glycogen and Coronary-Disease

Evidence is reviewed that favors the hypothesis that maintenance of glycolysis plays a special role in protecting membrane function in ischemia. Therefore all procedures stimulating glycolytic flux should be beneficial in ischemia, and procedures inhibiting flux should be harmful. However, a crucial consideration is the coronary flow rate. In severe ischemia, accumulation of protons, derived not directly from glycolytic flux but from the breakdown of ATP and from proton-producing cycles, will tend to inhibit glycolysis and to minimize any benefit from increased glycolytic flux. Therefore maintenance of intracellular pH is crucial to the concept of the benefits of glycolysis. It also follows that the severity of ischemia can determine whether or not enhanced glycolysis has a beneficial effect. It is argued that a multiple approach, including enhanced glycolytic flux, control of intracellular pH, and improved coronary flow, constitutes the combination most likely to benefit ischemia.

Topics: Coronary Disease; Glucose; Glycogen; Glycolysis; Humans; Lactates; Lactic Acid; Myocardium; NAD; Protons

Nuclear magnetic resonance (NMR) spectroscopy is a new technique to study myocardial metabolism in living tissues by noninvasive means. The biochemical studies on intact hearts are performed in multinuclear NMR spectrometers using Fourier transform techniques for data acquisition. The biological NMR experiments preserve the tissues and can be repeated with a temporal resolution of seconds to several minutes in a reproducible fashion. As a marker of the intermediary metabolism P-31, C-13, H-1, F-19, N-14, Na-23, and K-39 isotopes are commonly used. NMR spectrum analysis permits the identification of several important substrates of the myocardial metabolism and their concentrational changes. In addition, the biophysical parameters of magnetic relaxation properties are measured. In some instances enzyme kinetics can be assessed. The disadvantage of NMR spectroscopy is the low sensitivity: only substrates with a intracellular concentration of greater than or equal to 0.5 mM can be detected. Improvements in sensitivity can be achieved, if the number of scans per spectrum and magnetic field strength are increased. The application of NMR spectroscopy in cardiovascular medicine is new and systematic studies on myocardial metabolism in vivo are not yet available. However, using P-31 MR spectroscopy several important results concerning the changes of the high energy phosphates and the intracellular pH changes during myocardial ischemia, as well as interesting insights into the regulatory principles of the cellular respiration were obtained. Similarly, C-13 NMR spectroscopy successfully described some aspects of glycogen metabolism and the kinetics of citric acid cycle in the myocardium. The clinical application of NMR spectroscopy appears feasible in a near future. The practical importance of this promising technique in clinical cardiology will depend on availability of the whole-body MR spectrometers, on the development of pertinent techniques for spatial MR signal resolution, and on our ability to uncover and to understand the biochemical principles of cardiac diseases. However, it is already today evident that MR spectroscopy successfully shifted the research interests towards biochemical processes at the cellular level as important causes and markers of cardiac diseases and extended our knowledge of the pathophysiology of the myocardium.

Topics: Animals; Coronary Disease; Creatine Kinase; Dogs; Glycogen; Guinea Pigs; Heart; Humans; Magnetic Resonance Spectroscopy; Models, Biological; Myocardium; Phosphates; Rabbits; Rats; Thyroid Diseases

Myocardial recovery during reperfusion following ischemia is critical to patient survival in a broad spectrum of clinical settings. Myocardial functional recovery following ischemia correlates well with recovery of myocardial adenosine triphosphate (ATP). Adenosine triphosphate recovery is uniformly incomplete during reperfusion following moderate ischemic injury and is therefore subject to manipulation by metabolic intervention. By definition ATP recovery is limited either by (1) energy availability and application in the phosphorylation of adenosine monophosphate (AMP) to ATP or (2) availability of AMP for this conversion. Experimental data suggest that substrate energy and the mechanisms required for its application in the creation of high energy phosphate bonds (AMP conversion to ATP) are more than adequate during reperfusion following moderate ischemic injury. Adenosine monophosphate availability, however, is inadequate following ischemia due to loss of diffusable adenine nucleotide purine metabolites. These purine precursors are necessary to fuel adenine nucleotide salvage pathways. Metabolic interventions that enhance AMP recovery rather than those that improve substrate energy availability during reperfusion are therefore recommended. The mechanisms of various metabolic interventions are discussed in this framework along with the rationale for or against their clinical application.

Topics: Adenine; Adenosine; Adenosine Monophosphate; Adenosine Triphosphate; Aminoimidazole Carboxamide; Animals; Citric Acid Cycle; Coronary Circulation; Coronary Disease; Fructosediphosphates; Glucose; Glycogen; Heart; Humans; Inosine; Myocardium; Oxidative Phosphorylation; Ribonucleosides; Ribose

Mechanisms are described that are known to prolong survival of ischemic myocardium. Some of these mechanisms are species-specific: collateral blood flow does not contribute to survival in rats, rabbits, and pigs but it salvages subepicardial myocardium in the dog and probably in man. The most important defense mechanism is enlargement of collaterals by growth of pre-existing smaller vessels. This process is not operative in sudden coronary occlusion but may save a substantial portion of the myocardium if occlusion occurs more slowly, i.e. several days up to a week. Experimental evidence is presented that thrombotic occlusion, clot-retraction, and partial clot lysis by endothelium can be sufficiently dynamic to allow intermittent myocardial perfusion and to permit collaterals to grow. The glycogen stores of the heart are of limited importance. They are useful for glycolytic ATP-production, the limitation is imposed by the inhibition of glycolysis in ischemia due to unfavourable pH and lack of NAD. Some beta-blockers do interfere with glycogenolysis in the heart. The cardioprotective role of adenosine needs further study. An interesting concept is the change in resistance to ischemia after repeated cycles of ischemia. It is not known at present whether repeated cycles will increase or decrease the myocyte's resistance against ischemia.

Topics: Adaptation, Physiological; Adenosine; Adenosine Triphosphate; Animals; Collateral Circulation; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Endothelium; Glycogen; Glycolysis; Heart; Myocardium; NAD

Topics: Aged; Aging; Animals; Coronary Disease; Coronary Vessels; Dihydrolipoamide Dehydrogenase; Female; Glucosephosphate Dehydrogenase; Glycerolphosphate Dehydrogenase; Glycogen; Heart Diseases; Humans; Hydroxybutyrate Dehydrogenase; L-Lactate Dehydrogenase; Malate Dehydrogenase; Male; Myocardium; Organ Size; Rats; Succinate Dehydrogenase

Topics: Adenosine Triphosphate; Animals; Cell Nucleus; Citrates; Coronary Disease; Disease Models, Animal; Dogs; Endoplasmic Reticulum; Glycogen; Heart Arrest; Hypothermia; Microscopy, Electron; Mitochondria, Muscle; Myocardium; Phosphates; Phosphocreatine; Potassium; Potassium Chloride; Procaine; Rats

Electron-microscope studies of experimental models of myocardial ischaemia have provided basic information on the pathogenesis of hypoxic heart injury. Correlation of ultrastructural changes with biochemical data confirms the importance of catecholamine release and ionic shifts in the early evolution of ischaemic injury. An altered cellular metabolism induced by ischaemia causes rapid depletion of glycogen and is followed quickly by alterations in the nucleus, the mitochondria and the sarcotubular system; the myofibril is the organelle most resistant to hypoxia.Postmortem autolysis mimics early ischaemic change very closely and it probably has an initial hypoxic basis. Significant hypoxic-autolytic changes may begin during the agonal state. The time elapsing and the techniques of tissue preservation are critical in determining the amount of artefact. At present it is unrealistic to expect to obtain acutely ischaemic human myocardium soon enough after death to be of value in the estimation of the degree or duration of ischaemia by electron-microscope techniques. Rapidly progressive autolytic changes preclude the meaningful morphological assessment of hypoxic change at the ultrastructural level.

Topics: Animals; Cats; Coronary Disease; Disease Models, Animal; Dogs; Glycogen; Humans; Hypoxia; Magnesium Deficiency; Microscopy, Electron; Mitochondria; Myocardium; Myofibrils; Organoids; Postmortem Changes; Rabbits; Rats

The objective of the study was to investigate the impact of alteration of glycogen stores and metabolism on exercise performance in patients with heart failure.. In normal subjects, muscle glycogen depletion results in increased exertional fatigue and reduced endurance. Skeletal muscle biopsies have revealed reduced glycogen content in patients with congestive heart failure (CHF). Whether glycogen depletion contributes to reduced endurance and abnormal ventilation in these patients is unknown.. Bicycle exercise tests with measurement of respiratory gases were performed following dietary manipulations to induce glycogen depletion (60% protein, 40% fat) and slow glycogen utilization (60% carbohydrate, 30% fat, 10% protein) in 13 patients with CHF (left ventricular ejection fraction 22+/-6%; age 48+/-9 years) and 7 control subjects (age 45+/-5 years). Maximal exercise, exercise at 75% of peak workload until exhaustion and 1-min cycles of supramaximal exercise at 133% of peak were performed on three occasions over a two-week period.. Significant changes in resting respiratory quotients (RQs) in normal (Baseline: 0.78+/-0.03; Depleted: 0.69+/-0.05) and CHF subjects (Baseline: 0.84+/-0.05; Depleted: 0.72+/-0.05) were observed (both p<0.05). Peak Vo2 (oxygen consumption) in both groups was unchanged. The ventilatory response to exercise was analyzed by correlating CO2 production (V(CO2)) to minute ventilation (VE) in each test. The slopes of these correlations were not affected in either group. With glycogen depletion, exercise endurance was reduced from 17 to 6.1 min (57+/-19%) in normal subjects versus a reduction of 9.4 to 8.1 min (11+/-19%) in patients (p<0.05). With slowed glycogen use, CHF patients increased exercise endurance from 9.4 to 16.5 min (65%) versus 17 to 20.6 min (18%) in normal subjects (p<0.05).. Glycogen depletion minimally affects maximal exercise performance, endurance or ventilation in CHF patients, whereas slowed glycogen utilization markedly enhances exercise endurance. Therapeutic interventions that increase or slow use of glycogen stores may have clinical benefit.

Topics: Adult; Cardiomyopathy, Dilated; Coronary Disease; Diet; Exercise; Exercise Test; Female; Glycogen; Heart Failure; Humans; Male; Middle Aged; Muscle, Skeletal; Physical Endurance; Prospective Studies

To define the skeletal muscle abnormalities in patients undergoing exercise deconditioning and evaluate the metabolic effect of propionyl-L-carnitine (PLC), muscle biopsies were obtained from 28 patients with effort angina and 31 control subjects. Coronary artery disease patients received either placebo (n = 12), PLC (1.5 g i.v. followed by infusion of 1 mg/kg/min for 30 min, n = 10), or L-carnitine (1 g i.v. followed by infusion of 0.65 mg/kg/min for 30 min, n = 6) for 2 days. Exercise deconditioned patients treated with placebo showed normal muscle content of total carnitine and glycogen, and decrease in percentage of type 1 fibers (P < 0.01) and in the activity of citrate synthase (P < 0.05), succinate dehydrogenase (P < 0.05), and cytochrome oxidase (P < 0.05), as compared to controls. Both PLC and L-carnitine did not modify muscle fiber composition or enzyme activities, but significantly increased muscle levels of total carnitine by 42% and 31%, respectively (P < 0.05). Moreover, PLC significantly increased glycogen muscle content (P < 0.01), while the equimolar dose of L-carnitine did not. This effect, probably due to the anaplerotic activity of the propionic group of PLC, suggests that this drug may be effective in improving energy metabolism of muscles with impaired oxidative capacity.

Topics: Carnitine; Conditioning, Psychological; Coronary Disease; Exercise; Glycogen; Humans; Male; Middle Aged; Muscle Fibers, Skeletal; Muscle, Skeletal; Reference Values

Therapeutic administration of high doses of insulin achieves a shifting of metabolism to glycogenesis and glycolysis. The result is an accumulation of the myocardial glycogen stores and an improvement of glucose utilization as well. If on that basis an increased anaerobic provision of adenosine triphosphate will be maintained in the myocardium during ischemia, the myocardial cell viability during aortic cross-clamping will be saved as well. Thus a preventive insulin supply will preserve the heart from ischemic damage. Twenty patients undergoing mitral valve replacement were investigated in two randomized groups. One group received insulin (1 U/kg/hr) together with a 33% glucose infusion (0.5 gm/kg/h) and potassium (0.25 mEq/kg/hr) from the onset of anesthesia until aortic cross-clamping. The control group received Ringer's lactate at the same infusion rate. After an average ischemic time of 26 minutes, an excised papillary muscle tip was immediately plunged into liquid nitrogen and the content of adenosine triphosphate, adenosine diphosphate, and creatine phosphate was determined. The adenosine triphosphate/diphosphate quotient and the energy charge potential were calculated. The mean adenosine triphosphate content in the insulin group was 7.43 mumol/gm wet weight and was significantly (p less than 0.01) higher than that of the control group (4.28 mumol/gm). The mean ADP content was 1.43 mumol/gm in the insulin group versus 1.81 mumol/gm in the control group. The mean creatine phosphate content was again significantly (p less than 0.05) higher in the insulin group (6.70 mumol/gm) than in the control group (5.30 mumol/gm). Also, the mean adenosine triphosphate/diphosphate quotient (insulin group, 5.19; control group, 2.36) and the mean energy charge potential (insulin group, 0.919; control group, 0.851) were significantly (p less than 0.01) higher in the insulin group. It is concluded that the preventive application of high doses of insulin leads to an augmented myocardial adenosine triphosphate provision and a maintained cellular energy charge during coronary ischemia. As a result, ischemic tolerance is enhanced and myocardial protection is improved.

Topics: Adenine Nucleotides; Adult; Aged; Aorta; Cardiopulmonary Bypass; Constriction; Coronary Disease; Energy Metabolism; Glucose; Glycogen; Humans; Insulin; Intraoperative Complications; Middle Aged; Mitral Valve; Myocardium

Topics: Adult; Aged; Alcohols; Benzofurans; Clinical Trials as Topic; Coronary Disease; Evaluation Studies as Topic; Female; Glycogen; Heart; Humans; Male; Middle Aged; Myocardium; Pentaerythritol Tetranitrate

To investigate the role of high concentrations of dl-3-hydroxybutyrate (DL-3-HB) in preventing heart damage after prolonged fasting, infarct size and the incidence of apoptosis caused by ischemia-reperfusion were determined in four groups of Wistar rats. Fed rats (+/-DL-3-HB group) and fasted rats (+/-DL-3-HB group) were subjected to 30 min of left coronary artery occlusion and 120 min of reperfusion. DL-3-HB was administered intravenously 60 min before the coronary artery occlusion. Infarct size, defined by triphenylyetrazolium chloride (TTC) staining, was reduced from 72 +/- 3% (fed group), 75 +/- 5% (fed + DL-3-HB group), and 70 +/- 5% (fasting group), respectively, to 26 +/- 4% (P < 0.01 vs. fasting + DL-3-HB group). Apoptosis, as defined by single-stranded DNA staining, was significantly reduced in the subendocardial region in the fasting + DL-3-HB group (9 +/- 2%) compared with the other groups (39 +/- 6% in the fed group, 37 +/- 5% in the fed + DL-3-HB group, and 34 +/- 3% in the fasting group; P < 0.01). In addition, levels of ATP in the fasting + DL-3-HB group were significantly higher compared with other groups after 30 min of ischemia and 120 min of reperfusion (P < 0.01). In conclusion, the present study demonstrates that high concentrations of DL-3-HB reduces myocardial infarction size and apoptosis induced by ischemia-reperfusion, possibly by providing increased energy substrate to the fasted rat myocardium.

Topics: 3-Hydroxybutyric Acid; Acetoacetates; Adenosine Triphosphate; Animals; Apoptosis; Blood Glucose; Blood Pressure; Body Weight; Coronary Disease; Fasting; Fatty Acids, Nonesterified; Glycogen; Heart Rate; Insulin; Lactic Acid; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Wistar

Rhythm disorders are common complications in diabetic patients, due to their enhanced sensitivity to ischaemia. However, experimental studies are inconsistent, and both higher and lower vulnerability to injury has been reported. Our objectives were to compare susceptibility to ventricular arrhythmias in rats with prolonged duration of diabetes induced by streptozotocin (45 mg/kg, i.v.), utilising two different models. Following 8 weeks, either anaesthetised open-chest rats in vivo or isolated Langendorff-perfused hearts were subjected to 30 min regional zero-flow ischaemia induced by occlusion of LAD coronary artery. In addition, cardiac glycogenolysis and lactate production were measured. In open-chest rats, 90 % of the controls exhibited ventricular tachycardia (VT) which represented 55.4 % of total arrhythmias, whereby only 19.9 % of arrhythmias occurred as VT in 44 % of the diabetic rats (P < 0.05 vs controls). Duration of VT and ventricular fibrillation (VF) was reduced from 35.5 +/- 11.1 and 224.8 +/- 153.9 s in the controls to 4.8 +/- 2.5 and 2.2 +/- 0.2 s in the diabetics, respectively (P < 0.05). Accordingly, severity of arrhythmias (arrhythmia score, AS) was also lower in the diabetics (2.0 +/- 0.38 vs 3.3 +/- 0.3 in the controls; P < 0.05). In the isolated hearts, high incidence of VF was decreased in the diabetic hearts, and although VT occurred in almost all of the diabetic hearts, the duration of VT and VF was substantially shorter (61.5 +/- 14.5 and 5.5 +/- 0.5 s vs 221.5 +/- 37 and 398.5 +/- 55 s in the controls, respectively; P < 0.05). AS was reduced to 2.9 +/- 0.12 from 4.1 +/- 0.3 in the controls (P < 0.05). Postischaemic accumulation of lactate was lower in the diabetic than in the non-diabetic myocardium (20.4 +/- 1.9 vs 29.5 +/- 2.9 micromol/l/g w.wt.; P < 0.05). These results suggest that rat hearts with chronic diabetes, despite some differences in the arrhythmia profiles between the in vivo model and isolated heart preparation, are less sensitive to ischaemic injury and exhibit lower susceptibility to ventricular arrhythmias and reduced accumulation ofglycolytic metabolites.

