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Potential-dependent Ca2+ currents in isolated heart cells of hibernators.

Using the perforated patch-clamp technique, it has been shown that the potential-dependent Ca2+ current in cardiac myocytes of hibernators is not completely inhibited during hibernation. The residual Ca2+ current is classed as L-type Ca2+ current which is regulated by agonists and antagonists of Ca2+ channels. The effect of nifedipine, D600, isoproterenol and forskolin has been examined. It was found that isoproterenol affects the affinity of Ca2+ channels for the D600 blocker.

Animals↗

[The effect of exogenous catecholamines on the cardiac rhythm and thermoregulation of hibernating hedgehogs (Erinaceus europaeus L.)].

No disturbance was seen either in cardiac rhythm or in temperature of hibernating Hedgehog (Erinaceus europaeus L.) after an isotonic saline injection, with the help of a permanent aortic indwelling catheter. Partial or complete arousal was quickly obtained after increasing doses of norepinephrine (NE), while dihydroxyphenylalanine (L-Dopa), its natural precursor, induced the same effects more slowly. To differentiate the peripheral and central effects of L-Dopa, we used a pretreatment of Ro 4-4602, an inhibitor of the peripheral decarboxylation of L-Dopa; under these conditions we could not induce arousal in the hibernating animals. The arousals observed after NE and L-Dopa administration are suggested to be dependent upon a peripheral action of exogenous catecholamines, copying a natural mobilization of catecholamines reserves.

Animals↗

[The effect of thyrotropin-releasing hormone on the activity of the septal neurons in brain slices from hibernating and active susliks Citellus undulatus].

Effects of thyrotropin-releasing hormone (TRH) on spontaneous and evoked activity were tested in the medial septum--diagonal band neurons (MS--DB complex) in the slices taken from the brain of hibernating (HS) and waking (WS) ground squirrels. Administration of TRH (0.1 microM) into the flow of incubating medium increased the frequency of spontaneous activity of all the MS--DB neurons in HS and of the majority of neurons in the WS. However, in the septal slices of HS this increase was significantly more pronounced. The excitatory influence of TRH on the units was preserved in conditions of synaptic blockade. In the neurons from other structures in the brain slices of both HS and WS groups TRH did not affect usually the level of spontaneous discharges. When studying the responses of the MS--DB neurons to electrical stimulation of medial forebrain bundle, it was found that application of TRH led to disappearance of responses in a half of units in both groups of animals. The existence of the forebrain modulatory TRH-system which participates post- and, probably, presynaptically in regulation of the MS--DB neuronal activity is suggested. The role of TRH and of MS--DB in neural control of hibernation is discussed.

Animals↗

[Erythrocyte membrane permeability of Citellus undulatus during hibernation].

We have studied the influence of the erythrocyte hypothermic storage of long-tailed ground squirrels at various physiological states and white mongrel rats on the impairment of the barrier function of their membranes for ferricyanide. The membranes of sleeping and awakening ground squirrels demonstrate the highest stability (the structural integrity is sustained for 3-3,5 months), meanwhile rat blood erythrocytes maintain the barrier function only for 2 weeks. Beside structural and viscous changes in the erythrocyte membrane and the cytosol of hibernating ground squirrel an important role in maintaining barrier function under conditions of hypothermic storage is played by the content of animal blood plasma. Appearance of a non-typical EPR spin probe spectrum in some ground squirrel blood samples in non-equilibrium state of entering or arousing from hibernation has been observed.

Animals↗

Carboxyatractylate- and cyclosporin A- sensitive uncoupling in liver mitochondria of ground squirrels during hibernation and arousal.

Oxygen consumption and transmembrane electrical potential difference in liver mitochondria from hibernating, arousing and active ground squirrels have been compared. It is found that arousal from hibernation is accompanied by uncoupling which is mediated by two different mechanisms, one sensitive to cyclosporin A and the other suppressed by carboxyatractylate. Both uncoupling effects reach their maxima at 20 - 25 degrees C body temperatures. Involvement of an increase in the free fatty acid concentration in the arousal-induced uncoupling mechanisms is discussed.

Animals↗

Seasonal changes in myoglobin content in muscles of hibernating Yakutian ground squirrels.

