiac arrhythmia, or considerably weakened the already existing one. The data obtained substantiate the assumption that the onset of cardiac arrhythmia in acute ischemia is associated with the involvement of sympathic preganglionic neurons into the pathologic system, which may be suppressed by the activation of the functionally opposite systems.     

Acid hydrolase activity and cyclic nucleotide contents in the rat heart during myocardial ischemia and postischemic reperfusion

The acid phosphatase and cathepsin D activities and cAMP and cGMP levels in isolated perfused rat heart were investigated during various periods of ischaemic myocardial injury and postischaemic reperfusion. The effect of phosphodiesterase inhibitor--caffeine was also studied. Free acid hydrolases activities and cyclic nucleotide content were increased under 40 and 60 min ischemia and 20 min postischaemic reperfusion. Addition of 50 microM caffeine to perfusion solution after 30 min of ischaemia resulted in increase of cAMP level, cAMP/cGMP ratio, lysosomal bound activities of acid hydrolase and decrease of free acid hydrolase activities. The obtained results suggested that defect in cAMP synthesis might be present in lysosomal membranes labilization in cardiomyocytes injured during ischaemic conditions. Addition of such agents, as caffeine, which increased heart cAMP level, may be effective in lysosomal membranes stabilization under reversible heart ischaemia and reperfusion.     

Non-linear dynamic analysis of the cardiac rhythm during transient myocardial ischemia.

Coronary artery occlusions related to myocardial ischemia drive cardiac control system reactions that may lead to heart failure. The purpose of this study was to assess the autonomic nervous system (ANS) response during prolonged percutaneous transluminal coronary angioplasty (PTCA). Continuous ECG data were acquired from 50 patients before and during PTCA, with occlusions in the left anterior descending, left circumflex or right coronary artery. Heart rate variability (HRV) was analyzed for 3-min segments of the R-R interval signal obtained from ECG data. The ANS behavior was evaluated by HRV analysis using fractal-like indices. The fractal scalar exponent alpha(1) and power-law slope beta decreased considerably during PTCA. This indicates that significant reactions of autonomic control of the heart rate occurred during coronary artery occlusions, with a reduction in complexity of the ANS.     

Mechanisms of the regulation and functional significance of the theta rhythm. Roles of serotonergic and noradrenergic systems

The evidence for the role of serotonergic and noradrenergic effects on the septohippocampal theta oscillations obtained by the author and her colleagues are reviewed. Analysis of neuronal activity in the medial septal area or hippocampus and hippocampal EEG simultaneously recorded in awake rabbits exposed to different kinds of brainstem influences led to the following conclusions. 1. Serotonergic median raphe nucleus and noradrenergic locus ceruleus act as functional antagonists in theta regulation: the former structure restricts the theta rhythm generation, whereas the latter enhances this process. 2. Both transmitter systems control sensory reactions of septal and hippocampal neurons through up and down regulation of the theta activity. 3. When continuous theta activity induced by various experimental manipulations is recorded, responsiveness of septohippocampal neurons to sensory stimulation is strongly reduced. These findings provide support for the view that the theta oscillations act as an active filter in the information selection and registration. Interaction of different transmitter systems in the theta rhythm control as well as attention and memory is discussed.     

Geomagnetic activity and enhanced mortality in rats with acute (epileptic) limbic lability

Presumably unrelated behaviors (e.g. psychiatric admissions, seizures, heart failures) have been correlated with increased global geomagnetic activity. We have suggested that all of these behaviors share a common source of variance. They are evoked by transient, dopamine-mediated paroxysmal electrical patterns that are generated within the amygdala and the hippocampus of the temporal lobes. Both the probability and the propagation of these discharges to distal brain regions are facilitated when nocturnal melatonin levels are suppressed by increased geomagnetic activity. In support of this hypothesis, the present study demonstrated a significant correlation of Pearsonr=0.60 between mortality during the critical 4-day period that followed induction of libic seizures in rats and the ambient geomagnetic activity during the 3 to 4 days that preceded death; the risk increased when the 24 h geomagnetic indices exceeded 20 nT for more than 1 to 2 days.     

Dynamic changes in arylsulfatase activity in the initial period of acute focal myocardial ischemia in an experiment

The increase in arylsulphatase activity in the ischemic zone has been shown by histochemical method in progressing acute myocardial ischemia. The increase in the enzyme activity in a so-called "intact" zone was less marked.     

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.