Topics: Animals; Blood Glucose; Coronary Disease; Diabetes Mellitus, Experimental; Glycogen; In Vitro Techniques; Lactic Acid; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Wistar; Tachycardia, Ventricular

Topics: Animals; Coronary Disease; Energy Metabolism; Glucose; Glycogen; Humans; In Vitro Techniques; Insulin Resistance; Magnetic Resonance Spectroscopy; Models, Cardiovascular; Myocardium; Rats

The relevance of regional LV myocardial ischemia/reperfusion induced by temporary left anterior descending (LAD) coronary artery occlusion during minimally invasive direct coronary artery bypass (MIDCAB) grafting is controversial. The purpose of our study was (1) to determine the impact of conventional LAD occlusion during left internal thoracic artery (LITA)-LAD anastomosis on regional LV myocardial ischemia and function, and (2) to evaluate if intra-LAD shunt insertion during LITA-LAD anastomosis prevents potential regional LV ischemia and dysfunction in a pig model.. In 20 anesthetized, mechanically ventilated pigs we performed LITA-LAD anastomosis on the beating heart without cardiopulmonary bypass during either 15 min LAD occlusion (occlusion-group; n = 10) or 15 min intra-LAD shunt insertion to maintain blood supply to the myocardium beyond the anastomosis (shunt-group; n = 10). Besides standard hemodynamics we determined the global and regional LV wall motion score index (WMSI) using epimyocardial echocardiography. To quantitate structural myocardial alteration we determined the inducible heat-shock protein-70 (HSP-70) in LV anterior wall myocardial biopsies. Data were recorded at baseline, at 15 min of LAD occlusion or shunt insertion, respectively, and at 30 min of reperfusion. At the end of the experiments we determined myocardial adenine nucleotide (ATP, ADP, AMP) and glycogen content.. In both groups WMSI was not significantly different at 15 min LAD occlusion or shunt insertion, respectively, as compared to baseline. However, at 30 min reperfusion both global and regional WMSI demonstrated significant LV dysfunction in the occlusion-group, whereas LV function in the shunt-group remained normal. This was associated with higher myocardial HSP-70 expression in the occlusion-group (P < 0.05). Myocardial adenine nucleotide and glycogen contents were significantly better preserved in the shunt-group.. Our data show that in a porcine MIDCAB model 15 min LAD occlusion and 30 min reperfusion result in significant myocardial stunning. In contrast, maintenance of LAD perfusion using intracoronary shunt insertion minimizes ischemia/reperfusion injury and prevents regional LV dysfunction. Although our experiments were conducted in healthy pig hearts absent from coronary artery disease, similar results may--at least partially--be expected in humans, and thus, intracoronary shunts could be a useful tool for myocardial protection during 'off-pump revascularization'.

Topics: Adenine Nucleotides; Anastomosis, Surgical; Animals; Blood Vessel Prosthesis Implantation; Coronary Artery Bypass; Coronary Disease; Disease Models, Animal; Echocardiography; Female; Glycogen; Hemodynamics; HSP70 Heat-Shock Proteins; Male; Minimally Invasive Surgical Procedures; Myocardial Stunning; Myocardium; Swine

Studies in animal models and humans suggest that myocardium may adapt to chronic or intermittent prolonged episodes of reduced coronary perfusion. Stable maintenance of partial flow reduction is difficult to achieve in experimental models; thus, in vitro cellular models may be useful for establishing the mechanisms of adaptation. Since moderate hypoxia is likely to be an important component of the low-flow state, isolated adult rat cardiac myocytes were exposed to 1% O2 for 48 hours to study chronic hypoxic adaptation. Hypoxic culture did not reduce cell viability relative to normoxic controls but did enhance glucose utilization and lactate production, which is consistent with an anaerobic pattern of metabolism. Lactate production remained transiently increased after restoration of normal O2 tension. Myocyte contractility was reduced (video-edge analysis), as was the amplitude of the intracellular Ca2+ transient (indo 1 fluorescence) in hypoxic cells. Relaxation was slowed and was accompanied by a slowed decay of the Ca2+ transient. These changes were not due to alterations in the action potential. Tolerance to subsequent acute severe hypoxia occurred in cells cultured in 1% O2 and was manifested as a delay in the time to full ATP-depletion rigor contracture during severe hypoxia and enhanced morphological recovery of myocytes at reoxygenation. The latter was still seen after normalization of the data for the prolonged time to rigor, suggesting a multifactorial basis for tolerance. An intervening period of normoxic exposure before subsequent acute severe hypoxia did not result in loss of tolerance but rather increased the delay to subsequent ATP depletion rigor. Cellular glycogen was preserved during chronic hypoxic exposure and increased after the restoration of normal O2 tension. As mitochondrial cytochromes should be fully oxygenated at levels well below 1% O2, hypoxic adaptation may be mediated by a low-affinity O2-sensing process. Thus, adaptations that occur during prolonged periods of moderate hypoxia are proposed to poise the myocyte in a better position to tolerate impending episodes of severe O2 deprivation.

Topics: Action Potentials; Adaptation, Physiological; Adenosine Triphosphate; Animals; Calcium; Cells, Cultured; Coronary Circulation; Coronary Disease; Culture Media; Data Interpretation, Statistical; Glucose; Glycogen; Heart; Humans; Hypoxia; In Vitro Techniques; Lactates; Myocardial Contraction; Myocardium; Oxygen; Rats; Rats, Sprague-Dawley; Time Factors

Positron emission tomography (PET) is a powerful tool for in vivo measurements of physiologic processes such as regional myocardial blood flow and metabolism. Myocardial blood flow is often studied using radioactive labeled ammonia (13NH3) while myocardial metabolism can be investigated using 18F-fluorodeoxyglucose (FDG). Moreover, the use of appropriate kinetic models allows quantification of these processes. In this study, myocardial viability in both chronic and acute heart disease was investigated by the use of positron emission tomography. In this context, viable refers to dysfunctioning areas of the myocardium in which functional recovery is observed after revascularization. In patients suffering chronic coronary artery disease, PET findings of flow and metabolism were correlated with myocardial ultrastructure. In dysfunctional myocardial segments, normal 13NH3 uptake or decreased 13NH3 uptake with relatively increased FDG uptake (PET mismatch) indicates the possibility for functional recovery after bypass surgery. Since absence of scar tissue in these segments is likely to be required for functional recovery, it was not surprising that little fibrosis was found in myocardial biopsies taken in PET mismatch areas. The biopsies also revealed the presence of viable myocardial cells showing a variable loss of contractile material. The contractile material was replaced by glycogen. One could wonder about the time course needed for functional recovery after restoration of blood flow in the presence of a considerable amount of cells lacking a normal contractile apparatus. It would therefore be interesting to study functional recovery at different time points in patients with variable amounts of these myolytic cells. Probably, recovery of contractility would be slower in myocardial areas with a larger amount of abnormal cells. Another question that arises is the meaning of the increased FDG signal in dysfunctional, though viable myocardium. At first sight, glycogen storage in myolytic cells seems an excellent candidate to explain the increased intake of FDG in PET mismatch areas. However, in this study, in areas considered nonviable by PET, similar amounts of myolytic cells were found. Histologically altered cells might represent a structural and protective adaptation to long term hypoperfusion or to repetitive episodes of ischemia. Another possibility for the increased FDG uptake is an enhancement of glucose utilization in the mismatch areas not only in th

Topics: Acute Disease; Aged; Angioplasty, Balloon, Coronary; Chronic Disease; Coronary Circulation; Coronary Disease; Female; Glycogen; Humans; Male; Middle Aged; Myocardial Revascularization; Myocardial Stunning; Myocardium; Regional Blood Flow; Thrombolytic Therapy; Time Factors; Tomography, Emission-Computed

Myocardial regions perfused through a coronary stenosis may cease contracting, but remain viable. Clinical observations suggest that increased glucose utilization may be an adaptive mechanism in such "hibernating" regions. In this study, we used a combination of 13C-NMR spectroscopy, GC-MS analysis, and tissue biochemical measurements to track glucose through intracellular metabolism in intact dogs infused with [1-13C]glucose during a 3-4-h period of acute ischemic hibernation. During low-flow ischemia [3-13C]alanine enrichment was higher, relative to plasma [1-13C]glucose enrichment, in ischemic than in nonischemic regions of the heart, suggesting a greater contribution of exogenous glucose to glycolytic flux in the ischemic region (approximately 72 vs. approximately 28%, P < 0.01). Both the fraction of glycogen synthase present in the physiologically active glucose-6-phosphate-independent form (46 +/- 10 vs. 9 +/- 6%, P < 0.01) and the rate of incorporation of circulating glucose into glycogen (94 +/- 25 vs. 20 +/- 15 nmol/gram/min, P < 0.01) were also greater in ischemic regions. Measurement of steady state [4-13C)glutamate/[3-13C]alanine enrichment ratios demonstrated that glucose-derived pyruvate supported 26-36% of total tricarboxylic acid cycle flux in all regions, however, indicating no preference for glucose over fat as an oxidative substrate in the ischemic myocardium. Thus during sustained regional low-flow ischemia in vivo, the ischemic myocardium increases its utilization of exogenous glucose as a substrate. Upregulation is restricted to cytosolic utilization pathways, however (glycolysis and glycogen synthesis), and fat continues to be the major source of mitochondrial oxidative substrate.

Topics: Alanine; Animals; Coronary Disease; Coronary Vessels; Disease Models, Animal; Dogs; Endocardium; Fatty Acids, Nonesterified; Female; Glucose; Glutamic Acid; Glycogen; Glycolysis; Magnetic Resonance Spectroscopy; Male; Oxidation-Reduction; Pericardium; Regional Blood Flow

Short-term myocardial hibernation of 3 hours resulting from a moderate resting coronary flow reduction has been reproduced in pigs. This study was designed to determine whether any structural changes accompany short-term hibernation caused by a moderate flow reduction maintained for 24 hours and whether any such structural alterations are reversible after reperfusion.. A severe left anterior descending coronary artery (LAD) stenosis was created with a reduction of resting flow to approximately 60% of baseline and maintained for 24 hours. Regional coronary flow was measured by a flowmeter; wall thickening was determined by echocardiography, and local metabolic changes were measured. Of 17 pigs, 11 completed the study protocol of 24 hours. The LAD flow was reduced from 0.91 +/- 0.11 to 0.52 +/- 0.13 mL.min-1.g-1, a 43% mean decrease, at 15 minutes after the LAD stenosis and was maintained at 0.56 +/- 0.11 mL.min-1.g-1 at 24 hours. The reduction of regional coronary flow initially produced acute myocardial ischemia, as evidenced by reduced regional wall thickening (from 37.2 +/- 6.9% at baseline to 11.5 +/- 6.8%), regional lactate production (-0.34 +/- 0.28 mumol.g-1.min-1), and a decrease in regional coronary venous pH (from 7.41 +/- 0.035 at baseline to 7.30 +/- 0.030). At 24 hours, the reductions in coronary flow and wall thickening were maintained relatively constant and the rate-pressure product was relatively unchanged, but lactate production ceased and regional H+ concentration normalized, with a tendency toward a further reduction in regional oxygen consumption, from 3.10 +/- 0.90 mL.min-1.100 g-1 at 15 minutes after stenosis to 2.52 +/- 0.95 mL.min-1.100 g-1 at 24 hours (P = .06), indicating metabolic adaptation of the hypoperfused regions. Of 11 pigs, 6 were free of myocardial infarction; 3 had patchy necrosis involving 4%, 5%, and 6% of the area at risk; and 2 other pigs had a few scattered myocytes with necrosis, detected only by light and electron microscopy. Ultrastructural changes consisted of a partial loss of myofibrils and an increase in mitochondria and glycogen deposition. Regional wall thickening recovered 1 week after reperfusion in most pigs, and the ultrastructural changes reverted to normal.. In this pig model, moderately ischemic myocardium undergoes metabolic and structural adaptations but preserves the capacity to recover both functionally and ultrastructurally after reperfusion.

Topics: Actin Cytoskeleton; Animals; Coronary Circulation; Coronary Disease; Glycogen; Mitochondria, Heart; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Necrosis; Oxygen Consumption; Swine

Ischemic preconditioning depletes the myocardium of glycogen, thus blunting lactic acidosis during subsequent episodes of ischemia. Preconditioning also protects against reperfusion arrhythmias and infarction. To test whether glycogen depletion is necessary for this ischemic tolerance, we preconditioned two groups of intact rats with a series of 3-min coronary artery occlusions. In one group, preconditioning lowered the glycogen concentration of the ischemic region by approximately 50% (24.9 +/- 2.5 to 12.5 +/- 1.8 mumol/g; P < 0.01). In the other, the heart was first loaded with glycogen via glucose-insulin infusion so that preconditioning merely reduced its glycogen concentration back to normal physiological levels. Compared with nonpreconditioned control rats, preconditioned rats with both normal and subnormal glycogen concentrations were protected from reperfusion arrhythmias after a 6-min coronary occlusion (incidence: control rats, 100%; normal glycogen rats, 11%; reduced glycogen rats, 11%). In contrast, only rats with subnormal glycogen concentration after preconditioning exhibited reduced lactate formation and infarct size after a 45-min coronary occlusion [infarct size (percentage of risk area): control rats, 53 +/- 10%; normal glycogen rats, 50 +/- 16%, P = not significant; subnormal glycogen rats, 18 +/- 10%, P < 0.01]. Thus, in the intact rat, myocardial glycogen depletion appears to be necessary for the infarct-limiting, but not for the antiarrhythmic, effects of ischemic preconditioning.

Topics: Animals; Blood Glucose; Coronary Disease; Glycogen; Hemodynamics; Ischemic Preconditioning, Myocardial; Lactic Acid; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Osmolar Concentration; Potassium; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular

Adenosine possesses marked cardioprotective properties, but the mechanisms for this beneficial effect are unclear. The objective of this study was to determine the effect of adenosine given before ischemia or at reperfusion on mechanical function, glucose oxidation, glycolysis, and metabolite levels in isolated, paced (280 beats per minute) working rat hearts.. Hearts were perfused with Krebs-Henseleit buffer containing 11 mM glucose, 1.2 mM palmitate, and 500 microU.mL-1 insulin at an 11.5 mm Hg left atrial preload and 80 mm Hg aortic afterload. Adenosine (100 microM) pretreatment or adenosine (100 microM) at reperfusion markedly increased the recovery of mechanical function (from 44% to 81% and 96%, respectively) after 60 minutes of low-flow ischemia (coronary flow, 0.5 mL.min-1). Glucose oxidation (mumol.min-1 x g dry wt-1) was inhibited during ischemia (from 0.44 +/- 0.04 to 0.12 +/- 0.01), and this was not altered by adenosine (100 microM). During reperfusion, glucose oxidation recovered (to 0.38 +/- 0.02) and adenosine (100 microM), given at reperfusion, further increased glucose oxidation (to 0.52 +/- 0.06). The rate of glycolysis (mumol.min-1 x g dry wt-1), which was unaffected by ischemia per se, was inhibited by adenosine pretreatment (from 4.7 +/- 0.3 to 2.6 +/- 0.3). During reperfusion, glycolysis was also inhibited by adenosine relative to control (3.9 +/- 0.8) either when present during ischemia (2.6 +/- 0.6) or during reperfusion (1.4 +/- 0.4). These effects of adenosine on glucose metabolism reduced the calculated rate of H+ production attributable to glucose metabolism during the ischemic and reperfusion periods. Tissue lactate levels (mumol.g dry wt-1), which increased during ischemia (from 9.3 +/- 1.1 to 87.4 +/- 10.3) and then declined during reperfusion (to 26.2 +/- 3.7), were depressed further by adenosine pretreatment (to 19.7 +/- 4.1) and by adenosine at reperfusion (to 13.6 +/- 2.1). ATP levels (mumol.g dry wt-1), which were depressed by ischemia (from 18.1 +/- 1.1 to 10.6 +/- 1.3) and tended to be further depressed during reperfusion (to 7.1 +/- 0.7), were increased by adenosine pretreatment (to 14.1 +/- 1.2) and by adenosine at reperfusion (to 15.6 +/- 2.4).. The effects of adenosine on glucose metabolism that would tend to decrease cellular acidosis and hence, Ca2+ overload, may explain the beneficial effects of adenosine on mechanical function observed in these hearts during reperfusion after ischemia.

Topics: Adenosine; Adenosine Triphosphate; Animals; Coronary Disease; Female; Glucose; Glycogen; Glycolysis; Homeostasis; In Vitro Techniques; Lactates; Lactic Acid; Male; Myocardial Reperfusion; Myocardium; Oxidation-Reduction; Rats; Rats, Sprague-Dawley

Using NADH fluorometry to monitor myocardial metabolism, the mechanism of reperfusion injury was investigated after the delivery of an experimental reperfusate. Using an isolated working heart preparation, rat hearts underwent 15 min of global ischemia at 37 degrees C. Following the ischemic insult, an oxygenated enriched reperfusion solution was given for 5 min. The hearts were then returned to a working state and aortic flow recorded to evaluate recovery. NADH levels were monitored throughout the experiment with a fluorometer and glycogen, AMP, ADP, and ATP were measured biochemically pre- and postischemia, after reperfusion and after recovery. In this study, reperfusion injury was best abated by an enriched reperfusate. Our results indicate the mechanism for this amelioration is not high-energy phosphate replenishment. Rather, as indicated by NADH fluorescence, the hearts attain an intermediate level of metabolism that permits glycogen to be restored and functional recovery to be improved.