Myoglobin content in skeletal muscles of the Yakutian ground squirrel Citellus undulatus was measured during different periods of the annual life cycle: in active animals in summer, and in hibernating and awake animals in winter. It was found that the Mb content in winter, irrespective of the state of the animal (hibernating or awake), is 2.5-3-fold higher than in summer. Analysis of biochemical data available in the literature suggests that the increase in Mb content in winter is most probably related to a high oxygen demand of muscles at the first stage of arousal when the body temperature rises from 0 to 10-12 degrees C (non-shivering thermogenesis or thermoregulatory tonus). At this stage, the oxygen-dependent processes in muscles proceed under conditions of blocked peripheral blood flow and failure of anaerobic glycolysis.

Animals↗

Simulated hibernation of sea turtles in the laboratory: I. Feeding, breathing frequency, blood pH, and blood gases.

Captive immature green (Chelonia mydas) and Kemp's ridley (Lepidochelys kempi) sea turtles were examined to determine if a hibernation-like state could be induced under controlled conditions. Both species demonstrated that they are able to acclimate to cold temperatures behaviorally. However, the two species appeared to respond differently to decreasing temperature. Whereas the green turtles tolerated the onset of cold water temperatures by reducing swimming activity, the ridleys became very agitated and active as they were exposed to temperatures below 20 degrees C. Nevertheless, both species displayed semi-dormant behavior at temperatures below 15 degrees C, coming to the surface to breathe periodically at intervals of up to three hours. At low temperatures, venous blood pO2 and pCO2 decreased, whereas venous blood pH increased. Feeding also decreased as either species was exposed to cold temperature: greens (at 15 degrees C) and ridleys (at 20 degrees C) decreased food consumption to 50% of control levels, and ceased feeding below 15 degrees C. Thus, these species tolerated temperature drops and the associated hypophagia. They did not exhibit cold-stunning behavior, as has been observed in wild sea turtles exposed to rapid temperature drops, or prolonged periods of hibernation-like dormancy, as has been proposed for wild sea turtles during cold winter months.

Animals↗

[The action of insulin on cardiac contractility in active, hibernating and arousing susliks Citellus undulatus].

During the deep hibernation (at 5-6 degrees C of the heart temperature) and during arousal from hibernation (at 15-16 degrees C) insulin have no effect on contractility. Two opposite inotropic effects of insulin at concentrations 0.1-50 nM were found at higher temperature of arousing: a transient positive inotropic effect between 21-28 degrees C, and a negative one (about 20-30% from the control value) above 28 degrees C. In active summer and winter animals insulin produced mainly the negative inotropic effect.

Animals↗

Dedifferentiated cardiomyocytes from chronic hibernating myocardium are ischemia-tolerant.

Left ventricular biopsies from 21 patients with clinically diagnosed chronic hibernating myocardium (CHM) were examined by light- and electron microscopy. A mean of 27% of cardiomyocytes were structurally altered and were characterized as hibernating, because of reduced amount of myofibrils and increased glycogen content. Electron microscopy of these cells showed reduction of T-tubules and numerous small mitochondria, but few changes associated with degeneration, acute ischemia or apoptosis. The structural changes found in CHM are reminiscent of dedifferentiation rather than degeneration. The expression patterns of some structural proteins show resemblance with those in embryonic cardiomyocytes. Histochemically, mitochondrial NADH-oxidase and proton translocating ATPase activities were absent, whereas cytochrome c activity was present. Intracellular calcium distribution indicated normally bound sarcolemmal calcium and absence of excess mitochondrial calcium accumulation. Nuclear chromatin ranged from normal to dispersed with only a few nuclei that were clumped. These results suggest that cardiomyocytes from human CHM hearts are structurally altered, but viable, and lack morphologic and cytochemical characteristics suggestive of apoptosis or acute ischemia.

Apoptosis↗

Clinical aspects of hibernating myocardium.

Hibernating myocardium is a condition that is characterized by persistently impaired myocardial and left ventricular function at rest resulting from reduced myocardial blood flow. It is a result of adaptation or from downregulation. It may occur in unstable and chronic stable angina, acute myocardial infarction, and LV dysfunction and congestive heart failure. Recovery of the hibernating myocardium has clearly been shown to occur by successful revascularization either by coronary bypass surgery or by percutaneous catheter techniques.

