Effect of drugs on the resistance of the myocardium to hypoxia

A method for the investigation of drug effects in the myocardium resistance to hypoxia has been suggested. It is based on the determination of drug effects on the performance of the isolated spontaneously contracting atrium (ISCA) of rats under hypoxic conditions. Hypoxia was induced by oxygen displacement from the nutritional solution by nitrogen. ISCA resistance to hypoxia was assessed by the mechanogram of the heart preparation (the duration and volume of ISCA performance being up to 50% of the initial amplitude). Using the inhibitor analysis, it has been demonstrated that the given model of myocardial hypoxia adequately reflects the role of energy cellular metabolism in the regulation of ISCA resistance to hypoxia and can be used in the search for myocardial antihypoxic agents.     

Effects of adaptation to exposure to short-term stress on indices of resistance of energy metabolism and contractile function of the myocardium to acute hypoxic hypoxia and reoxygenation

Effect of preliminary adaptation to immobilization stress with progressive duration from 15 min. to 1 h (every second day, 8 sessions) on the resistance of indices of myocardial energy metabolism and contractile function to acute hypoxic hypoxia and subsequent reoxygenation was studied. It was shown, that adaptation to short-term stress exposure by some way provided the retention of activities of important enzymes like creatine-phosphokinase and phosphorylase under the harmful action of acute hypoxia and subsequent reoxygenation. At the same time, the ATP restoration and the CP super-restoration were observed during reoxygenation. This effect, in its turn, was accompanied by a more pronounced super-restoration of the heart contractile function than in control.     

急性低氧对体外培养乳鼠心肌细胞肌红蛋白的影响

本实验观察了低氧、复氧时培养的乳鼠心肌细胞肌红蛋白（Ｍｂ）、ｃＡＭＰ、心肌收缩频率的变化以及磷酸二酯酶抑制剂茶碱和抑制肌质网上钙释放的普鲁卡因地低氧下心肌细胞Ｍｂ表达和心肌细胞收缩频率的影响。结果表明,随低氧时间的延长Ｍｂ增加,ｃＡＭＰ和心肌收缩下降,Ｍｂ、ｃＡＭＰ和心肌细胞收缩频率经复氧可以得到恢复。普鲁卡因使低氧时心肌细胞的收缩频率更漫和Ｍｂ的表达减弱;茶碱使低氧下心肌细胞的收缩频率和Ｍｂ的表     

Prevention of disorders of the electric stability of the heart in experimental infarct using adaptation to hypoxia

It has been shown on rats preadapted to hypoxia in an altitude chamber that myocardial infarction induced by ligation of the coronary artery was accompanied by less disturbances in the electrical stability of the heart, namely by a twofold decrease in ventricular fibrillation threshold and a considerable decrease in the heart ectopic activity. Preliminary adaptation provided the maintenance of myocardial contractility in infarction.     

Acceleration generated by the myocardium as a criterion of its contractility

In experiments on cat heart-lung preparations cooled from 38 to 25 degrees C, acceleration of the heart muscle (in mm Hg . s-2) was the only criterion of myocardial contractility, which showed identical changes under an equivalent increase (1.5-fold) of heart load with volume or resistance. The latter indicates that acceleration of the myocardium is the most adequate criterion of myocardial contractility.     

Effect of emotional and pain stress on the contractile function of the hypertrophied heart muscle

Rats with compensatory hypertrophy of the heart and control animals were subjected to emotional painful stress (EPS). It was established that EPS led to the lowering of the main indicators of the contractile function of an isolated papillary muscle and reduced the resistance of the function under study to excess/Na+ and H+ forcing out Ca2+ from the binding sites on the sarcolemma. Compensatory hypertrophy of the heart itself was accompanied by a reduction of the myocardial contractility but the increase of the concentration of Na+ and H+ in the perfusate led to a far greater depression of the contractile parameters than in the myocardium of the control animals. Contractile function of the hypertrophied myocardium after stress turned out to be reduced to the level close to that seen in heart insufficiency.     

The effect of graded hypoxia on the embryonic chick heart

Embryonic ventricular function in the chick was measured in response to graded levels of hypoxia. Myocardial contractility, as measured by cinephotoanalysis and expressed as shortening fraction, was significantly depressed after 1 hour of moderate hypoxia (6% O2) and after 5 hours of milder (16% O2 and 11% O2) levels of hypoxia (P less than .05). Microscopy confirmed associated myocyte damage with cell death noted after 5 hours of moderate hypoxic stress. Heart rate change was not related to the severity of hypoxia. The greatest level of tachycardia was noted with conditions of mildest hypoxia (16% O2). The data confirm that cardiac contractility, as measured by shortening fraction, is depressed on exposure to hypoxia, with impairment of function related to the severity of the hypoxic conditions.     