Topics: Animals; Aorta; Cardiac Output; Coronary Circulation; Coronary Disease; Fluorescence; Fluorometry; Glycogen; Male; Monitoring, Physiologic; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; NAD; Oxygen; Phosphates; Rats; Rats, Inbred Strains; Ventricular Function

We assessed the relationship between myocardial glucose metabolism and blood flow during ischemia in eight open-chest swine. Coronary flow was controlled by an extracorporeal perfusion circuit. Left anterior descending coronary arterial (LAD) flow was reduced by 60%, while left circumflex flow was normally perfused. The rate of glucose uptake (Rg) was measured with a coronary infusion of 2-deoxy-D-[14C]glucose and myocardial blood flow with radiolabeled microspheres. Myocardial biopsies were taken after 50 min of ischemia. Regional arterial-venous glucose difference was calculated as Rg per myocardial blood flow. Subendocardial blood flow decreased from 1.27 +/- 0.19 to 0.25 +/- 0.11 ml.g-1.min-1 (P less than 0.0001). The subendocardial arterial-venous glucose difference was greater in the LAD bed (1.38 +/- 0.35 mumol/ml) than the left circumflex coronary arterial perfusion bed (0.10 +/- 03; P less than 0.01); however, there was no statistically significant difference in the rate of glucose uptake between the two beds. Subendocardial glycogen concentration in the LAD perfusion bed was reduced to 26% of circumflex bed values. In conclusion, acute ischemia stimulated a dramatic increase in glucose extraction; however, this did not compensate for the decrease in blood flow, and thus the rate of glucose uptake did not increase significantly. The high rate of glycolysis is primarily supported by accelerated net glycogen breakdown rather than increased glucose uptake.

Topics: Acute Disease; Animals; Coronary Circulation; Coronary Disease; Glucose; Glycogen; Ion Exchange; Lactates; Lactic Acid; Myocardium; Osmolar Concentration; Swine; Tissue Distribution; Ventricular Function, Left

The dietary polyunsaturated fatty acids are well known to promote the cardiac output and to protect the myocardium against arrhythmias. The exogenous glucose is generally considered as a protective agent against arrhythmias resulting from ischemia and reperfusion. But the effects of dietary fats, which also influence arrhythmias, on this beneficial effect of glucose has not been yet considered. We have studied the effects of a 7 days diet with or without polyunsaturated fatty acids on the cardiac performance and arrhythmias of isolated rat hearts, perfused with saline containing either glucose 5.5 mM or 11 mM. Acute regional ischemia was produced by ligature of the left main coronary artery with subsequent release to achieve reperfusion for some hearts. Previously, our results showed that the dietary polyunsaturated fatty acids led to an enhancement of the cardiac performance and to a decreased susceptibility to arrhythmias. The present data showed that the protective action of the exogenous glucose appeared to be dependent of the dietary lipid profile. Dietary polyunsaturated fatty acids increase cardiac performance under ischemia and decrease ventricular arrhythmias' occurrence under ischemia and on reperfusion. It might be related to endogenous substrate utilization and exogenous glucose availability which was influenced by the coronary flow.

Topics: Animals; Arrhythmias, Cardiac; Cardiac Output; Coronary Circulation; Coronary Disease; Dietary Fats, Unsaturated; Glucose; Glycogen; Heart Rate; Male; Myocardium; Oxygen Consumption; Phospholipids; Rats; Rats, Inbred Strains; Reperfusion Injury; Triglycerides

The effect of induced myocardial ischemia on cardiac glycogen utilization was investigated in trained and untrained male Sprague-Dawley rats. Following a 12 to 15 week endurance training program, myocardial ischemia was induced by ligation of the left coronary artery. Prior to and at 5 min intervals following ligation, affected tissues of five trained and untrained animals were removed, frozen in liquid nitrogen, and analyzed for glycogen and lactic acid. The glycogen content for both groups declined significantly (p less than 0.05) during the first 5 min, 38% and 15% for the trained and untrained, respectively, with a concomitant rise in the lactic acid of 150% and 40%. Overall, the cardiac lactate in the trained hearts was lower (p less than 0.05) than in untrained hearts but the pattern of response was the same. During the final 5 min of ischemia, cardiac glycogen rose in the trained hearts and declined in the sedentary hearts. The difference between the two groups at 30 min was significant (p less than 0.05). The results show that trained and untrained rat hearts utilize glycogen differently but produce similar quantities of lactic acid during brief periods of myocardial ischemia. Similar lactate despite greater glycogen utilization may indicate reduced anaerobic stress in the trained rat heart.

Topics: Animals; Coronary Disease; Glycogen; Glycolysis; Heart Rate; Lactates; Lactic Acid; Male; Physical Conditioning, Animal; Rats; Rats, Inbred Strains

Myocardium which has been preconditioned by one or several brief episodes of ischemia has much slower energy utilization during a subsequent sustained episode of ischemia. Since preconditioned tissue also is 'stunned', the reduced energy utilization of preconditioned tissue may be due to reduced contractile effort. This study was done to assess whether differences in energy utilization persisted or disappeared under conditions of total ischemia, in vitro, when contractile activity was abolished in both control and preconditioned regions by hyperkalemic cardiac arrest. Preconditioned myocardium was produced in open-chest anesthetized dogs by exposing the circumflex bed to four 5-min episodes of ischemia each followed by 5 min of arterial reperfusion. Non-preconditioned anterior descending bed was used as control myocardium. Hearts were arrested with hyperkalemia after the last reperfusion period in order to reduce or eliminate the effects of contractile activity. Metabolite content was measured in sequential biopsies of the tissue. Large differences in the rate of energy metabolism of the two regions were noted during the first 15 minutes of ischemia. During this time, the preconditioned tissue utilized less glycogen, and produced less lactate, glucose-6-phosphate (G6P), glucose-1-phosphate (G1P), and alpha-glycerol phosphate (alpha GP), than did control myocardium. Moreover, there was a much smaller decrease in net tissue ATP in the preconditioned than in the control tissue. Thus, the decrease in the demand of preconditioned tissue for energy, which has been observed in vivo, persisted despite the elimination of differences in contractile effort between control and preconditioned myocardium. Although the cause of this decrease in energy demand in preconditioned myocardium remains unknown, the present results suggest that it is not due to concomitant stunning.

Topics: Adenine Nucleotides; Animals; Coronary Disease; Dogs; Energy Metabolism; Female; Glycogen; Glycolysis; Heart Arrest, Induced; Kinetics; Male; Myocardium; Potassium Chloride

Myocardial glycogen and the factors which primarily regulate its metabolism were studied during post-ischemic reperfusion. Myocardial [13C]glycogen was continuously monitored by 13C-NMR spectroscopy in beating rat hearts perfused with oxygenated solutions containing [1-13C]glucose (5 mM) and insulin, during normal flow at 15 ml/min (n = 5), and during reperfusion after 30 min of 1 ml/min (n = 5), or 0 ml/min (n = 4) ischemia. Mean myocardial [13C]glycogen fell during reperfusion from 1.1 +/- 0.6 at the end of zero-flow ischemia to 0.4 +/- 0.4 mumol of [13C]glucosyl units/g wet wt (P less than 0.02) over the first 7 min of reperfusion; it also fell during reflow following 1 ml/min ischemia, from 2.3 +/- 1.4 to 1.7 +/- 1.0 mumol (P less than 0.03) over the same interval. In parallel experiments, glycogen phosphorylase % a (GPA%) content was higher at the end of 30 min of 0 ml/min (37.3 +/- 7.3%, P less than 0.01), and trended higher after 1 ml/min flow (30.8 +/- 12.1%, P = 0.18) than under baseline conditions (20.1 +/- 7.4%). However GPA% returned to baseline values within 1 min of reflow after both 0 and 1 ml/min ischemic periods (20.6 +/- 3.0% and 19.0 +/- 8.0%, respectively). Inorganic phosphate, as determined by simultaneous 31P-NMR, remained elevated during early reperfusion relative to baseline, and significantly correlated with the extent of decline in [13C]glycogen during reperfusion (r = 0.79, P less than 0.01). Thus, glycogen breakdown continues to occur during early post-ischemic reperfusion, but the mechanism is not related to elevated GPA%, and may be due to persistently increased inorganic phosphate at that time.

Topics: Adenosine Monophosphate; Animals; Coronary Disease; Glucose-6-Phosphate; Glucosephosphates; Glycogen; In Vitro Techniques; Kinetics; Magnetic Resonance Spectroscopy; Male; Myocardial Contraction; Myocardial Reperfusion; Phosphates; Phosphorylases; Rats; Rats, Inbred Strains

The relationships among myocardial ATP, intracellular pH, and ischemic contracture in Langendorff-perfused rat hearts were investigated by 31P nuclear magnetic resonance spectroscopy during total global normothermic ischemia while the left ventricular pressure was recorded continuously via an intraventricular balloon. Glucose-perfused hearts (n = 63) were divided into five groups based on the time of onset of contracture (TOC), and three other groups of hearts were treated to vary the ischemic glycogen availability. ATP levels, which showed no evidence of accelerated ATP depletion during contracture, were significant and variable at TOC. Intracellular pH initially declined and then leveled off at TOC, with lower final pH in hearts with later TOC. We conclude that contracture began when anaerobic glycolysis (and thus glycolytic ATP synthesis) stopped. These results, though consistent with the concept that ischemic contracture in normal hearts results from rigor bond formation due to low ATP levels at the myofibrils, suggest that TOC is more closely related to glycolytic ATP production than to total cellular ATP content, thus providing evidence of some degree of subcellular compartmentation or metabolite channeling. In glycolytically inhibited hearts, the quite early contracture may have a Ca2+ component.

Topics: Anaerobiosis; Animals; Coronary Disease; Glycogen; Glycolysis; Hydrogen-Ion Concentration; In Vitro Techniques; Intracellular Membranes; Magnetic Resonance Spectroscopy; Myocardial Contraction; Myocardium; Phosphocreatine; Phosphorus; Rats; Time Factors

The development of muscle fatigue due to exhaustive exercise is associated with impaired sarcoplasmic reticulum (SR) Ca-transport activity. This study tested the hypothesis that SR failure is a consistent feature of cardiac and skeletal muscle fatigue owing to relative functional overload regardless of the method of induction: excessive stimulation, diminished performance capacity, or excessive excitation-contraction coupling. The Ca-transport activity was determined using three unique models of muscle fatigue: chronic and rapid ventricular pacing in dogs; metabolic inhibition caused by global cardiac ischemia in swine; and the hypermetabolic syndrome of porcine malignant hyperthermia (MH). Both pacing- and ischemia-induced fatigue resulted in reduction of SR Ca-transport ATPase activity: from 275 +/- 58 to 159 +/- 57 nmol.min-1.mg-1 (mU/mg) and from 577 +/- 82 to 177 +/- 133 mU/mg, respectively. Both pacing-induced fatigue and halothane-induced MH resulted in reduction of Ca-sequestration activity of muscle homogenates from 5.95 +/- 2.4 to 3.11 +/- 0.67 nM/s at 300 nM Ca and 38.7 +/- 10.5 to 16.3 +/- 8.0 nM/s at 1500 nM Ca, respectively (all p less than 0.01). The isolated SR Ca-ATPase activity correlated with Ca-sequestration activity of myocardial homogenates (r = 0.76; p less than 0.005). Different models were used to study the relationship of Ca-transport activity with relaxation function, degree of acidosis, and ionized Ca concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcium; Cardiac Pacing, Artificial; Coronary Disease; Dogs; Echocardiography; Electric Stimulation; Glycogen; Heart; Hemodynamics; Hydrogen-Ion Concentration; Lactates; Lactic Acid; Male; Malignant Hyperthermia; Muscle Contraction; Muscle Relaxation; Muscles; Myocardial Contraction; Myocardium; Sarcoplasmic Reticulum

The purpose of this study was to compare the degree of ischemic and hypoxic injury in normal versus hypertrophied rat hearts to investigate basic mechanisms responsible for irreversible myocardial ischemic injury. Hearts from rats with bands placed on the aortic arch at 23 days of age (BAND) and sham-operated rats (SHAM, 8 weeks postoperative) were isolated, perfused with Krebs buffer, and had a left ventricular balloon to measure developed pressure. Hearts were made globally ischemic until they developed peak ischemic contracture and were reperfused for 30 minutes. Additional hearts were perfused for 15 minutes with glucose-free hypoxic buffer followed by 20 minutes of oxygenated perfusion. There was an 87% increase in heart weight of BAND compared with SHAM (p less than 0.01). During ischemia, lactate levels increased faster in BAND compared with SHAM, ischemic contracture occurred earlier in BAND than in SHAM despite no difference in ATP levels, and postischemic recovery of left ventricular pressure was less in BAND (26.8 +/- 5.6% of control left ventricular pressure, mean +/- SEM) compared with SHAM (40 +/- 4.6%, p less than 0.05). During hypoxic perfusion, lactate release was greater in BAND than in SHAM (48.8 +/- 1.2 versus 26.6 +/- 0.97 mumols/g, p less than 0.01), and with reoxygenation, lactate dehydrogenase release was less in BAND than in SHAM (13.2 +/- 0.7 versus 19.5 +/- 0.2 IU/g, p less than 0.01). After hypoxia and reoxygenation, left ventricular pressure recovery was greater in BAND than in SHAM (93 +/- 8.4% versus 66 +/- 5.3%, p less than 0.01). Thus, this study suggests that hypertrophied hearts have a greater potential for glycolytic metabolism, resulting in an increased rate of by-product accumulation during ischemia, which may be responsible for the increased susceptibility of hypertrophied hearts to ischemic injury.

Topics: Adenosine Triphosphate; Animals; Aorta; Cardiomegaly; Constriction; Coronary Disease; Glycogen; Heart Ventricles; Hypoxia; Lactates; Lactic Acid; Male; Microscopy, Electron; Myocardial Contraction; Myocardium; Phosphocreatine; Pressure; Rats; Rats, Inbred Strains

The effect of different training regimes (three programmes of both swimming and running exercise) on the heart hypertrophy index and some biochemical indices was evaluated and compared individually with the sensitivity of the corresponding heart to ischaemia in order to elucidate the significance of training intensity and observed changes in the development of heart ischaemic injury. The sensitivity of the heart to ischaemia, evaluated by the rate of development of ischaemic contracture 48 h after completing the exercise programme, increased in parallel with an increase in the heart hypertrophy index. Experiments with different swimming programmes showed that the extent of cardiac hypertrophy increased together with an increase in the duration of everyday swimming bouts. Hypertrophied hearts from trained rats were characterized by greater mobilization of glycogen and increased incorporation of 32P into ATP when investigated 10 min after isoprenaline administration. During total ischaemia the development of ischaemic contracture was accelerated in catecholamine-stimulated trained hearts due to more rapid hydrolysis of ATP compared with that in the hearts from sedentary animals. It is suggested that the observed difference between hearts from sedentary and trained animals is, at least partially, connected with the higher sensitivity of myofibrils to Ca2+ in trained hearts.

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Cardiomegaly; Coronary Disease; Glycogen; Heart; Isoproterenol; Male; Myocardial Contraction; Myocardium; Physical Conditioning, Animal; Rats; Rats, Inbred Strains; Running; Swimming

Abdominal aorta constriction was performed in 10-week-old Lewis rats (Aoband). Ten weeks later the hearts were isolated and attached to a non-recirculating perfusion apparatus. The hearts could eject against a diastolic aortic pressure of either 60 or 100 mmHg. The functional recovery was compared with that of hearts of sham-operated (Sham) rats. After 45 min of global ischemia, Sham hearts regained cardiac output up to 75% and 70% of the pre-ischemic levels at 60 and 100 mmHg, respectively. At 60 mmHg Aoband hearts showed a minor recovery of ejection function. However, at 100 mmHg the recovery of Aoband hearts was completely comparable with that of Sham hearts. At 60 mmHg but not at 100 mmHg, the pre-ischemic and post-ischemic coronary flow was lower in Aoband than in Sham hearts (P less than or equal to 0.05). During the initial reperfusion phase Sham hearts, perfused at 60 mmHg, released more degradation products of adenine nucleotides and lactate dehydrogenase (LDH) than Aoband hearts (P less than or equal to 0.05), while the Aoband hearts lost more degradation products and LDH than the Sham hearts later during the reperfusion phase (P less than or equal to 0.05). In the groups perfused at 60 mmHg, higher tissue levels of ATP were found in Sham than in Aoband hearts at the end of the reperfusion period (P less than or equal to 0.05). However, at 100 mmHg comparable levels were found in the Sham and Aoband hearts. It is concluded that the height of the coronary perfusion pressure is of critical importance for the post-ischemic functional recovery of the compensated hypertrophied heart. At sufficiently high perfusion pressure levels, the functional and biochemical recovery of the hypertrophied heart is at least as good as in the non-hypertrophied heart. However, in the hypertrophied heart a coronary perfusion pressure which is too low leads to relative underperfusion during the initial reperfusion period which is associated with severely depressed cardiac performance and delayed wash-out of metabolites and intracellular enzymes.

Topics: Adenine Nucleotides; Animals; Cardiomegaly; Coronary Circulation; Coronary Disease; Creatine Kinase; Glycogen; Hemodynamics; L-Lactate Dehydrogenase; Male; Myocardium; Rats; Rats, Inbred Lew

The effects of elevated glucose on cardiac function during hypoxia were investigated in isolated arterially perfused rabbit interventricular septa. Rest tension, developed tension, intracellular potential, 42K+ efflux, lactate production, exogenous glucose utilization, and tissue high-energy phosphate levels were measured during a 50-min period of hypoxia with 4, 5, or 50 mM glucose present (isosmotically balanced with sucrose) and during reoxygenation for 60 min with perfusate containing 5 mM glucose/45 mM sucrose. At physiologic (4 or 5 mM) and supraphysiologic glucose (50 mM), lactate production and high-energy phosphate levels during hypoxia were equally well maintained, yet cardiac dysfunction was markedly attenuated by 50 mM glucose. Despite identical rates of total glycolytic flux, exogenous glucose utilization was enhanced by 50 mM glucose so that tissue glycogen levels remained normal during hypoxia, whereas glycogen became depleted with 4 or 5 mM glucose present during hypoxia. Most of the beneficial effects of 50 mM glucose occurred during the first 25 min of hypoxia. Prior glycogen depletion had no deleterious effects during hypoxia with 50 mM glucose present, but exacerbated cardiac dysfunction during hypoxia with 5 mM glucose present. These findings indicate that enhanced utilization of exogenous glucose improved cardiac function during hypoxia without increasing total glycolytic flux or tissue high-energy phosphate levels, suggesting a novel cardioprotective mechanism.