Humans↗

Hibernation and myocardial ischemia: clinical detection by positron emission tomography.

Regions of myocardium supplied by severely diseased epicardial arteries may develop chronic ischemia at rest and exhibit reduced contractility, contributing to a reduction in global left ventricular function. However, after revascularization, contractility in these regions may return to normal. These regions of asynergy are described as "hibernating myocardium." Such myocardium in which normal contractility may be restored often coexists with areas of infarcted, or scar, tissue, leading to the definition of hypoperfused hibernating myocardium as viable myocardium. It is important to identify viable myocardium, as revascularization of these areas should lead to the greatest improvement in left ventricular function and, thus, improvement in survival. Positron emission tomography is the best noninvasive method for quantifying regional myocardial blood flow and metabolism. Using 18F-fluorodeoxyglucose, which measures myocardial glucose utilization, it is possible to identify myocardial tissue that is hypoperfused at rest with preserved or increased glucose uptake. This mismatch of blood flow to metabolism has a high predictive accuracy in the recovery of contractile function. In order to reduce the need for metabolic imaging in documenting myocardial viability, a regional index of perfusable tissue derived from imaging with 15O water has been recently developed that also allows the quantification of tissue viability.

Cell Survival↗

Distribution of calcium in a subset of chronic hibernating myocardium in man.

The structural correlates of 'chronic hibernating myocardium' in man consist of myocardial cells which transformed from a functional state (rich in contractile material) to a surviving state (poor in contractile material, rich in glycogen). Since the calcium-handling organelles such as SR, sarcolemma and mitochondria underwent structural changes in cells so affected, the distribution of calcium was investigated in biopsies obtained from 'hibernating' areas. The material was processed for microscopic localization of total calcium (laser microprobe mass analysis, LAMMA) and of exchangeable calcium (phosphate-pyroantimonate precipitation method, PPA). Subcellular distribution of total calcium as assessed by LAMMA revealed that in the structurally affected cells the areas in which sarcomeres were replaced by glycogen contained significantly more calcium than all other areas probed such as mitochondria, remaining sarcomeres at the cell periphery and subcellular areas of normally structured cells. Calcium precipitate, obtained after PPA assessment, was localized at the sarcolemma but was virtually absent in the mitochondria of affected cells. The high calcium content in the myolytic areas of affected cells most probably belongs to a pool of bound calcium. The observations that calcium is retained at the sarcolemma and that mitochondria are devoid of precipitate favour the hypothesis that cells structurally affected as such are not ischaemic and are still able to regulate their calcium homeostasis.

Calcium↗

Chronic hibernating myocardium: interstitial changes.

Chronic left ventricular dysfunctional but viable myocardium of patients with chronic hibernation is characterized by structural changes, which consist of depletion of contractile elements, accumulation of glycogen, nuclear chromatin dispersion, depletion of sarcoplasmic reticulum and mitochondrial shape changes. These alterations are not reminiscent of degeneration but are interpreted as de-differentiation of the cardiomyocytes. The above mentioned changes are accompanied by a marked increase in the interstitial space. The present study describes qualitative and quantitative changes in the cellular and non-cellular compartments of the interstitial space. In chronic hibernating myocardial segments the increased extracellular matrix is filled with large amounts of type I collagen, type III collagen and fibronectin. An increase in the number of vimentin-positive cells (endothelial cells and fibroblasts) compared with normal myocardium is seen throughout the extracellular matrix. The increase in interstitial tissue is considered as one of the main determinants responsible for the lack of immediate recovery of contractile function after restoration of the blood flow to the affected myocardial segments of patients with chronic left ventricular dysfunction.

Actins↗

Value of low dose dobutamine Doppler tissue imaging for detecting hibernating myocardium.