Cardiovascular peripheral effector mechanism in postflight orthostatic intolerance: a simulation study

Orthostatic intolerance (OI) following exposure to microgravity or head-down bed rest is frequently observed and is thought to be multifactorial origin. Although hypovolemia is considered as the primary cause of OI, the role played by other factors, such as the lowered vasoconstrictor responsiveness (VCR) of resistance vessels, the enhanced vasoconstriction response of cerebral vessels, and the depressed myocardial contractility need to be elucidated. It is difficult to assess experimentally how each of these changes would affect orthostatic tolerance and how these factors interact with each other. An alternative approach is to conduct simulation studies by use of mathematical models of cardiovascular system (CVS) capable of simulating the CVS response to orthostatic stress. This presentation describes the construction of the model used, and presents the preliminary simulation results illustrating the effects of varying individually the level of hypovolemia, VCR of the resistance vessels in lower limbs and abdominal viscera, VCR of the brain vessels or myocardial contractility on responses to orthostatic stress. The ultimate goal of our work was to integrate the new experimental findings and to simulate the complexity to get a thorough understanding of the mechanism of postflight cardiovascular dysfunction and orthostatic intolerance.     

Effect of preliminary blockade of alpha- and beta-adrenoreceptors on stress-induced disorders of myocardial relaxation and contractile functions

Effect of preliminary administration of the alpha-adrenoblocker phentolamine and the beta-adrenoblocker inderal on stress-induced disturbances of myocardial extensibility, contractile function and myocardial resistance to hypoxia and excess Ca2+ was studied on an isometrically contracting isolated right atrium of the rat. Inderal substantially prevented the post-stress decrease in atrial extensibility and almost completely prevented the stress-induced decline in the developed tension and the Frank-Starling mechanism efficiency. At the same time inderal prevented the post-stress increase in hypoxic and hypercalcium contracture of the atrium. Phentolamine did not produce any such protective effects. It is suggested that the damaging action of catecholamine excess occurring under stress is mediated via beta-adrenoreceptors but not via alpha-adrenoreceptors of the heart.     

Effect of preliminary adaptation to short-term stress exposure on the resistance of the spontaneously contracting myocardium to a lipid peroxidation inducer

Contractile function of the isolated right atrium was studied in male Wistar rats adapted to short-term stressor exposures at varying times after adaptation was completed. Adaptation to short-term stressor exposures induced a limited decrease in myocardial contractility immediately after adaptation was over. On the 3d day an additional reduction in the characteristics of contractile function was still observed. However, by the 5th day the characteristics recovered to the control level. At the same time adaptation completely prevented the derangement of myocardial contractility, induced by exposure to a prolonged stress. That protective effect was observed as early as adaptation was completed, on days 3 and 5 after adaptation, and became lessened on the 10th day. It is assumed that on the 5th day after adaptation the animals are in a postadaptation state where the untoward effect of adaptation disappears whereas the protective effect is demonstrable to a full extent. As a result all the characteristics of myocardial contractility following a prolonged stress on the 5th day after completion of short-term stressor exposures differed in no way from the control parameters.     

Effect of preliminary local myocardial hypoxia on the development of immune heart damage

The changes in hemo- and cardiodynamics, myocardial contractility and its structural and histochemical alterations were studied in two series of experiments (immune and combined hypoxic and immune action on the myocardium) on 27 mongrel dogs anesthesized with chloralose and urethane. It was established that preliminary short-term hypoxia of the myocardium essentially increases the alterative effect of immune factors, causing a rise in the involved area as well as in the degree of metabolic shifts in this area and in the intensity of the disorders of heart function and hemodynamics.     

Effects of hypoxic and CO hypoxia on isolated hearts.

Isolated perfused dog hearts were made hypoxic by respiring the support dog with low oxygen (hypoxic hypoxia) or with carbon monoxide (CO hypoxia). Each heart was exposed to both types of hypoxia, separately. Effects on coronary flow (Qt), coronary vascular resistance, cardiac oxygen consumption (Vo2), and contractility (%deltadP/dt) were studied. Two series of experiments were done. Series I: At constant perfusion pressure. As oxygen content (Cao2) was lowered from 20 to 5 vol%, Qt doubled with hypoxic hypoxia and almost tripled with CO hypoxia (P less than 0.01). Vo2 and contractility increased with both types of hypoxia. Beta-adrenergic blockade eliminated the increase in VO2 and contractility but not the difference in Qt increase between hypoxic and CO hypoxia. Series II: At constant Qt (with beta-blockade), vascular resistance decreased more with CO than hypoxic hypoxia. Finally, alpha-blockade eliminated the difference in vascular resistance and thus with complete (alpha and beta) blockade, the two types of hypoxia have the same effect and are indistinguishable.     