Topics: Animals; Coronary Disease; Cyclic AMP; Energy Metabolism; Glucose; Glycogen; Glycolysis; Heart; Hypoxia; Insulin; Potassium; Rabbits

The contribution of poor metabolic control to myocardial ischemic failure was determined in isolated working hearts from insulin-dependent BB Wistar rats. Removal of insulin treatment 24 h prior to study (uncontrolled diabetic rats) resulted in significant increases in serum glucose, serum fatty acids, and myocardial triglyceride, compared with animals in which insulin treatment was not withheld (insulin-treated diabetic rats). Isolated working hearts obtained from these two groups were subjected to a 40% reduction in coronary flow in the presence of a maintained metabolic demand (hearts were paced at 200 beats/min and perfused at an 80 mmHg (1 mmHg = 133.3 Pa) left aortic afterload, 11.5 mmHg left atrial preload). Within 15 min of ischemia, a significant deterioration of mechanical function occurred in the uncontrolled diabetic rats, whereas function was maintained in the insulin-treated diabetic rats. Oxygen consumption by the two groups of hearts was similar prior to the onset of ischemia and decreased during ischemia in parallel with the work performed by the hearts. This suggests that the accelerated failure rate in uncontrolled diabetic rat hearts is unlikely a result of an increased oxygen requirement. These data are a direct demonstration that acute changes in metabolic control of the diabetic can contribute to the severity of myocardial ischemic injury.

Topics: Animals; Blood Glucose; Coronary Disease; Diabetes Mellitus, Experimental; Fatty Acids; Female; Glycogen; Heart; Insulin; Male; Myocardium; Oxygen Consumption; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Triglycerides

This study compares the metabolism and functional responses of adult and immature hearts to a standard ischemic insult. Ten adult dogs (25 to 27 kg) and 10 puppies (6 to 10 weeks old) underwent 45 minutes of aortic clamping on bypass. Preoperative and postoperative ventricular performance (Starling curves), biochemical factors, and water content were measured. Global ischemia in adults produced a 30% mortality rate (3/10) and low output syndrome in survivors (33% recovery of stroke work index). Conversely, all puppies survived and stroke work index returned to 85% of control, with less edema developing (0.4% versus 2% water gain, p less than 0.05). Puppies expended comparable glycogen stores but used more glutamate (15.4 versus 8.6 mumol/gm dry weight), produced more alanine (18.9 versus 6.4 mumol, p less than 0.05), succinate (19 versus 8.2 mumol, p less than 0.05), and malate (2.6 versus 0.15 mumol, p less than 0.05) during ischemia, and recovered better postischemic aerobic metabolism (410 versus 255 nmol tissue pyruvate, p less than 0.05). We conclude that tolerance of immature hearts to ischemia is related to amino acid utilization by transamination and increased substrate level phosphorylation, as occurring in diving mammals, suggesting retention of intrautero adaptive mechanisms.

Topics: Adenosine Triphosphate; Aging; Amino Acids; Animals; Aorta; Body Water; Citric Acid Cycle; Constriction; Coronary Circulation; Coronary Disease; Dogs; Glycogen; Heart; Myocardium; Phosphocreatine; Ventricular Fibrillation; Ventricular Function, Left

This study tests the importance of amino acid transamination in determining the tolerance of immature hearts to ischemic damage. Amino acid transamination was inhibited metabolically by pretreatment with aminooxyacetic acid. The aminooxyacetic acid dose and duration were determined by incubating in vitro tissue homogenate and showing that an 8 mmol/L AOA dose for 5 minutes blocked 90% of alanine aminotransferase and aspartate aminotransferase activity. Control studies in nonischemic hearts showed that coronary perfusion with aminooxyacetic acid for 5 minutes did not impair myocardial performance. In contrast, pretreatment of immature puppies with aminooxyacetic acid severely impaired recovery after 45 minutes of normothermic global ischemia (30% versus 85% recovery in untreated hearts, p less than 0.05). Biochemical analyses of hearts undergoing ischemia showed aminooxyacetic acid to limit lactate production, impair glutamate utilization, prevent alanine production, and limit succinate accumulation (p less than 0.05). These data suggest that amino acid transamination is an important adaptive process in the immature heart that improves its resistance to ischemic damage.

Topics: Adenosine Triphosphate; Aging; Amino Acids; Aminooxyacetic Acid; Animals; Aorta; Body Water; Constriction; Coronary Circulation; Coronary Disease; Dogs; Glycogen; Heart; Lactates; Lactic Acid; Myocardium; Phosphocreatine; Ventricular Function, Left

This study analyzes the importance of the source and rate of ATP production (glucose flux, glycogenolysis, and oxidative phosphorylation) in the prevention of ischemic contracture in isolated rat hearts. Ischemic contracture was initiated at about 10 minutes by buffer perfusion with nonglycolytic substrates whereas the addition of 11 mM glucose prevented contracture for 2 hours. Tissue values of ATP, phosphocreatine, and lactate could be dissociated from onset of ischemic contracture. In hearts perfused with acetate or free fatty acid, with 11 mM glucose, glycolytic ATP production was 2.3-2.8 mumol/g fresh wt/min; as initial rates of glycogenolysis fell, glycolysis was maintained by a steady increase of glucose flux to values in excess of 2 mumol ATP/g fresh wt/min. Decreasing the glucose flux by lowering the perfusate glucose or by the addition of 2-deoxyglucose precipitated ischemic contracture. When oxidative phosphorylation was further reduced by hypoxia, glucose still prevented ischemic contracture; however, when oxidative phosphorylation dropped to near zero (near-anoxic) rates, glycolysis was inhibited, and glucose could only delay ischemic contracture to about 45 minutes. Combined ATP production rates could be dissociated from contracture. The metabolic parameter that correlated best with prevention or delay of ischemic contracture was the rate of glycolytic flux from glucose, which in this model of global low-flow ischemia had to accelerate to provide a rate of ATP production from glucose in excess of 2 mumol/g fresh wt/min within 30 minutes of the start of ischemia to prevent ischemic contracture.

Topics: Acetates; Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Fatty Acids, Nonesterified; Glucose; Glycogen; Heart; Lactates; Lactic Acid; Male; Myocardial Contraction; Phosphocreatine; Rats; Rats, Inbred Strains; Time Factors

We explored the effects of sustained low-flow ischemia on function and metabolism in isolated neonatal hearts. The hearts were extracted from 21 piglets (1-12 days old) and set up as modified Langendorff preparations beating isometrically. They were perfused with red blood cell-enhanced buffer at controlled rates of coronary flow. Mechanical measurements, O2 usage, and substrate oxidation were determined simultaneously at 30-minute intervals for 2 hours. In control hearts, coronary flow was maintained at 1.8 ml/min/g. There was no significant change in mechanical function, diastolic compliance, or O2 or substrate metabolism after 2 hours. In the ischemia group, coronary flow was reduced to 0.2 ml/min/g and sustained for 2 hours. With the onset of ischemia, mechanical function promptly fell to 20% of control. Although O2 delivery was reduced to 11%, O2 extraction doubled so that myocardial O2 consumption was 22% of control, matching mechanical function. Glucose oxidation fell from 37 to 12 nmol/min/g, and lactate release appeared. These measures and ventricular compliance remained constant for the full 2 hours. Concentrations of glycogen and creatine phosphate did not differ from the control group; ATP was 76% of controls. These studies indicate that when myocardial O2 supply is limited, mechanical function rapidly diminishes, largely preserving critical energy stores and preventing irreversible myocellular injury. Although the signal remains to be determined, the strategy is similar to that employed by hibernating species to survive extended periods of O2 deprivation.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Biological Availability; Coronary Circulation; Coronary Disease; Diastole; Glycogen; Heart; Hibernation; In Vitro Techniques; Myocardium; Oxidation-Reduction; Oxygen; Oxygen Consumption; Perfusion; Phosphocreatine; Swine

We have shown previously that preconditioning myocardium with four 5-minute episodes of ischemia and reperfusion dramatically limited the size of infarcts caused by a subsequent 40-minute episode of sustained ischemia. The current study was undertaken to assess whether the same preconditioning protocol slowed the loss of high energy phosphates, limited catabolite accumulation, and/or delayed ultrastructural damage during a sustained ischemic episode. Myocardial metabolites and ultrastructure in the severely ischemic subendocardial regions were compared between control and preconditioned canine hearts. Hearts (four to 10 per group) were excised after 0, 5, 10, 20, or 40 minutes of sustained ischemia. All groups had comparable collateral blood flow. Preconditioned hearts developed ultrastructural injury more slowly than controls; evidence of irreversible injury was observed after 20 minutes in controls but not until 40 minutes in preconditioned hearts. Furthermore, after 40 minutes of ischemia, irreversible injury was homogeneous in controls but only focal in preconditioned myocardium. Preconditioning reduced starting levels of ATP by 29%. Nevertheless, it also slowed the rate of ATP depletion during the episode of sustained ischemia, so that after 10 minutes of ischemia, preconditioned hearts had more ATP than controls. However, after 40 minutes, ATP contents were not significantly different between groups. Preservation of ATP resulted from reduced ATP utilization and was not due to increased ATP production. Accumulation of purine nucleosides and bases (products of adenine nucleotide degradation) was limited in preconditioned myocardium. Accumulation of glucose-1-phosphate, glucose-6-phosphate, and lactate also was reduced markedly by preconditioning, due to reduced rates of glycogen breakdown and and anaerobic glycolysis. We propose that preconditioning reduces myocardial energy demand during ischemia, which results in a reduced rate of high energy phosphate utilization and a reduced rate of anaerobic glycolysis. Either preservation of ATP or reduction of the cellular load of catabolites may be responsible for delaying ischemic cell death.

Topics: Adenine Nucleotides; Animals; Collateral Circulation; Coronary Disease; Dogs; Energy Metabolism; Female; Glycogen; Glycolysis; Male; Myocardial Reperfusion; Myocardium; Phosphates; Time Factors

Propranolol is a well-known powerful betareceptor-blocking agent. Its quaternary dimethyl derivative, designated as pranolium was firstly prepared by Lucchesi. Compared to propranolol it possesses no betareceptor-blocking activity and no local anaesthetic properties but shows the same antiarrhythmic action as the starting material. The synthesis of pranolium and its optical isomers starting from the corresponding propranolol derivatives is described. Their pharmacological activities have been tested. No significant differences regarding the pharmacological action could be observed.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Chemical Phenomena; Chemistry; Coronary Disease; Female; Glycogen; Guinea Pigs; Heart; In Vitro Techniques; Isomerism; Isoproterenol; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Propranolol; Rats; Rats, Inbred Strains; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet

The ability to resist transient ischemia was studied in isolated hearts of 18 months old spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Both types of hearts showed optimal performance during the preischemic period when perfused at a diastolic perfusion pressure of 8.0 (WKY) and 13.3 (SHR) kPa. Hemodynamic recovery of WKY hearts during reperfusion at 8.0 kPa, following 45 min global ischemia, was satisfactory. coronary perfusion completely normalized, contractility (dPlv/dtmax) was slightly depressed and cardiac output returned, on the average, to 40% of the preischemic values. In contrast, hemodynamic function of SHR hearts reperfused at 13.3 kPa was greatly depressed, as evidenced by almost complete abolition of cardiac output, severe reduction of dPlv/dtmax and persistent underperfusion of the endocardial layers. In addition, the postischemic release of lactate dehydrogenase was retarded and enhanced. The release patterns of degradation products of adenine nucleotides showed a shift to the endstage products xanthine and uric acid. The enhanced vulnerability of the hypertrophied heart to ischemia was even more expressed when the SHR hearts were reperfused at 8.0 kPa. Postischemic function was characterized by electrical instability, loss of contractility and cardiac output, and noreflow in the endocardial layers. Persistent accumulation of lactate and degradation products of adenine nucleotides in the postischemic hearts are in line with the lack of reperfusion. The present results indicate that a detailed mechanistic explanation for the reduced ability to withstand ischemia of SHR cannot be based on differences in ATP content or an altered anaerobic glycolitic activity prior and during ischemia. It is suggested that a defect on the circulatory level, probably caused by enhanced reactivity of the coronary vessels towards ischemia-elicited factors, is responsible for the higher vulnerability of hypertrophied heart to an ischemia insult.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiac Output; Cardiomegaly; Coronary Circulation; Coronary Disease; Glycogen; L-Lactate Dehydrogenase; Myocardial Contraction; Myocardial Reperfusion; Phosphates; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

We have investigated the role of endogenous catecholamines in myocardial carbohydrate metabolism in isolated, perfused rat hearts after left coronary artery occlusion for 30 min. A significant decrease in ATP and glycogen, and an increase in glucose-6-phosphate (G-6-P) content in the ischaemic myocardium was obtained. After depletion of the cardiac noradrenaline stores by reserpine or guanethidine pretreatment the increase in the G-6-P levels was very markedly enhanced, and the myocardial glycogen content of non-ischaemic control hearts was significantly increased by reserpine. However, the amount of glycogen broken down during the ischaemia in pretreated animals was similar to that in the ischaemic myocardium from control animals, and the decrease in the myocardial ATP was not altered by reserpine or guanethidine. Thus the well known release of noradrenaline during myocardial ischaemia is not an essential prerequisite for the activation of the ischaemic breakdown of glycogen. Rather, it is of importance for later steps in anaerobic carbohydrate metabolism, probably for the activation of phosphofructokinase, as suggested by the large ischaemic accumulation of G-6-P in noradrenaline depleted hearts.

Topics: Adenosine Triphosphate; Animals; Carbohydrate Metabolism; Coronary Disease; Energy Metabolism; Glucose-6-Phosphate; Glucosephosphates; Glycogen; Guanethidine; Male; Myocardium; Norepinephrine; Phosphofructokinase-1; Rats; Rats, Inbred Strains; Reserpine

The effect of flunarizine, a calcium entry-blocker, on the ischemic myocardial metabolism of the open-chest dog heart was examined and compared to that of diltiazem. During ischemia, initiated by ligating the left anterior descending coronary artery, the metabolism of the myocardium switched from aerobic to anaerobic; the levels of glycogen, fructose-1,6-diphosphate (FDP), adenosinetriphosphate and creatinephosphate decreased, and the levels of glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), lactate, adenosine diphosphate and adenosine monophosphate increased during 3 min of ischemia. The calculated energy charge potential decreased, and the [( G6P] + [F6P]/[FDP] ratio and the lactate/pyruvate ratio were increased by ischemia. Flunarizine (0.3 or 1 mg/kg) or diltiazem (0.1 mg/kg) was injected i.v. 5 min before the start of ischemia. Pretreatment with either flunarizine or diltiazem reduced the decrease in the energy charge potential and the increase in the [( G6P] + [F6P]/[FDP] ratio during ischemia. Flunarizine (1 mg/kg) and diltiazem (0.1 mg/kg) reduced the accumulation of lactate due to ischemia, leading to a decrease in the lactate/pyruvate ratio. Flunarizine and diltiazem may lessen the influence of ischemia on the myocardial tissue.

Topics: Adenine Nucleotides; Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Diltiazem; Dogs; Female; Flunarizine; Fructose; Glucose; Glucosephosphates; Glycogen; Heart Rate; Male; Myocardium; Phosphocreatine

We have previously studied the relation between long-chain fatty acid and pyruvate metabolism in reperfused myocardium and noted a rapid return of fatty acid oxidation to at least preischemic values accompanied by a marked decrease in pyruvate oxidation. The purpose of the present report is to further characterize carbohydrate metabolism during reflow by describing rates of glucose oxidation using [6-14C]glucose. Oxidative performance was determined with and without preserved fatty acid utilization; the latter condition was effected by oxfenicine, which inhibits palmitoylcarnitine transferase I. In the main protocol, two groups of working swine hearts (n = 18) were perfused aerobically for 30 minutes, rendered regionally ischemic (-60 delta % in anterior descending coronary flow) for 45 minutes, and reperfused at control flows for a final 50 minutes of perfusion. An emulsion of Intralipid with heparin was administered systemically throughout the studies to augment serum fatty acids (average fatty acid values, 1.05 +/- 0.05 mumol/ml for both groups). Serum glucose was monitored and maintained at or about 100 mg/dl with additional infusions of glucose as needed. Oxfenicine (33 mg/kg) was administered systemically by bolus injection at time 0 and 60 minutes of perfusion in nine animals. Decreased mechanical performance, that is, stunning, during reflow was evident in both groups (-50 delta % in regional systolic shortening, p less than or equal to 0.05 compared with aerobic values in the control group, and -32 delta %, p less than or equal to 0.05 compared with aerobic values in treated hearts).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Coronary Disease; Fatty Acids; Glucose; Glycine; Glycogen; Heart; Myocardial Contraction; Myocardial Reperfusion; Myocardium; Oxidation-Reduction; Oxygen Consumption; Swine

The use of NMR spectroscopy in the non-invasive assessment of myocardial metabolism has greatly increased over the last decade. The initial experiments were performed on isolated perfused heart preparations, but these have since been extended to whole animal and clinical studies. The use of the phosphorus-31 nucleus allows assessment of energetic metabolism and intramyocardial pH. Carbon-13 spectroscopy based on the use of substrates selectively enriched with the C-13 isotope enables the study of a specific chosen metabolic pathway and provides qualitative and quantitative information about the metabolic changes. Research is now preceding in two directions: firstly, the study of fundamental problems such as the mechanisms of ischaemia, the consequences of intracellular acidosis and the precise role of ATP and phosphocreatine: secondly, very active clinical and pharmacological research in using NMR in animal models of cardiac pathology. Finally, recent technological progress suggests that NMR spectroscopy will soon be used for direct studies of the human heart.