In order to assess the value of Doppler tissue imaging (DTI) in detecting viable hibernating myocardium, 20 patients with coronary artery disease and chronic left ventricular dysfunction underwent low dose dobutamine stress echocardiography and low dose dobutamine stress DTI. The results showed that among the 100 asynergic segments, 35 segments showed improvement after dobutamine infusion (group H) and no changes were observed in the remaining 65 segments (group N). The left ventricular echocardiographic score index decreased from 1.60 +/- 0.35 to 1.44 +/- 0.36 (n = 20, P < 0.01). During low dose dobutamine stress DTI, there was no difference in the values of velocity of S wave (V.) before dobutamine infusion between two groups. However, after dobutamine infusion, the values of Vs and VR in group H were significantly higher than those in group N (Vs: 10.1 +/- 3.0 cm/s vs 7.3 +/- 2.2 cm/s, P < 0.01; VR: 60% +/- 41% vs 25% +/- 32%, P < 0.001), 95.7% asynergic myocardial segments with VR < or = 0 had no viability while 86% asynergic segments with VR > 80% were viable myocardium. It is concluded that the different reactions to dobutamine stress between hibernating and necrosis myocardium could be showed by DTI and it is more clinically significant when VR < or = 0 and VR > 80%.

Coronary Disease↗

The hibernating myocardium.

The hibernating myocardium refers to resting LV dysfunction due to reduced coronary blood flow that can be partially or completely reversed by myocardial revascularization and/or by reducing myocardial oxygen demand. It is different from the stunned myocardium. Methods for its detection are not yet perfect. Hibernating myocardium has been demonstrated to be present in several clinical subgroups of patients; however, currently its full clinical presence and impact are not adequately defined.

Angina Pectoris↗

Myocardial hibernation in the infarcted region cannot be assessed from the presence of stress-induced ischemia: usefulness of delayed image of exercise thallium-201 scintigraphy.

To examine the relationship between the improvement of wall motion in infarcted regions after percutaneous transluminal coronary angioplasty (PTCA) and thallium-201 uptake in the delayed image of exercise thallium-201 scintigraphy before PTCA, 14 patients with anterior old myocardial infarction were studied. Exercise thallium-201 scintigraphy was performed before PTCA of left anterior descending artery, and mean percent thallium-201 uptake of abnormal segments was calculated in the initial and 4-hour delayed images. Left ventricular angiography was performed during catheterization, before, and 4 to 13 months after PTCA; and regional ejection fraction of anterior wall was calculated. Atrial pacing stress test with the measurement of lactate concentration of aorta and great cardiac vein was performed during catheterization before PTCA. In five patients with mean percent thallium-201 uptake in the delayed image < or = 50% (group I), regional ejection fraction did not increase after PTCA (23% +/- 9% to 24% +/- 12%). In the other nine patients with mean percent thallium-201 uptake > 50% (group II), regional ejection fraction increased significantly after PTCA (39% +/- 18% to 47% +/- 14%; p < 0.05). There was no significant difference in regional ejection fraction, lactate extraction ratio during maximal pacing, and the redistribution of exercise thallium-201 scintigraphy between the two groups before PTCA. Thus the delayed image before PTCA is useful to detect reversible nonfunctioning viable myocardium (hibernating myocardium) in the infarcted region. However, the wall-motion abnormality and the degree of stress-induced ischemia in the infarcted region before PTCA may not be necessarily useful for the detection of hibernating myocardium.

Aged↗

Altered myocardial states. The stunned and hibernating myocardium.

There are several potential outcomes of myocardial ischemia. When ischemia is severe and prolonged, myocyte cell death occurs and there is no recovery of contractile function of these cells. When myocardial ischemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function, which may be a protective mechanism whereby these cells attempt to reduce their oxygen demand in the setting of reduced oxygen supply. The resultant chronic left ventricular dysfunction has been termed "hibernating myocardium." Finally, myocardial ischemia may be reversed with coronary artery reperfusion resulting in salvage of the myocytes. However, the viable myocardium may demonstrate relatively prolonged but transient postischemic contractile dysfunction, the situation termed "stunned myocardium." The concepts of stunned myocardium are reviewed as they apply to both coronary reperfusion during evolving acute myocardial infarction, as well as brief periods of ischemia that may occur during angina pectoris, or coronary vasospasm, or both. The concept of hibernating myocardium is reviewed as it applies to left ventricular function prior to and after coronary artery bypass surgery.

Coronary Circulation↗