Dependence of heart chamber dimensions and dynamics on chamber demands and myocardial properties

A heart chamber undergoes eccentric hypertrophy in response to a chronic elevation of stroke-displacement demand, and it undergoes concentric hypertrophy in response to a chronic elevation of systolic-pressure demand. Both of these adaptations, which occur in various combinations, involve two myocardial plastic properties, "stretch normalization" and "stress normalization". We have developed a model which predicts dimensions and dynamics of the left ventricle as functions of myocardial properties and of the loads to which the chamber is adapted. The model involves: a stress-normalization rule which describes how myocardial volume depends on average systolic pressure, cavity volumes and the responsiveness of growth to stress; a stretch-normalization rule which describes how the cavity volume of standard stretch relates to average end-diastolic and end-systolic volumes; and a pressure-volume-curve equation giving isometric pressures as functions of cavity volume and myocardial volume relative to standard-stretch cavity volume, and elastic properties including contractility. The model shows how the relations among average dimensions, dynamics and loads depend on myocardial properties, particularly contractility and the growth response to stress. These properties are the main determinants of myocardial performance. In addition to the load adaptations mentioned above, the model predicts eccentric hypertrophy incident to reduced contractility, chronic dilation incident to reduced growth response to stress, myocardial stricture incident to excessive growth response to stress, and concentric hypertrophy (similar to high-pressure adaptation) incident to deposition of inert material. It allows some refinements in the evaluation of myocardial performance and in the evaluation of the abnormal properties responsible for abnormal performance.     

Myocardial contraction in the reverse development of adaptation to short-term exposure to stress

Contractile function of an isolated right atrium was studied in short-term stressor effects-adapted male Wistar rats at different times after adaptation was completed. Adaptation to short-term stressor effects was shown to produce a restricted decrease of myocardial contractility shortly after adaptation was completed. At the 3d day another decrease of contractile function was noted. However, contractile function returned to the control level by the 5th day. At the same time adaptation completely prevented the impairment of myocardial contractility, induced by prolonged stress. The protective effect was seen immediately after adaptation, by days 3 and 5 after it, being reduced by day 10. It is assumed that at the 5th day after adaptation, the animals experience the post-adaptation state marked by disappearance of the negative adaptation effect and by remarkable protective effect of adaptation. As a result, all the characteristics of myocardial contractility evaluated after prolonged stress experienced by the animals at the 5th day following short-term stressor effects do not differ from control parameters.     

Alterations in mitochondrial dynamics with age‐related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte contractility

Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) protects cardiac function against ischemia/reperfusion (I/R) injury. Mitochondria are critical in response to myocardial I/R injury as disturbance of mitochondrial dynamics contributes to cardiac dysfunction. It is hypothesized that SIRT1 and SIRT3 are critical components to maintaining mitochondria homeostasis especially mitochondrial dynamics to exert cardioprotective actions under I/R stress. The results demonstrated that deficiency of SIRT1 and SIRT3 in aged (24–26 months) mice hearts led to the exacerbated cardiac dysfunction in terms of cardiac systolic dysfunction, cardiomyocytes contractile defection, and abnormal cardiomyocyte calcium flux during I/R stress. Moreover, the deletion of SIRT1 or SIRT3 in young (4–6 months) mice hearts impair cardiomyocyte contractility and shows aging‐like cardiac dysfunction upon I/R stress, indicating the crucial role of SIRT1 and SIRT3 in protecting myocardial contractility from I/R injury. The biochemical and seahorse analysis showed that the deficiency of SIRT1/SIRT3 leads to the inactivation of AMPK and alterations in mitochondrial oxidative phosphorylation (OXPHOS) that causes impaired mitochondrial respiration in response to I/R stress. Furthermore, the remodeling of the mitochondria network goes together with hypoxic stress, and mitochondria undergo the processes of fusion with the increasing elongated branches during hypoxia. The transmission electron microscope data showed that cardiac SIRT1/SIRT3 deficiency in aging alters mitochondrial morphology characterized by the impairment of mitochondria fusion under I/R stress. Thus, the age‐related deficiency of SIRT1/SIRT3 in the heart affects mitochondrial dynamics and respiration function that resulting in the impaired contractile function of cardiomyocytes in response to I/R.     