Topics: Carbon Radioisotopes; Cardioplegic Solutions; Citric Acid Cycle; Coronary Disease; Energy Metabolism; Glycogen; Heart Arrest, Induced; Humans; Magnetic Resonance Spectroscopy; Myocardium; Phosphorus Radioisotopes

The effect of cibenzoline, an antiarrhythmic drug, on myocardial ischemia was studied in the anesthetized open-chest dog. Ischemia was induced by completely ligating or partially occluding the left anterior descending coronary artery. The levels of ATP and creatine-phosphate decreased, and the ADP and AMP levels increased during ischemia. The level of glycogen was also decreased, and that of lactate was increased by ischemia, resulting in myocardial acidosis. Pretreatment with either 2 mg/kg or 8 mg/kg of cibenzoline prevented the decrease in ATP level and the increase in lactate level. These results suggest that cibenzoline reduces the influence of ischemia on the myocardium.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Anti-Arrhythmia Agents; Coronary Disease; Dogs; Female; Glycogen; Hydrogen-Ion Concentration; Imidazoles; Male; Myocardium; Phosphocreatine

The effect of depletion of energy stores of rat hearts on their resistance to a total of 25 min ischemia was investigated by using a 31P-NMR method. Three experimental groups were compared: (1) pyruvate-perfused hearts depleted of adenine nucleotides (35% of normal) by 2-deoxyglucose (DG) treatment and containing deoxyglucose-6-phosphate (c. 40 mumol/g dry wt); (2) hearts partially depleted of glycogen stores (40 to 50% of initial) by long-term (2h) perfusion with pyruvate; (3) glucose perfused (11 nM) hearts with normal ATP and glycogen contents. By the end of ischemia the intracellular pH was decreased by 0.33, 0.90 and 1.40 units, respectively. Time to peak of ischemic contracture increased in this series from 3 to 18 and 24 min, respectively. At the peak of ischemic contracture ATP content was c. 30 to 40% (6 to 8 mumol/g dry wt) of normal value in all three groups. Reperfusion of hearts resulted in development of significant reperfusion contracture in glucose-perfused hearts and minor contracture in other series. Recovery of high energy phosphates and cardiac work index in DG-treated, glycogen-depleted and glucose-perfused hearts were: for phosphocreatine (PCr), 72, 102 and 83%; for ATP, 29, 47 and 56% and for cardiac work, 66, 78 and 24%, respectively. Recovery of cardiac work did not correlate linearly with tissue ATP. These data demonstrate that post-ischemic recovery of the contractile function of isovolumic heart may be dissociated from pre-ischemic myocardial ATP and glycogen contents. This dissociation can be explained by the two major factors: (1) the contribution of ischemic acidosis and catabolites accumulation to the cell damage and (2) by ATP compartmentation.

Topics: Adenosine Triphosphate; Animals; Coronary Disease; Deoxy Sugars; Deoxyglucose; Glucose; Glucose-6-Phosphate; Glucosephosphates; Glycogen; Magnetic Resonance Spectroscopy; Male; Myocardial Contraction; Myocardium; Perfusion; Phosphocreatine; Pyruvates; Rats; Rats, Inbred Strains; Time Factors

The effects of 11.7 mM glucose, insulin, and potassium (GIK) on metabolism during ischemia were investigated in the perfused guinea pig heart using magnetic resonance spectroscopy. Intracellular metabolites, primarily glycogen and glutamate, were labeled with 13C by addition of [1-13C]glucose to the perfusate during a normoxic, preischemic period. 13C and 31P NMR spectroscopy was used to observe the metabolism of 13C-labeled metabolites simultaneously with high-energy phosphorus metabolites and pH. The extent of acidosis and the rate and amount of labeled lactate accumulation during ischemia were the same in control (3 mM glucose + insulin) and GIK-treated hearts. In contrast, the rate of labeled glycogen mobilization during ischemia in GIK-treated hearts was one third the rate observed in control hearts. These observations suggest that GIK decreased the rate of glycogenolysis during ischemia without affecting the rate of glycolysis. We propose that glucose contributed as a glycolytic substrate to a greater extent during ischemia in GIK-treated hearts than in hearts perfused with 3 mM glucose and insulin. The glycogen-sparing effect of GIK demonstrated in these studies could delay the onset of ischemic damage in a clinical setting by prolonging the availability of glycolytic substrate necessary for production of high-energy phosphate.

Topics: Aerobiosis; Animals; Carbon Isotopes; Coronary Circulation; Coronary Disease; Glucose; Glycogen; Glycolysis; Hydrogen-Ion Concentration; In Vitro Techniques; Insulin; Lactates; Lactic Acid; Magnetic Resonance Spectroscopy; Perfusion; Phosphorus; Potassium

We tested the hypothesis that depletion of glycogen prior to myocardial ischemia diminishes lactate buildup and improves functional recovery on reperfusion in the isolated rabbit heart. Cardiac glycogen was reduced either by substituting N2 for O2 in the perfusate or by perfusion with substrate-free solution, before the onset of ischemia. Hearts were subjected to either 30 minutes of normothermic (37 degrees C) or 60 minutes of hypothermic (4 degrees C) ischemia followed by 30 minutes of reperfusion with oxygenated Krebs-Henseleit buffer. Function was assessed by measuring peak left ventricular pressure at end-diastolic pressures ranging from 0 to 20 mm Hg. N2 perfusion for 15 minutes lowered myocardial glycogen by 60% and decreased ATP and phosphocreatine (p less than 0.001). Glycogen depletion did not decrease lactate accumulation during ischemia, but it impaired recovery with reperfusion (-46%, p less than 0.05). N2 perfusion for 5 minutes also reduced glycogen by 60%, but energy-rich phosphates were not reduced and functional recovery was still impaired (-40%, p less than 0.05). Perfusion with substrate-free medium diminished glycogen by 33% (p less than 0.05). Although lactate accumulation was significantly reduced (-45%, p less than 0.05), recovery following reperfusion was not improved. The results suggest that preservation of glycogen stores, but not the prevention of lactate buildup during ischemia, is beneficial for the recovery of function with reperfusion.

Topics: Animals; Coronary Disease; Glycogen; Heart; Heart Arrest; Heart Ventricles; Hypothermia, Induced; Male; Perfusion; Rabbits

The phosphorylase specific activity was lowered in total ischaemia in all examined parts of the myocardium and the conduction system of the heart. Sixty-minute ischaemia had a considerable effect on glycogen degradation in right bundle branch and in the working myocardium, however, its glycogenolytic effect on the AV-node and penetrating bundle of His was insignificant. Phosphorylase "a" evaluated as a percentage of the total phosphorylase activity decreased in the working myocardium and increased in the AV-node during ischaemia. The data obtained support the hypothesis according to which conductive tissue is more resistant to ischaemia than the working myocardium. The results serve evidence that the right bundle branch is more susceptible to metabolic damage caused by ischaemia than the AV-node and penetrating bundle of His.

Topics: Animals; Cattle; Coronary Disease; Female; Glycogen; Heart Conduction System; Male; Myocardium; Phosphorylase a; Phosphorylases

The myocardial energy requirements of the noradrenergic nerve terminal to retain its transmitter during acute myocardial ischemia were examined in the isolated perfused rat heart. In hearts perfused with glucose as exogenous substrate no increased release of noradrenaline (NA) could be detected during ischemia. In contrast, an increased efflux of NA was seen from glucose-perfused hearts when the glycolytic pathway was inhibited with 0.5 mM iodacetic acid. Accordingly, induction of ischemia in glycogen-depleted hearts (in the absence of exogenous substrate) or in hearts perfused with either lactate, pyruvate or acetate was also associated with a marked efflux of NA. However, no efflux was detected from glycogen-depleted hearts when glucose was present during the ischemic period. Uncoupling of oxidative metabolism with 0.1 mM 2.4-dinitrophenol did not cause any increased loss of NA during ischemia. In conclusion, these results demonstrate that severe restriction in coronary flow is accompanied by increased release of myocardial NA. Furthermore, maintainance of anaerobic glycolysis is of crucial importance for retention of the noradrenergic transmitter during ischemic conditions.

Topics: 2,4-Dinitrophenol; Anaerobiosis; Animals; Coronary Disease; Dinitrophenols; Glycogen; Glycolysis; Iodoacetates; Iodoacetic Acid; Male; Myocardium; Norepinephrine; Oxidative Phosphorylation; Perfusion; Rats; Rats, Inbred Strains

The purpose of this investigation was to compare the biochemical responses of normal and streptozotocin (STZ) diabetic rat hearts to myocardial ischemia. As expected, left ventricular peak systolic pressure (LVPSP) declined with the onset of ischemia. The time required to reach 75% (LVPSP75) and 50% (LVPSP50) of baseline LVPSP100 was significantly (p less than 0.05) more rapid in diabetic and iodoacetate-treated hearts when compared to control animals. Diabetic rats experienced a significant (p less than 0.05) reduction in myocardial glycogen levels with ischemia. Despite enhanced glycogenolysis in diabetic rat hearts, cardiac lactate failed to accumulate in significant amounts. Overall, myocardial ATP and CP levels declined, but the reduction appears not to be associated with the fall in LVPSP. The results confirm that ventricular pressure development decreases rapidly following iodoacetate treatment. Similar declines in function were observed in the diabetic heart suggesting that glycolytic pathway inhibition and/or diminished glycolytic flux is responsible for the reduction in left ventricular pressure during myocardial ischemia.

Topics: Animals; Blood Pressure; Coronary Disease; Diabetes Mellitus, Experimental; Glycogen; Heart Ventricles; Lactates; Male; Myocardium; Rats; Rats, Inbred Strains; Streptozocin

The effect of 30 min of myocardial ischemia on cardiac glycogenolysis and lactate accumulation was investigated in streptozotocin (STZ) diabetic and normal rats. In normal rats, ischemia caused a significant reduction in cardiac glycogen and a significant increase in cardiac lactate. STZ rats experienced a similar, but larger, reduction in cardiac glycogen with ischemia but did not accumulate significant quantities of lactic acid suggesting that diabetic rats have a reduced capacity for non-oxidative carbohydrate metabolism in myocardial ischemia.

Topics: Animals; Coronary Disease; Diabetes Mellitus, Experimental; Fasting; Glycogen; Lactates; Lactic Acid; Male; Myocardium; Rats; Rats, Inbred Strains; Swimming

The effects of the antianginal and antiarrhythmic drug amiodarone on mitochondrial function and high-energy phosphate content were assessed during normothermic ischaemic cardiac arrest and reperfusion in Langendorff-perfused rat heart. Total ischaemia for 30 min at 37 degrees C produced highly significant changes in mitochondrial oxidative phosphorylation and high-energy phosphate content. Pretreatment of the rats with one single dose of amiodarone (20 mg/kg i.v., 30 min before killing) markedly attenuated the deleterious effect of ischaemia on mitochondrial function and slightly reduced ATP depletion. In normally perfused hearts, amiodarone pretreatment did not modify any parameter of mitochondrial respiratory function nor did it influence high-energy phosphate or glycogen content. After reperfusion for 15 min, amiodarone-treated hearts showed improved recovery of mitochondrial oxidative phosphorylation and tissue high-energy phosphate content as compared to control hearts. Pretreatment of hearts with amiodarone did not reduce ischaemia-induced leakage of total adenylic nucleotides but highly significantly reduced lactate dehydrogenase release during reperfusion. These results indicate that amiodarone could exert substantial protection on the infarcting myocardium.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Amiodarone; Animals; Coronary Circulation; Coronary Disease; Glycogen; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Mitochondria, Heart; Myocardial Contraction; Perfusion; Rats; Rats, Inbred Strains

The development of ischemic contracture in rat was evaluated in relation to glycolytic production of ATP and Ca2+ homeostasis. When the rate of glycolysis was reduced by glycogen depletion (swimming at 33 degrees C for 2 h, administration of isoprenaline or heart perfusion with it), the rate of ischemic contracture development increased. Isoprenaline increased the development of contracture in a dose-dependent manner, and dexamethasone potentiated the effect of isoprenaline. The decrease in the intensity of ATP/P1 exchange, probably reflecting the intensity of glycolytic phosphorylation of ADP, which, in our conditions, arose from ATP hydrolyzed mostly by Ca2+-ATPase and Na, K-ATPase, correlated with the development of ischemic contracture. Experiments with the rapid equilibration of the extracellular compartment with Ca2+ in various concentrations in the presence or absence of verapamil suggest that the development of ischemic contracture depends on the rate of Ca2+ accumulation in myoplasm. This rate of Ca2+ accumulation correlates with the rate of glycogenolysis and glycolysis which seems to produce ATP for active transport of cations.

Topics: Adenosine Triphosphate; Animals; Calcium; Coronary Disease; Glycogen; Glycolysis; Homeostasis; Myocardium; Rats; Rats, Inbred Strains

Topics: Adult; Aged; Anthracenes; Blood Platelets; Colorimetry; Coronary Disease; Energy Metabolism; Glycogen; Glycolysis; Humans; Middle Aged

Topics: Animals; Coronary Circulation; Coronary Disease; Deoxyglucose; Glycogen; Rats; Rats, Inbred Strains

Myocardial exogenous substrate preference was studied under conditions of increased plasma lactate concentration before and after a severe (halving of tissue ATP concentration, sixfold increase in tissue lactate concentration) but reversible (less than 1% necrosis on reperfusion) global ischaemic stress produced by continuous hypothermic electromechanical arrest of the heart of four hours' duration by aortic cross clamping and multidose potassium cardioplegia. Fatty acid oxidation was studied using 1-14C-palmitate under steady state conditions and under similar isovolumic fixed pressure conditions with the heart at a constant rate using a left ventricular intracavitary balloon. Exogenous free fatty acid oxidation during the pre-ischaemic period with an increased lactate concentration (3.9-5.8 mmol . litre-1) was 0.62(0.21) mumol . min-1 X 100 g-1 (mean (SEM)). This represented a mean of 32% of the total carbon dioxide produced in contrast to a post-ischaemia free fatty oxidation rate of 2.67(0.87) mumol . min-1 X 100 g-1, in the presence of even further increased plasma lactate concentrations (8.47-11.17 mmol . litre-1), representing a mean of 82% of the total carbon dioxide output. These data suggest that the substrate preference of the myocardium, under conditions of increased plasma lactate concentration, shifts to greater oxidation of exogenous free fatty acids after ischaemic stress.

Topics: Adenosine Triphosphate; Animals; Coronary Disease; Disease Models, Animal; Dogs; Fatty Acids, Nonesterified; Glycogen; Heart; Lactates; Myocardial Contraction; Myocardium; Oxygen; Phosphocreatine

The effect of diltiazem on post-ischemic metabolic and functional recovery was investigated in regionally ischemic dog hearts. The duration of ischemia was 60 min, followed by 60 min of reperfusion. Diltiazem (bolus injection of 0.1 mg X kg-1 body weight prior to ischemia, followed by a continuous infusion of 0.1 mg X kg-1 X h-1) had no effect on residual coronary flow in the centre of the ischemic area, but blunted the reactive hyperemia response after restoration of flow. The drug partially prevented the depletion of ATP and glycogen in the severely underperfused subendocardial layers, i.e. when residual flow was below 0.1 ml X min-1 X g-1. Reduction of the content of these substances in the subepicardial layers was moderate and not influenced by diltiazem. Segment shortening in the subepicardial layers disappeared whereas segment lengthening was observed in the subendocardial layers during the ischemic period. Diltiazem did not prevent the loss of contractile function. Despite an initial restoration of contractile function within 10 min after reperfusion, no significant beneficial effect of diltiazem treatment on mechanical function of the reperfused area was present thereafter.

Topics: Adenosine Triphosphate; Animals; Benzazepines; Cardiac Output; Coronary Circulation; Coronary Disease; Diltiazem; Dogs; Female; Glycogen; Heart; Male; Myocardial Contraction; Myocardium; Phosphocreatine; Time Factors

Topics: Adult; Angina Pectoris; Cell Movement; Chemotaxis, Leukocyte; Chronic Disease; Coronary Disease; Glycogen; Humans; Leukocytes; Lipids; Middle Aged; Neutrophils; Physical Exertion

The left anterior descending coronary artery (LAD) of the dog was ligated completely for 1.5 min, and immediately after LAD ligation the heart was taken for determination of the glycogen phosphorylase and glycogen. Trimetazidine was injected intravenously 20 min before LAD ligation. LAD ligation increased the activity of glycogen phosphorylase and decreased the level of glycogen in both ischemic (LAD) and nonischemic (circumflex) areas. Trimetazidine at the dose of 0.3 or 1.0 mg/kg, being the dose that did not affect blood pressure and heart rate markedly, inhibited the ischemia-induced changes in glycogen phosphorylase and glycogen level. It is concluded that trimetazidine inhibits the ischemia-induced increase in the utilization of glycogen in the dog myocardium.

Topics: Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Female; Glycogen; Heart Rate; Ligation; Male; Myocardium; Phosphorylases; Piperazines; Trimetazidine

Myocardial metabolism in live guinea pigs was investigated by 13C and 31P nuclear magnetic resonance (NMR) at 20.18 and 32.5 MHz, respectively. 13C NMR studies allowed monitoring of myocardial glycogen synthesis during intravenous infusion of D-[1-13C]glucose and insulin. Anoxia resulted in degradation of the labeled glycogen within 6 min and appearance of 13C label in lactic acid. Infusion of sodium [2-13C]acetate resulted in incorporation of label into the C-4, C-2, and C-3 positions of glutamate, reflecting "scrambling" of the label expected from tricarboxylic-acid-cycle activity. 31P NMR spectra of heart in live guinea pigs were obtained continuously in 20.5-sec time blocks during 3 min of anoxia, during subsequent reoxygenation, and, in separate animals, during terminal anoxia. Reversible anoxia resulted in rapid degradation of phosphocreatine (t1/2 = 54.5 +/- 2.5 sec), which recovered fully during reoxygenation. Heart inorganic phosphate increased during anoxia and returned to basal levels after oxygen was restored. During 3 min of anoxia, no significant changes in ATP levels or pH were detected.

Topics: Adenosine Triphosphate; Animals; Carbon Isotopes; Coronary Disease; Energy Metabolism; Female; Glucose Solution, Hypertonic; Glutamates; Glutamic Acid; Glycogen; Guinea Pigs; Heart Arrest; Hydrogen-Ion Concentration; Insulin; Lactates; Lactic Acid; Magnetic Resonance Spectroscopy; Myocardium; Phosphates; Phosphocreatine; Phosphorus Isotopes

We assessed the histochemical, ultrastructural and cytochemical effects of reperfusion on ischemic myocardial cells during the early and late reperfusion phases in two groups of dogs. Group A were 8 dogs undergoing 1 hour occlusion of LAD, and Group B were 14 dogs undergoing 1 hour occlusion of LAD followed by 2 hour reperfusion period. The results of the histochemical study (PAS stain) demonstrated that in Group A, a patchy distribution of glycogen occurred primarily in the subepicardial region. Three-dimensional analysis of this distribution revealed peninsulas of glycogen running parallel with a vessel. The cells in Group B, mainly subepicardium, showed a moderate glycogen content which was more extensive than those in Group A. The ultrastructural changes were assessed after a 60-minute ischemia and subsequent recovery (after 5 minutes and 120 minutes of reflow) using transmural biopsy specimens. Each myocardial cell was graded from 0-4 according to the degree of ischemic injury and recovery. The degree of ischemic damage varied in intensity from slight to severe, in both the subepicardium and the subendocardium. Ca++-ATPase activity was examined cytochemically in myocardial cells of Group B. After 60-minute occlusion, the moderately ischemic cells (especially in the subepicardium) that were without amorphous dense bodies or marked sarcolemmal lifting-off made significantly greater ultrastructural recovery (p less than 0.05) with restoration of Ca++-ATPase activity on sarcoplasmic reticulum and mitochondria after 120 minutes of reflow. This occurred even though after 5 minutes of reflow the cell showed temporary deterioration such as contraction bands, vacuoles and severe destruction of some mitochondria.

Topics: Animals; Calcium-Transporting ATPases; Coronary Disease; Coronary Vessels; Cytoskeleton; Dogs; Female; Glycogen; Ligation; Male; Microscopy, Electron; Mitochondria, Heart; Myocardium; Perfusion; Sarcoplasmic Reticulum

The oral hypoglycemic agent tolbutamide has been found to protect the ischemic myocardium against irreversible mechanical failure. The possibility that this salutary effect of tolbutamide was related to its ability to alter energy metabolism was examined in ischemic rat hearts perfused with 5 mM glucose, 5mM acetate and 2.5 units/l insulin. In the presence of 0.6 mM tolbutamide, coronary flow and oxygen consumption were unaltered; however, glucose utilization was stimulated by 30%, glycogenolysis was enhanced by 23%, and the drop in ATP content was reduced by 17% after 30 min, of low-flow perfusion. This elevation in glycolytic flux occurred without a parallel rise in the production of inhibitory metabolites; lactate production was unaltered and tissue lactate/pyruvate ratio decreased. Pyruvate dehydrogenase flux measurements reveal that the mechanism by which tolbutamide increases glycolysis without increasing lactate production is by promoting the entry of pyruvate into the mitochondria. The basis for the observed stimulation of anaerobic metabolism and pyruvate oxidation and how this contributes to the increase in ATP content and benefits the ischemic heart is discussed.

Topics: Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Energy Metabolism; Glucose; Glycogen; Male; Myocardium; Pyruvates; Pyruvic Acid; Rats; Rats, Inbred Strains; Tolbutamide

Hearts of chicks fed the creatine analog, 1-carboxymethyl-2-iminoimidazolidine (cyclocreatine), accumulated 15 mumol/g wet wt of the synthetic phosphagen, cyclocreatine-3-P; had total creatine levels reduced from the normal 6 mumol/g to only 1.8 mumol/g; and had their glycogen levels tripled. During total ischemia in vitro these hearts utilized the cyclocreatine-P for synthesis of ATP, had greatly prolonged glycolysis, and exhibited a two- to fivefold delay in depletion of both ATP and the total adenylate pool, relative to controls. Accumulation from the diet of comparable levels of the closely related 1-carboxyethyl-2-imino-3-phosphonoimidazolidine (homocyclocreatine-P) by heart was accompanied by only slight lowering of total creatine to 4.2 mumol/g, and a tripling of glycogen levels. During ischemia these hearts exhibited prolonged glycolysis, but they did not utilize the very stable homocyclocreatine-P (200,000-fold less reactive than creatine-P) and thus formed less Pi; most significantly, there was no delay in depletion of ATP levels relative to controls. Feeding of creatine doubled total creatine levels in heart, but had no marked effect on ATP depletion during ischemia; in all dietary groups creatine-P pools had fallen to less than or equal to 1.2 mumol/g by first tissue sampling. Although adaptive responses were also involved, maximal conservation of ATP and total adenylate pools in heart during ischemia apparently required, in addition to adequate glycogen reserves, substantial levels of a kinetically competent phosphagen that is thermodynamically poised to continue to assist glycolysis in buffering decreases and oscillations in the [ATP]/[free ADP] ratio at the lower phosphorylation potentials and more acid pH characteristic of later stages of ischemia. Decreases and oscillations in the [ATP]/[free ADP] ratio cannot be buffered effectively late in ischemia by the creatine-P system for thermodynamic reasons, or by the homocyclocreatine-P system because of kinetic limitations.

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Chickens; Coronary Disease; Creatinine; Glycogen; Imidazolidines; In Vitro Techniques; Kinetics; Male; Myocardium; Phosphocreatine; Thermodynamics

An important question in energy metabolism of the reperfused, previously ischemic myocardium is whether the return of a normal tissue adenosine triphosphate (ATP) content is a prerequisite for normal rates of oxygen consumption (that is, ATP turnover) and cardiac function. To study this problem, isolated working rat hearts were perfused with bicarbonate saline solution containing glucose (10 mM) at near physiologic work load. After 20 minutes, hearts were made totally ischemic by clamping the aortic and atrial lines for 5, 10 or 20 minutes and then were reperfused for another 10 minutes. Heart rate, aortic pressure, cardiac output and myocardial oxygen consumption were measured continuously. Adenine nucleotides, phosphocreatine, glycogen and the products of glycolysis were determined in freeze-clamped tissue extracts. Functional recovery was assessed by return of aortic pressure and oxygen consumption to preischemic values. Time required for return of function after reperfusion was 90 seconds after 5 minutes and 124 seconds after 10 minutes of ischemia. No recovery was observed after 20 minutes of ischemia. Tissue ATP content decreased significantly at the end of 5 (-38%) and 10 (-56%) minutes of ischemia and did not increase significantly at return of aortic pressure and oxygen consumption to preischemic values. Glycogen stores decreased by more than 50% at the end of 10 minutes of ischemia and did not normalize on recovery. In contrast to ATP or glycogen, the phosphocreatine content decreased to even lower levels at the end of ischemia, but returned to levels higher than the control level after recovery from 5 to 10 minutes of ischemia in association with return of function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Coronary Disease; Energy Metabolism; Glycogen; Lactates; Male; Myocardium; Phosphocreatine; Rats

[14C]inosine in a range of concentrations of 20 microM to 1 mM was administered to the isolated perfused rat heart for 30 min. The incorporation of the nucleoside into myocardial adenine nucleotides increased for extracellular concentrations of the precursor up to 50 microM, reaching a plateau at 60 nmol . g-1 X 30 min-1 with concentrations ranging between 50 and 200 microM. The supply of 500 microM and 1 mM of inosine induced a further increase in cardiac adenine nucleotide synthesis to about 200 nmol . g-1 X 30 min-1. When supplied during low flow ischaemia (0.5 mL . min-1, 30 min.), 1 mM of inosine protected the heart against ATP degradation, while 100 microM of inosine was inefficacious. In the presence of 1 mM of inosine on reperfusion the adenine nucleotide content of the heart was similar to that observed in the absence of the nucleoside. The incorporation of [14C]inosine into adenine nucleotides was, in this last condition, below the value measured before ischaemia. Inosine administration was effective in protecting the heart against ischaemic breakdown of glycogen and favoured postischaemic restoration of glycogen stores.

Topics: Adenine Nucleotides; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Aerobiosis; Animals; Carbon Radioisotopes; Coronary Disease; Female; Glycogen; In Vitro Techniques; Inosine; Kinetics; Myocardium; Perfusion; Rats; Rats, Inbred Strains

Inadequate delivery of cardioplegic solution distal to coronary artery stenosis may result in increased injury during ischemic arrest. This study was performed to determine the effects of cardioplegic perfusion pressure on cardioplegia delivery and myocardial preservation in hearts with critical coronary artery stenosis. Twenty dogs underwent 90 minutes of cold potassium cardioplegic arrest with partial occlusion of the circumflex coronary artery. Group 1 received cardioplegia at 50 mm Hg pressure, Group 2 at 90 mm Hg pressure, and Group 3 at 130 mm Hg pressure. It was found that cooling rates were 5.4 degrees, 9.1 degrees, and 18.2 degrees C per minute in the nonischemic area (p = 0.004) and 2.0 degrees, 4.5 degrees, and 7.9 degrees C in the ischemic area (p = 0.008) in Groups 1, 2, and 3, respectively. Total of cardioplegic solution flows were 86, 188, and 262 ml per minute per 100 gm in Groups 1, 2, and 3, respectively (p = 0.001). However, flow did not differ significantly between groups in the ischemic area. Rate of rise of left ventricular (LV) pressure decreased significantly in Groups 1 and 2 but not in Group 3 (p = 0.002). Other measured variables did not differ significantly between groups, although LV function curves showed less deterioration in the high-pressure groups. It is concluded that higher cardioplegic perfusion pressure resulted in more rapid cooling in normal and ischemic areas and slightly better preservation of ventricular function as measured by some indexes. However, preservation was generally good for each of the pressures for up to 90 minutes of ischemia when the septum was consistently cooled to 10 degrees C.

Topics: Adenosine Triphosphate; Animals; Coronary Disease; Dogs; Glycogen; Heart; Heart Arrest, Induced; Microscopy, Electron; Mitochondria, Heart; Myocardium; Perfusion; Pressure

An ischaemia-like state in cultured heart cells has been obtained by markedly restricting the volume of extracellular medium combined with total deprivation of oxygen (anoxia) and glucose. Cellular injury, as reflected by the release of both cytoplasmic and lysosomal enzymes was significantly greater than during anoxia alone (oxygen deprivation with a larger extracellular volume). This is most likely due to inadequate washout of metabolites during "ischaemia" rather than reduced energy production since glycolytic flux as reflected by lactate production was similar in both experimental states. Glucose administration during either anoxia or "ischaemia" delayed enzyme release. We believe that cytoplasmic enzymes are released mainly during the reversible period of oxygen deprivation, while lysosomal enzyme release reflects the onset or irreversible injury, occurring at a time when ATP levels and glycogen stores are almost completely exhausted.

Topics: Animals; Cells, Cultured; Coronary Disease; Culture Media; Glucose; Glycogen; Hypoxia; L-Lactate Dehydrogenase; Lysosomes; Myocardium; Time Factors

Using the indirect immunofluorescence technique, we studied the distribution of myoglobin in normal and ischemic human myocardium obtained at autopsy and at surgery. Glycogen, diastase-PAS staining of the sarcoplasm, and IgG were also studied and compared with the structure of the lesions and the distribution of myoglobin. The surgical material we used was largely free of autolysis and was the most satisfactory. Prolonged fixation of tissues in formaldehyde solution or perfusion fixation of autopsy specimens both proved to be unsatisfactory as myoglobin was absent from the myocardium. This loss presumably represents diffusion of myoglobin due to autolysis and the method of fixation. Another group of autopsy specimens that was briefly fixed by immersion in formaldehyde solution prior to processing was more satisfactory. Although they showed some extracellular diffusion of myoglobin, the autolyzed normal areas could still be clearly differentiated from the autolyzed ischemic areas.

Topics: Amylases; Animals; Coronary Disease; Dogs; Eosinophilia; Fluorescent Antibody Technique; Glycogen; Heart; Humans; Immunoglobulin G; Myocardium; Myoglobin; Necrosis; Periodic Acid-Schiff Reaction

Shortening of the action potential duration and the attendant reduction of refractory period in regional myocardial ischaemia might set the stage for the genesis and re-entry of ectopic impulses. We investigated the mechanism by which neutral lactate shortens the action potential duration since lactate accumulates highest in regions where coronary flow is lowest after experimental coronary artery occlusion. In preliminary experiments (unpublished) when 10 mM of L(+)-Na lactate was substituted for glucose (10 mM), action potential duration shortened in the majority of guinea pig papillary muscles. In some of the muscles, the action potential duration lengthened. When the perfusate contained neither glucose nor lactate (i.e. substrate free) action potential duration shortened in the majority of experiments. As mechanism, we supposed that the relatively high contraction rate of the preparations (120/min) could exhaust glycogen stores thereby limiting glycolysis and shortening the action potential duration. Thus variable action potential duration during lactate or substrate-free superfusion, might be explained by a corresponding variability of pre-existing glycogen stores. Therefore, in the present study we attempted to reduce the demand on glycogen stores by decreasing the contraction rate to 30/min. In the latter preparation, when the diastolic (passive) tension was completely normal, lactate (10 mM) shortened the action potential duration by 30%, whereas the action potential duration was not altered during substrate free superfusion. We then explored the possibility that lactate shortened the action potential duration by inhibition of glycolysis. First, muscles were made to perform external work by increasing passive tension to the peak of the active length-tension curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Action Potentials; Animals; Coronary Disease; Deoxyglucose; Glucose; Glycogen; Glycolysis; Guinea Pigs; Lactates; Lactic Acid; Mannitol; Papillary Muscles

The effect of myocardial catecholamine depletion on cellular electrophysiology and arrhythmias was assessed in Langendorff perfused guinea pig hearts during ischaemia and reperfusion. Myocardial noradrenaline was reduced to 0.17 +/- 0.04 microgram X g-1 by intracardiac injection of 6-hydroxydopamine (450 mg X kg-1 in six doses over 20 days) compared with 1.5 +/- 0.2 microgram X g-1 in vehicle injected controls. Myocardial catecholamine depletion significantly reduced the incidence of ventricular tachycardia and fibrillation during 30 min of global ischaemia and subsequent reperfusion. Myocardial catecholamine depletion prolonged action potential duration and refractory period during control perfusion and blunted ischaemia induced reduction in action potential amplitude, Vmax, and duration, but accentuated the prolongation in conduction time and QRS width. Catecholamine depletion abolished or attenuated reperfusion induced shortening of action potential duration and refractory period. Catecholamine depletion increased myocardial glycogen levels from 2.47 +/- 0.3 mg X g-1 wet weight to 4.39 +/- 0.3 mg X g-1; fasting animals for 48 h prior to study reversed this with no attenuation of the electrophysiological or antiarrhythmic action. These results provide further evidence that release of endogenous myocardial catecholamines contributes to the electrophysiological changes and arrhythmias associated with myocardial ischaemia and reperfusion.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Catecholamines; Coronary Disease; Glycogen; Guinea Pigs; Heart; Hydroxydopamines; In Vitro Techniques; Male; Myocardium; Norepinephrine; Oxidopamine; Perfusion; Tachycardia; Ventricular Fibrillation

In ischemic myocardium the time course of nonesterified fatty acid (NEFA) accumulation was studied in relation to changes in regional metabolism and mechanics. In open-chest dogs a coronary artery was partially occluded for 120 min. In the ischemic myocardium no increase was observed in NEFA content within 10 min, whereas changes were found in regional shortening, high-energy phosphate content, and glucose arteriologcal venous difference. During prolonged ischemia NEFA content increased, the highest values being found in the inner and middle layers after 120 min (112 and 85 nmol X g-1, respectively; control values 30); the value in the outer layers after 60 min was 93 nmol X g-1. After 120 min of ischemia, accumulation of NEFA generally occurred when myocardial blood flow was below 0.3 ml X min-1 X g-1 and ATP content was below 10 mumol X g dry wt-1. Under these circumstances the individual NEFA with the highest relative increase was arachidonic acid. The present findings indicate that the changes in mechanical function and metabolism, as observed in myocardium rendered ischemic for 10 min, are not caused by increased NEFA content and that NEFA accumulation may partly result from hydrolysis of glycerophospholipids.

Topics: Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Dogs; Fatty Acids, Nonesterified; Female; Glycogen; Male; Models, Cardiovascular; Myocardium; Phosphocreatine; Regional Blood Flow; Time Factors

Glycogen synthesis from D-[1-13C]glucose was observed in the perfused rat heart by 13C-NMR spectroscopy at 62.9 MHz. The glycogenogenesis was stimulated by pretreatment of the animals with isoprenaline. Whereas in hearts from control rats the incorporation of D-[1-13C]glucose into the glycogen remained below the detection threshold, 5 min proton-decoupled 13C-NMR spectra revealed, in hearts from treated rats, a significant labelling of the glycogen within the first minutes of the perfusion and a further linear increase of the glycogen resonance for up to 25 min. This model was used to monitor the appearance of 13C-labelled lactate during ischemia.

Topics: Animals; Coronary Disease; Glucose; Glycogen; Lactates; Lactic Acid; Magnetic Resonance Spectroscopy; Myocardium; Perfusion; Rats; Rats, Inbred Strains

To identify and characterize the border zone, anesthetized dogs were subjected to 1-hour occlusion of the left anterior descending coronary artery with (Group R) or without (Groups A and B) 2 hours of subsequent reperfusion. Histochemical analysis of glycogen distribution, biochemical determination of lactate and adenosine triphosphate (ATP), and ultrastructural examination were carried out. In Group A, the epicardial edge of cyanosis was clearly visible and the sharply demarcated glycogen-depleted area contained peninsulas of cells with varying amounts of glycogen in its epicardial half, which were suggested to depend on collateral blood flow by intracoronary dye injection. In Group B, the edge of cyanosis was obscure and the glycogen-depleted area contained above-mentioned peninsulas at its lateral edge also. In Group R, although the edge of cynaosis was clear on occlusion, the peninsulas were numerous at the lateral edge as well as in the subepicardium after reperfusion. Lactate accumulation and ATP degradation corresponded well to glycogen decrease in all groups and were reduced significantly by reperfusion (p less than 0.005). Ultrastructural examination confirmed these findings. Therefore epicardial, and in some cases also lateral, salvageable border zones may exist and be composed of peninsulas of normal and intermediately injured cells dependent on collateral blood flow.