外源γ-氨基丁酸对营养液低氧胁迫下网纹甜瓜幼苗抗氧化酶活性和活性氧含量的影响

在营养液低氧胁迫处理下,研究了γ-氨基丁酸(GABA)处理对低氧敏感性不同的网纹甜瓜品种植株根和叶抗氧化酶活性和活性氧(ROS)含量的影响.结果表明:在低氧胁迫下,GABA处理提高了网纹甜瓜植株根和叶抗氧化酶SOD、POD、CAT活性,降低了H2O2、O2-·、MDA等ROS含量,其中GABA 50mmol/L处理效果显著高于GABA 25和100 mmol/L的处理;与耐低氧性弱的"西域一号"品种相比,GABA处理对耐低氧性强的"东方星光"品种效果更明显,表明外源GABA处理通过促进抗氧化酶活性的提高,降低了低氧胁迫下植株体内ROS含量,增强植株的耐低氧的能力.     

Positive inotropic action of insulin on piglet heart.

This study was designed to investigate changes in cardiac performance during hypoglycemia produced by the administration of insulin in the newborn piglet. With heart rate, aortic pressure, and aortic flow held constant, the treated group demonstrated a pronounced positive inotropic response manifested by an increase of dP/dt max to 138% of control values. Central nervous system function and beta adrenergic activity were excluded from the preparation by ligation of the brachiocephalic vessels and administration of practolol. For reasons discussed, it is unlikely that the findings can be ascribed to glucagon contamination. Therefore, the increase in contractility presumably resulted from a direct effect of insulin upon the myocardium. Clinical and laboratory data suggest that the resistance of the neonate to hypoxia is modified by glycogen stores. Insulin is known to increase glycogen synthesis, and this effect might be expected to augment myocardial resistance to hypoxia. Under the conditions of these experiments, however, pretreatment with insulin had no demonstrable influence on the rate of deterioration of cardiac function during hypoxia. The mechanism of cardiac stimulation by insulin is unknown but may involve calcium fluxes.     

Experimental and Computational Investigation of the Role of Stress Fiber Contractility in the Resistance of Osteoblasts to Compression

The mechanical behavior of the actin cytoskeleton has previously been investigated using both experimental and computational techniques. However, these investigations have not elucidated the role the cytoskeleton plays in the compression resistance of cells. The present study combines experimental compression techniques with active modeling of the cell’s actin cytoskeleton. A modified atomic force microscope is used to perform whole cell compression of osteoblasts. Compression tests are also performed on cells following the inhibition of the cell actin cytoskeleton using cytochalasin-D. An active bio-chemo-mechanical model is employed to predict the active remodeling of the actin cytoskeleton. The model incorporates the myosin driven contractility of stress fibers via a muscle-like constitutive law. The passive mechanical properties, in parallel with active stress fiber contractility parameters, are determined for osteoblasts. Simulations reveal that the computational framework is capable of predicting changes in cell morphology and increased resistance to cell compression due to the contractility of the actin cytoskeleton. It is demonstrated that osteoblasts are highly contractile and that significant changes to the cell and nucleus geometries occur when stress fiber contractility is removed.     

Developmental programming of cardiovascular dysfunction by prenatal hypoxia and oxidative stress

Fetal hypoxia is a common complication of pregnancy. It has been shown to programme cardiac and endothelial dysfunction in the offspring in adult life. However, the mechanisms via which this occurs remain elusive, precluding the identification of potential therapy. Using an integrative approach at the isolated organ, cellular and molecular levels, we tested the hypothesis that oxidative stress in the fetal heart and vasculature underlies the molecular basis via which prenatal hypoxia programmes cardiovascular dysfunction in later life. In a longitudinal study, the effects of maternal treatment of hypoxic (13% O(2)) pregnancy with an antioxidant on the cardiovascular system of the offspring at the end of gestation and at adulthood were studied. On day 6 of pregnancy, rats (n = 20 per group) were exposed to normoxia or hypoxia ± vitamin C. At gestational day 20, tissues were collected from 1 male fetus per litter per group (n = 10). The remaining 10 litters per group were allowed to deliver. At 4 months, tissues from 1 male adult offspring per litter per group were either perfusion fixed, frozen, or dissected for isolated organ preparations. In the fetus, hypoxic pregnancy promoted aortic thickening with enhanced nitrotyrosine staining and an increase in cardiac HSP70 expression. By adulthood, offspring of hypoxic pregnancy had markedly impaired NO-dependent relaxation in femoral resistance arteries, and increased myocardial contractility with sympathetic dominance. Maternal vitamin C prevented these effects in fetal and adult offspring of hypoxic pregnancy. The data offer insight to mechanism and thereby possible targets for intervention against developmental origins of cardiac and peripheral vascular dysfunction in offspring of risky pregnancy.