Topics: Adenosine Triphosphate; Animals; Coronary Disease; Dogs; Female; Glycogen; Histocytochemistry; Lactates; Lactic Acid; Male; Myocardium

In attempts to determine the mechanism(s) underlying reflow rhythm disturbances, we have studied the relationship between extent of coronary flow impairment and incidence of reperfusion arrhythmias. In isolated guinea pig hearts perfused with pyruvate (10 mmol/l) and glucose (0.5 mmol/l), coronary flow was reduced to different extents (18, 11, 6, 1, and 0.5%). Following 10 minutes of ischemia, reflow arrhythmias were quantitated with computer-aided statistical determination of rate-independent variations in beat intervals. The results (19 +/- 1, 13 +/- 5, 22 +/- 4, 8 +/- 3 and 6 +/- 1, n = 6, Rhythm Disturbance Units respectively) revealed that rhythm disturbances were more serious after less severe ischemia than after more severe ischemia. To investigate this "paradoxical" observation, we compared the metabolic changes during ischemia and the severity of subsequent reflow arrhythmias. Electrical instability during reperfusion was not related to accumulation of lactate, increase in cyclic AMP or decline in energy status. These were at a maximum in the severely ischemic myocardium. The reduced incidence of arrhythmias following severe (1% and 0.5% flow) as opposed to moderate ischemia, however, may have been associated with a major increase in glycogenolysis (from 1.2 to 7.4 and 7.6 mumol glucose equivalents/min per g dry weight).

Topics: Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Coronary Disease; Cyclic AMP; Glucose; Glycogen; Glycolysis; Guinea Pigs; Lactates; Lactic Acid; Male; Myocardium; Perfusion; Potassium; Pyruvates

Guinea pig hearts, perfused with (5-3H) glucose (8 mmol . litre-1) and subjected to 30 min of reduced (6%) coronary flow, exhibited two distinctly different metabolic and electrophysiological responses to ischaemia. In 22 of the 50 hearts studied (Group 1) glucose utilisation declined during ischaemia from 2.5 +/- 0.2 to 1.3 +/- 0.2 mumol . litre-1 . g-1 dry wt. In these hearts, endogenous substrates such as glucogen and triglyceride were mobilised and, although input into glycolysis may have been initially increased through accelerated glycogenolysis, estimated glycolytic flux (1.7 +/- 0.1 mumol hexose . min-1 . g-1 dry wt) remained limited. Instead, there was a large accumulation of the intermediates of glycolysis, an increase in the content of AMP and cAMP and a particularly marked decline in creatine phosphate levels. With subsequent reperfusion, these hearts all fibrillated. In contrast, in the other 28 hearts (Group 2) glucose utilisation (5.1 +/- 0.4 mumol . min-1 . g-1 dry wt) and estimated glycolytic flux (4.1 +/- 0.01 mumol hexose . min-1 . g-1 dry wt) were increased during ischaemia. In these preparations, relatively little glycogen and triglyceride were utilised, and there was less accumulation of glycolytic intermediates. Further, lower levels of AMP and cAMP were observed and creatine phosphate: creatine ratios were better maintained. These hearts did not fibrillate during reperfusion. Thus the variable susceptibility of the myocardium to ischaemic damage, as evidenced by the random incidence of ventricular fibrillation during reperfusion, may have been related to two distinctly different metabolic responses to restricted perfusion.

Topics: Adenine Nucleotides; Animals; Coronary Disease; Glucose; Glycogen; Guinea Pigs; Male; Myocardium; Oxygen Consumption; Perfusion; Phosphocreatine; Triglycerides; Ventricular Fibrillation

In an experimental study on isolated isovolumetric guinea-pig hearts, a 2.2-fold reduction of the coronary duct combined with metabolic block caused by dinitrophenol (0.05 mM) resulted in an eleven-fold drop in the attained pressure, and a shorter electric systole, a smaller P wave, and an ST displacement on the ECG. Deep suppression of mechanical and electric activity was combined with reduced glycogen content, and greater K+ and Na+ withdrawal from the heart. Quantitatively, the drop in contractility correlated with K+ withdrawal and ST displacement. A sudden increase in coronary perfusion rate was accompanied by a rapid increase in the rate of K+ elimination from the heart which was proportionate to the rate of hyperfusion, with a simultaneous transitory rise in attained pressure, a great increment in diastolic pressure and the emergence of arrhythmia and fibrillation, the severity of the changes correlating with the degree of K+ loss. A moderate increase in K+ concentration of the perfusate prevented the development of fibrillation and drastically reduced the degree of contracture and glycogen drop during hyperfusion. The obtained results suggest that moderate accumulation of extracellular K+ during the early phase of energy generation disorder can be of a protective nature, as it contributes to a sharp reduction in contractility and energy spending to improve cell survivability in critical conditions.

Topics: Animals; Coronary Disease; Energy Metabolism; Extracellular Space; Glycogen; Guinea Pigs; Hypokalemia; Myocardium; Organ Culture Techniques; Perfusion; Potassium

Isolated rat hearts were subjected to 30 min low flow ischaemia (0.5 ml X min-1). During reperfusion, uridine (5 X 10(-5) mol X litre-1) was added to the perfusion medium for 30 min. The concentrations of creatine phosphate, adenine nucleotides, uridylic nucleotides and glycogen were determined at the end of the experiments. The purpose of this work was to study the effects of uridine supply on the concentration of energetic compounds during reperfusion recovery. Low flow ischaemia induced a breakdown of creatine phosphate, adenosine triphosphate, and total adenine nucleotides by 53%, 23% and 15% respectively. The creatine phosphate content was restored during reperfusion without uridine, but the adenine nucleotides remained unchanged. The uridylic nucleotides and the glycogen were also degraded during ischaemia by 56% and 53% for uridine triphosphate and glycogen respectively. Reperfusion without uridine induced a partial resynthetisation of uridylic nucleotides but glycogen stores were not significantly restored. When tested in oxygenated hearts, uridine supply induced a fall in creatine phosphate concentration and an enhancement of uridine triphosphate level but it had no effect on adenosine triphosphate, uridine diphosphate glucose or glycogen concentrations. If supplied during reperfusion, the nucleoside induced the complete restoration of myocardial ATP, total adenine nucleotide content, an increase in the uridylic nucleotide concentration and the resynthetisation of glycogen to supra-normal value.

Topics: Adenine Nucleotides; Animals; Coronary Disease; Female; Glycogen; Heart; Myocardium; Perfusion; Phosphocreatine; Rats; Rats, Inbred Strains; Uracil Nucleotides; Uridine

Progressive morphological changes have been quantitated in ischemic and control regions of canine hearts previously assessed biochemically and physiologically. Muscle strips removed after a 5 or 10-min occlusion of the left circumflex artery were compared to those removed after reperfusion for 20 or 60 min following 10 min occlusion and to those removed immediately from normal and sham-operated dogs. Decreased glycogen content and decreased mitochondrial matrix were observed in fibers from ischemic regions as early as 5 min after ligation. Changes in the mitochondrial volume fraction were calculated by the point counting method and changes in the number of lipid droplets per unit area were determined. Mitochondrial volume fractions in ischemic regions were not significantly higher when compared to control regions of the same hearts, and were similar to the values measured for 10 and 70-min sham-operated dogs. We conclude that in early acute ischemia considerable variability in the different control groups emerges with extensive sampling and must be considered in interpreting ultrastructural changes.

Topics: Animals; Coronary Disease; Cytoplasmic Granules; Dogs; Glycogen; Lipid Metabolism; Microscopy, Electron; Mitochondria, Heart; Myocardium

Myocardial ischemia was produced in 12 dogs by ligation of the anterior descending branch of the left coronary artery. The animals were sacrificed 0.5, 1, 3, 6, 12, and 24 hours later. The ischemic area was compared with control tissue from the posterior aspect of the left ventricle as to the glycogen content, myoglobin content, intracellular diffusion of IgG, diastase resistant-periodic acid-Schiff (PAS) (D-PAS) staining material and basic fuchsin-staining material. In the earliest time period studied, 0.5 hours, glycogen loss marked a large area of ischemic change. Myoglobin loss, intracellular diffusion of IgG, D-PAS-staining material and basic fuchsin-staining material were also found but involved only a small area within the glycogen-depleted zone. As the length of ischemic period increased, the area occupied by these changes approached the size of the area of glycogen loss. In all animals, the area of myoglobin loss, intracellular diffusion of IgG, D-PAS staining and basic fuchsin staining were in the area of glycogen loss. The IgG, D-PAS, and basic fuchsin parameters, in turn, were within the area of myoglobin loss but usually did not completely fill it. That is, some fibers showing myoglobin loss did not show the other changes. Can any of these changes serve as early markers for irreversible ischemic injury? Glycogen loss clearly does not. Additional data are needed to determine whether the extracellular diffusion of myoglobin and the intracellular diffusion of IgG are markers of irreversible injury.

Topics: Animals; Coronary Disease; Dogs; Fluorescent Antibody Technique; Glycogen; Heart Ventricles; Histocytochemistry; Immunoenzyme Techniques; Immunoglobulin G; Myocardium; Myoglobin; Time Factors

The effects of long-term administration of prenylamine gluconate were studied to define changes induced by chronic treatment that may alter the responses of the myocardium to ischaemic stress. Prenylamine gluconate was administered orally to rats (10 mg or 100 mg/kg per day) for 2 weeks. At the end of this period, hearts were excised for perfusion studies. In comparison with gluconate-treated controls, hearts from the group treated with the lower dose of prenylamine showed a significant reduction in basal cardiac function that was not apparent in the group treated with the higher dose of prenylamine. After a period (35 min) of ischaemia stress (reduced flow), a reduction in enzyme leakage and an increase in post-ischaemic functional recovery were observed in hearts from animals treated with the lower dose of prenylamine. In contrast, hearts from the group treated with the higher dose showed no significant improvement. However, chronic prenylamine therapy was shown to reduce in a dose-dependent manner the incidence of post-ischaemic arrhythmias. Thus, although the antiarrhythmic efficacy of long-term treatment with this agent appears to be proportional to the dosage, the ability of prenylamine to reduce ischaemic damage and promote functional recovery does not show a linear relationship with the drug dose.

Topics: Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Coronary Disease; Dose-Response Relationship, Drug; Glycogen; Heart; Heart Function Tests; Male; Myocardium; Perfusion; Phosphocreatine; Prenylamine; Rats; Rats, Inbred Strains

The ischemic myocardium utilizes glycogen as metabolic substrate. The effects of oral nutrition on the levels of glycogen in the myocardium and of myocardial glycogen content on myocardial tolerance to ischemia were studied. Rats were divided into groups and fed (a) rat chow, (b) rat chow plus 5% dextrose, and elemental diets (c) Flexical (Mead Johnson) or (d) Vital (Ross Laboratories). Another group was starved. All fed groups gained weight normally while the starved rats lost 23% of their body weight. Compared with the effect on rat chow, myocardial glycogen levels were elevated in the Flexical and starvation groups, while Vital depressed the level (P less than 0.01). Thus, both caloric intake and diet affected myocardial glycogen content. Elevation of myocardial glycogen content after starvation contrasted with glycogen disappearance from the liver. The level of myocardial glycogen and left ventricular function after global ischemia were correlated in dogs under cardiopulmonary bypass conditions. During 30 minutes of normothermic aortic cross-clamping, hearts with a preischemic myocardial glycogen content greater than 0.4 g% had less asystole or ventricular fibrillation. Their left ventricular function (stroke work index, myocardial contractility) upon reperfusion was substantially better than those with a myocardial glycogen level of less than 0.4 g%. Dietary manipulation and the nutritional status can thus affect the myocardial glycogen content and may be useful in protecting the myocardium from ischemia.

Topics: Animals; Coronary Disease; Energy Intake; Food, Formulated; Glycogen; Heart Ventricles; Liver Glycogen; Male; Myocardial Contraction; Myocardium; Nutritional Requirements; Rats; Rats, Inbred Strains; Starvation; Stroke Volume

Topics: Adolescent; Adult; Aged; Coronary Disease; Female; Glycogen; Glycolysis; Heart Conduction System; Histocytochemistry; Humans; Lipids; Male; Middle Aged; Myocarditis; Myocardium; Pentosephosphates; Purkinje Fibers; Succinate Dehydrogenase

Topics: Animals; Coronary Disease; Glycogen; Hypoxia; In Vitro Techniques; Ligation; Male; Mitochondria, Heart; Myocardium; Perfusion; Rats; Rats, Inbred Strains

A comparative study of the beta-receptor blockers propranolol, pindolol and carazolol, with respect to their cardio-protective properties against stress (hypoxia or isoprenaline injection) in rats showed the following. The beta-blockers investigated protected the heart against glycogen depletion during hypoxia. Carazolol was active at considerably lower doses than pindolol (about 25 times less) and propranolol (about 100 times later). All three beta-blockers protected against the induction of cardiac necroses by isoprenaline, but only carazolol produced almost complete protection. There is a good correlation between the protection against the development of cardiac necroses and the inhibition of tachycardia induced by isoprenaline (r = 0.96). The results are discussed from the point of view of the possible mechanisms by which the beta-blockers prevent cardiac damage induced by stress situations.

Topics: Adrenergic beta-Antagonists; Animals; Coronary Disease; Glycogen; Heart Diseases; Isoproterenol; Membranes; Myocardium; Pindolol; Propanolamines; Propranolol; Rats; Rats, Inbred Strains

Topics: Adenosine Triphosphate; Adult; Coronary Artery Bypass; Coronary Disease; Creatine Kinase; Glycogen; Hemodynamics; Humans; Hypothermia, Induced; Isoenzymes; Mitochondria, Heart; Myocardium; Necrosis; Phosphocreatine

Dosaged restriction of coronary blood flow (by 30, 50, 70 and 90%) was reproduced for 30 minutes in dogs with a closed chest. In all degrees of coronary blood flow restriction the loss of glycogen, accumulation of lactic acid and cAMP (in reduction of blood flow by 50 and 70%) and activation of glycogenolysis, phosphorylase and phosphofructokinase were recorded in the zone of ischemia. The changes advanced with the deepening of ischemia. Similar, though less pronounced changes were found outside the ischemic zone. Marked metabolic shifts were disclosed in the right ventricle. The mechanisms of anaerobic oxidation activation in ischemia are discussed.

Topics: Animals; Carbohydrate Metabolism; Coronary Disease; Cyclic AMP; Dogs; Enzyme Activation; Glycogen; Lactates; Myocardium; Phosphofructokinase-1; Phosphorylases

Topics: Acyl Coenzyme A; Animals; Carnitine; Coronary Circulation; Coronary Disease; Fatty Acids; Glucose; Glycogen; Hypothermia, Induced; In Vitro Techniques; Lactates; Lactic Acid; Male; Myocardium; Rats; Rats, Inbred Strains

Topics: Acute Disease; Adenosine Triphosphate; Animals; Coronary Disease; Glycogen; Lactates; Myocardium; Osmolar Concentration; Perfusion; Phosphocreatine; Potassium; Sodium; Swine; Water

Topics: Animals; Biomechanical Phenomena; Calcium; Coronary Circulation; Coronary Disease; Dogs; Energy Metabolism; Glycogen; Heart; Heart Arrest, Induced; Myocardium; Perfusion; Water

1. The uptake and subsequent phosphorylation of deoxyglucose into perfused rat hearts was monitored by 31P n.m.r. 2. The accumulated deoxyglucose 6-phosphate provided (a) an independent method for measuring cytosolic pH in the normoxic and ischaemic heart tissue and (b) a way of studying the activity of phosphorylase during ischaemia. 3. The cytosolic pH measured from the 31P n.m.r. resonance position of deoxyglucose 6-phosphate is in good agreement under all conditions studied with that obtained previously from the Pi resonances. This eliminates any possible doubts about the use of Pi for measuring intracellular pH. 4. Deoxyglucose 6-phosphate in vitro inhibits phosphorylase b but not phosphorylase a. Its inhibitory effect on glycogenolysis during ischaemia is monitored by measuring tissue acidosis by n.m.r. In the initial stages of ischaemia phosphorylase activity is not inhibited, whereas after about 5 min approx. 50% of the activity is inhibited. These observations are interpreted in terms of the relative contributions of phosphorylase a and the AMP-dependent phosphorylase b activities during ischaemia.

Topics: Animals; Coronary Disease; Cytosol; Deoxyglucose; Glucose-6-Phosphate; Glucosephosphates; Glycogen; Hydrogen-Ion Concentration; In Vitro Techniques; Magnetic Resonance Spectroscopy; Male; Phosphorylases; Phosphorylation; Rats

In this study we have assessed the possibility that long-term beta-blockade may offer additional protection against myocardial ischaemia that is separate from that afforded by acute beta-blockade. In addition, the effect of intrinsic sympathomimetic activity (ISA) on this additional protection was also investigated. Equipotent doses (4 mg . kg-1 body wt . day-1) of oxprenolol (possessing ISA) or propranolol (without ISA) were administered orally to rats for 3 weeks. Hearts were excised an perfused as isolated "working" heart preparations at variable times after the last dose. Hearts excised on the final day of drug administration showed significantly higher basal functional performance compared with untreated hearts. After 30 min reduced flow ischaemia (in the presence of exogenous catecholamine drive) hearts were aerobically reperfused and functional recovery measured. In both chronically beta-blocked groups, at times when plasma drug levels were undetectable, the number of hearts that recovered function and the cellular levels of creatine phosphate and glycogen were significantly increased. In addition, hearts from the oxprenolol-treated group perfused on the final day of drug administration, exhibited a greater recovery of heart rate compared with both propranolol treated and untreated groups. These results indicate that secondary consequences of long-term beta-blockade are beneficial to the ischaemic myocardium in the presence of high catecholamine drive. In addition, the possession of ISA by oxprenolol offered some advantages in terms of post-ischaemic functional recovery.

Topics: Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Glycogen; Hemodynamics; In Vitro Techniques; Male; Oxprenolol; Phosphocreatine; Propranolol; Rats; Rats, Inbred Strains

Topics: Adult; Aortic Diseases; Arteriosclerosis; Capillaries; Coronary Disease; Glycerolphosphate Dehydrogenase; Glycogen; Glycolysis; Humans; Hypertension; L-Lactate Dehydrogenase; Middle Aged; Periodontium

The haemodynamic indices proposed by Buckberg et al. have been used to evaluate total coronary flow and its distribution to the subendocardial tissue. The following conclusions were drawn from the data obtained in humans and in experimental pathology: 1) in regional ischaemia (angina, myocardial infarction), the DPTI/TTI ratio expresses the degree of subendocardial hypoperfusion with fair approximation, although it has some theoretical limitations, 2) in total myocardial ischaemia, as occurs during ECC, the index provides an accurate picture of the subendocardium and a useful idea of the real effectiveness of the means of myocardial protection.

Topics: Angina Pectoris; Animals; Coronary Artery Bypass; Coronary Circulation; Coronary Disease; Glycogen; Lactates; Myocardium; Swine

Topics: Acetates; Action Potentials; Adenine Nucleotides; Animals; Caprylates; Coronary Disease; Fatty Acids, Nonesterified; Glycogen; Guinea Pigs; Heart; Humans; Linoleic Acids; Palmitic Acids; Phosphocreatine

The effect of pretreatment with 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine carbonic acid-bis(2-propoxyethyl) ester (niludipine, Bay a 7168) (10 microgram/kg i.v.) on myocardial metabolic response to coronary artery ligation was studied in dogs anesthetized with pentobarbital. The results are summarized as follows: 1. Bay a 7168 lowered systolic and diastolic blood pressures markedly, and decreased heart rate slightly. 2. Bay a 7168 increased the endo- and epicardial phosphorylase activity significantly. 3. Bay a 7168 increased the endo- and epicardial ATP levels significantly. 4. Coronary artery ligation increased the endo- and epicardial activity of phosphorylase and decreased the endo- and epicardial glycogen levels. 5. In the presence of Bay a 7168, acceleration of glycogenolysis being caused by coronary artery ligation, was not detected. 6. Changes in the levels of myocardial carbohydrate intermediates being caused by coronary artery ligation, were not modified by pretreatment with Bay a 7168.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Coronary Disease; Coronary Vessels; Dogs; Female; Fructosephosphates; Glucosephosphates; Glycogen; Heart Rate; Male; Myocardium; Nifedipine; Pyridines; Time Factors

Topics: Acute Disease; Animals; Coronary Disease; Electrocardiography; Electrophysiology; Energy Metabolism; Glycogen; Heart; Hyperkalemia; Hypoxia; Membrane Potentials; Perfusion; Species Specificity; Swine

Glucose-insulin-potassium (GIK) was infused preoperatively in 30 patients scheduled for coronary artery operation. Before cardiopulmonary bypass (CPB) each patient received an intravenous infusion of 50% glucose. Myocardial protection was achieved with a cardioplegic solution containing glucose. A similar group of 30 patients received an equal volume of NaCl infused preoperatively and before CPB, and their cardioplegic solution contained no glucose. Clinically and by hemodynamic evaluation postoperatively one could not separate the two groups. Glycogen grading of the myocardium prior to bypass demonstrated no difference in glycogen levels in patients receiving glucose and those receiving NaCl. However, at the end of cardioplegic arrest only the group receiving glucose maintained normal grading of myocardial glycogen.

Topics: Biopsy; Cardiopulmonary Bypass; Coronary Disease; Glucose; Glucose Solution, Hypertonic; Glycogen; Heart Arrest, Induced; Hemodynamics; Humans; Hypothermia, Induced; Insulin; Myocardial Contraction; Myocardium; Potassium Chloride; Saline Solution, Hypertonic

A study has been made of the simultaneous evolution of cardiac activity and metabolism in the dog heart in situ, during the perfusion of isoproterenol in a dose comparable to therapeutic doses (1 micrograms x kg-1 x min-1, 30 min). A total cardiopulmonary by-pass system allowed of taking the repeated myocardial tissue samples necessary for the determination of the main energetic substrate and high-energy phosphate content. Samples were taken from subendocardial and subepicardial layers separately. The acceleration of heart rate due to isoproterenol was quickly regressive but, in the well-irrigated heart, the drug elicited a rapid fall in glycogen content and a considerable rise in lactate content, a slower reduction in free fatty acid concentration restricted to the subendocardial layer, and no significant variation of creatine phosphate or ATP. In the ischemic heart, isoproterenol aggravated the glycolysis disturbances without completely losing its effects on lipolysis when the ischemia was not too marked.

Topics: Adenosine Triphosphate; Animals; Cardiopulmonary Bypass; Coronary Disease; Dogs; Fatty Acids, Nonesterified; Female; Glucose; Glycogen; Heart; Heart Rate; Isoproterenol; Lactates; Male; Myocardium; Phosphocreatine

Construction and fit to the experimental data of a computer model of glycolysis, the Krebs cycle, and related metabolism in an ischemic dog heart preparation, involving 122 metabolites, 65 enzymes, and 406 chemical reactions, is described. The experimental preparation simulated is a dog heart excised from the body, placed in a beaker of Tyrode's solution, and sampled for 100 min; the model required only moderate modification from models representing perfused rat hearts, and little modification from a model of another ischemic dog heart preparation. Common underlying mechanisms for the ischemia are indicated, although this preparation appears to evolve more slowly with time, perhpas owing to heavy sedation and diffusion-limited transport. Lactate is, at first, exported and then accumulates intracellularly; pH falls, but not as much in the mitochondria as the cytoplasm; redox couples go reduced, but with counterintuitive time courses; calcium phosphate is calculated to precipitate, as often observed in cardiac ischemia.

Topics: Adenine Nucleotides; Animals; Computers; Coronary Disease; Dogs; Glycogen; Glycolysis; Hydrogen-Ion Concentration; Kinetics; Mitochondria, Heart; Models, Biological; Myocardium; NAD

1. Phosphorus-nuclear-magnetic-resonance measurements were made on perfused rat hearts at 37 degrees C. 2. With the improved sensitivity obtained by using a wide-bore 4.3 T superconducting magnet, spectra could be recorded in 1 min. 3. The concentrations of ATP, phosphocreatine and Pi and, from the position of the Pi resonance, the intracellular pH (pHi) were measured under a variety of conditions. 4. In a normal perfused heart pHi = 7.05 +/- 0.02 (mean +/- S.E.M. for seven hearts). 5. During global ischaemia pHi drops to 6.2 +/- 0.06 (mean +/- S.E.M.) in 13 min in a pseudoexponential decay with a rate constant of 0.25 min-1. 6. The relation between glycogen content and acidosis in ischaemia is studied in glycogen-depleted hearts. 7. Perfusion of hearts with a buffer containing 100 mM-Hepes before ischaemia gives a significant protective effect on the ischaemic myocardium. Intracellular pH and ATP and phosphocreatine concentrations decline more slowly under these conditions and metabolic recovery is observed on reperfusion after 30min of ischaemia at 37 degrees C. 8. The relation between acidosis and the export of protons is discussed and the significance of glycogenolysis in ischaemic acid production is evaluated.

Topics: Acidosis; Adenosine Triphosphate; Animals; Coronary Disease; Glycogen; Hydrogen-Ion Concentration; In Vitro Techniques; Intracellular Fluid; Kinetics; Magnetic Resonance Spectroscopy; Male; Myocardium; Perfusion; Phosphocreatine; Phosphorus; Rats

Analysis of the ischemic dog heart preparation described in the preceding paper indicates that it is an analogue in slow motion of the tissue in the center of a cardiac infarct. It is respiring very slowly and not capable of performing mechanical work. Glycolysis starts up with both glucose and glycogen as inputs. Later hexokinase and to some extent phosphofructokinase become limiting owing to inhibitor accumulation or acidosis. Metabolism then results primarily from cAMP-driven glycogenolysis, largely limited by the glycogen debranching enzymes at later times, with accumultion not only of lactate and alpha-glycerophosphate but of glucose as well. Amino acid levels oscillate with time while fatty acids accumulate at late times. The elevation of cAMP at later times may involve disturbances in its metabolism as well as mechanisms such as adenosine accumulation that are more important in cardiac ischemia than in normal heart. The clinical implications of this behavior are discussed.

Topics: Amino Acids; Animals; Computers; Coronary Disease; Cyclic AMP; Dogs; Fatty Acids; Glycerophosphates; Glycogen; Glycolysis; Models, Biological; Myocardium; Oxygen Consumption

Topics: Adenosine Triphosphate; Animals; Coenzyme A; Cold Temperature; Coronary Disease; Cytochrome c Group; Dogs; Glycogen; Heart; Myocardium

The appearance of the ventricular myocardium in 6 patients electing coronary bypass operation was evaluated by electron microscope before and after aortic cross-clamping. Bypassing protocol included the induction of hypothermic cardioplegia by intermittent aortic root perfusion, with potassium chloride added to cold blood serving as the cardioplegic agent. Cross-clamp intervals ranged from 66 to 125 minutes. Ultrastructural alterations following bypass manipulations, and distinct from those observed before cross-clamping, were limited to the presence of extensive myocardiocytic pooling of glycogen. Scrutiny of the intramyocardial capillary bed following perfusion with the cardioplegic solution revealed no abnormalities attributable to, or intensified by, the bypass maneuver. These findings indicate that hypothermic potassium cardioplegia, as specified, is not injurious to human myocardial ultrastructure.

Topics: Adult; Aged; Biopsy; Coronary Artery Bypass; Coronary Disease; Coronary Vessels; Female; Glycogen; Heart Arrest, Induced; Humans; Hypothermia, Induced; Male; Microcirculation; Middle Aged; Myocardium; Organoids

One hundred seventeen patients undergoing elective coronary bypass were divided into four groups according to prebypass myocardial glycogen levels and the use of potassium chloride cardioplegia. Myocardial glycogen levels were enhanced with a preoperative fat loading diet and overnight glucose loading. The control group (n = 27) which had mean cardiac glycogen levels of 750 mg/100 gm heart weight and no cardioplegia, had a transmural myocardial infarct rate of 14.4%; 35% had severe atrial arrhythmias 65% had severe ventricular arrhythmias, and 31% had severe vasopressor dependence. The group (n = 30) with low cardiac glycogen (736 mg/100 gm) and with potassium chloride cardioplegia had an infarct rate of 6.4%; 6.7% had severe atrial arrhythmias, 18% had severe ventricular arrhythmias, and 16.7% had severe vasopressor dependence. However, the group (n = 26) which had high cardiac glycogen levels (1,208 mg/100 gm) and no cardioplegia had no myocardial infarctions; 3.8% had severe atrial arrhythmias, 27% had severe ventricular arrhythmias, and only 7.8% had severe vasopressor need. The group (n = 34) which had high glycogen levels (1,516 mg/100 gm) and potassium chloride cardioplegia did best of all with no myocardial infarctions or no severe atrial arrhythmias; 14% had severe ventricular arrhythmias and 2.81% severe vasopressor need. The lessening of vasopressor dependence and severe atrial and ventricular arrhythmias were significant by chi square contingency tables at p less than 0.05 and p less than 0.001, respectively. One cardiac-related death each occurred in the two groups with low glycogen and none in those with high glycogen levels. This suggests that better preoperative cardiac nutrition as represented by enhanced cardiac glycogen helps that heart tolerate anoxic stress whether cardioplegia is utilized or not and is additive to potassium chloride cardioplegia.

Topics: Aorta; Arrhythmias, Cardiac; Cardiac Surgical Procedures; Constriction; Coronary Artery Bypass; Coronary Disease; Dietary Fats; Energy Intake; Female; Glucose; Glycogen; Heart Arrest, Induced; Humans; Intraoperative Complications; Male; Middle Aged; Myocardial Contraction; Myocardial Infarction; Myocardium; Postoperative Complications; Potassium Chloride; Preoperative Care; Prospective Studies

Topics: Animals; Coronary Disease; Coronary Vessels; Cytoplasmic Granules; Dihydrolipoamide Dehydrogenase; Embolism; Glycogen; L-Lactate Dehydrogenase; Lipid Metabolism; Male; Mitochondria, Heart; Myocardium; Rats; Sarcoplasmic Reticulum; Succinate Dehydrogenase

Topics: Adenosine Triphosphate; Animals; Arterial Occlusive Diseases; Coronary Disease; Electrophysiology; Glycogen; Heart; Histocytochemistry; Lactates; Membrane Potentials; Myocardium; Phosphocreatine; Swine; Time Factors

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.

Topics: Animals; Coronary Disease; Dogs; Energy Metabolism; gamma-Aminobutyric Acid; Glycerolphosphate Dehydrogenase; Glycogen; Guanylthiourea; Indoles; Isatin; L-Lactate Dehydrogenase; Male; Myocardium; NADPH Dehydrogenase; Phosphorylase a; Phosphorylase b; Succinate Dehydrogenase; Thiourea

Carbocromen prevents to some extent, particularly in subendocardial layer, carbohydrate cardiac metabolism alterations induced by the ischemia obtained by intermittent occlusion of left coronary artery.

Topics: Animals; Chromonar; Coronary Disease; Coumarins; Dogs; Fatty Acids, Nonesterified; Glucose; Glycogen; Heart; Lactates; Myocardium

Topics: Amiodarone; Animals; Benzofurans; Blood Vessels; Connective Tissue; Coronary Circulation; Coronary Disease; Dogs; Glycogen; Mitochondria, Heart; Myocardial Infarction; Myocardium; Ribonucleoproteins

The effect of pretreatment with verapamil (100 micrograms/kg i.v.) or nifedipine (10 micrograms/kg i.v.) on ischemic myocardial metabolism was studied in dogs anesthetized with pentobarbital. The results are summarized as follows: 1. Verapamil or nifedipine lowered both systolic and diastolic blood pressures markedly, and increased heart rate slightly. 2. Verapamil or nifedipine increased both endo- and epicardial phosphorylase activities significantly. 3. Coronary artery ligation increased the phosphorylase activity, and also increased the levels of glucose-6-phosphate, fructose-6-phosphate, and lactate, and decreased the levels of glycogen, fructose-1,6-diphosphate, and phosphocreatine in both endo- and epicardial layers, without affecting the level of the endo- and epicardial adenosine triphosphate. 4. In the presence of verapamil or nifedipine, coronary artery ligation did not increase but decreased the phosphorylase activity that had been increased by verapamil or nifedipine alone. 5. Changes in the levels of intermediates induced by coronary artery ligation were not markedly influenced by pretreatment of the dog with verapamil or nifedipine.

Topics: Animals; Blood Pressure; Coronary Disease; Dogs; Female; Glycogen; Heart Rate; Lactates; Male; Myocardium; Nifedipine; Phosphorylases; Pyridines; Pyruvates; Time Factors; Verapamil

Tissue energy metabolism was examined in posterior (ischemic) and anterior ("control") regions of canine ventricles after 5 and 10 minutes of left circumflex coronary artery occlusion. When compared to identical regions of normal hearts, the following changes were found: (1) decreases in glycogen and phosphorylase activity in the anterior and posterior regions, (2) depressed state 3 rates of oxygen consumption of isolated mitochondria in both anterior and posterior regions, (3) shifts in optimum substrate concentrations for palmityl-CoA (+ carnitine) oxidation by mitochondria in the anterior and posterior regions, and (4) decreases in the apparent zero order and first order rates of mitochondrial palmitylcarnitine production. These changes correlated with a marked decrease in developed tension in the posterior regions. Depression in tension development in the posterior regions of the heart still was present after 30--60 minutes of reperfusion following a 10-minute period of occlusion. Glycogen content in the reperfused areas was significantly decreased after 60 minutes of reperfusion when compared to normal areas and to control hearts perfused for 70 minutes. After reperfusion, mitochondrial function appeared to return toward "normal." However, the slow restoration of contraction of the ischemic area suggests that cellular mechanisms operative in vivo to restore pump function still might be abnormal.

Topics: Acyl Coenzyme A; Acyltransferases; Animals; Carnitine; Carnitine O-Palmitoyltransferase; Citric Acid Cycle; Coronary Disease; Dogs; Glutamates; Glycogen; Mitochondria, Heart; Myocardium; Oxidation-Reduction; Oxygen Consumption; Palmitoyl Coenzyme A; Palmitoylcarnitine; Papillary Muscles; Phosphorylase b; Phosphorylases

1. Morphologic as well as biochemical alterations in chronic ischemic myocardial tissue without infarction were studied in dogs utilizing the Ameroid constrictor. 2. Serum creatine kinase activity elevated at around three weeks after placing the Ameroid constrictor around the circumflex branch of the left coronary artery suggestive of myocardial tissue injury followed by the initial activation caused by surgery. 3. Subendocardial proliferation of connective tissue was observed in about 60% of the experiments, but the middle and the subepicardial muscles were morphologically intact. 4. The marked increase in glycogen particles was observed in the subendocardial muscle cells in most of the experiments, and mild features of myocardial cellular necrosis were found in approximately 60% of the experiments. 5. ATPase activities of the structural proteins as well as sarcoplasmic reticulum in the ischemic myocardium shoed relatively higher values than those in the non-ischemic myocardium. However, no substructural changes were observed in SDS gel electrophoresis in both the fractions. 6. The alterations in the chronic myocardial ischemia are supposed to be essentially the same as those in myocardial necrosis followed by acute coronary occlusion.

Topics: Adenosine Triphosphatases; Animals; Calcium; Caseins; Constriction; Coronary Disease; Coronary Vessels; Creatine Kinase; Dogs; Glycogen; Histocytochemistry; Hydrogels; Medical Laboratory Science; Myocardium; Plastics

Topics: Animals; Computers; Coronary Disease; Glucose; Glycogen; Glycogen Debranching Enzyme System; Glycolysis; Kinetics; Lactates; Models, Biological; Pyruvates; Rats

Topics: Acid Phosphatase; Alkaline Phosphatase; Coronary Disease; Enzyme Activation; Glycogen; Humans; Leukocytes; Lipids; Oxidoreductases

Topics: Adenosine Triphosphate; Animals; Coronary Disease; Creatine Kinase; Cytoplasm; Glycogen; Hypoxia; Injections, Subcutaneous; Male; Mitochondria, Heart; Myocardium; Oxygen Consumption; Phosphocreatine; Propranolol; Rabbits; Time Factors

Occlusion of the circumflex branch of the coronary artery of rabbit hearts for 45 minutes elicits structural and cytochemical changes in myocytes similar to those observed in ischemic dog myocardium, which are indicative of irreversible cell injury. When methylprednisolone is administered prior to occluding the artery, myocytes are transiently protected and many of the electron microscopic signs of irreversible damage are delayed for 15 minutes or more. During this period, the steroid preferentially protects mitochondria, lysosomes, and sarcolemma from the ischemic changes that normally develop. However, some other events, including depletion of glycogen and margination of nuclear chromatin, are only minimally influenced by the therapy, if at all. In all hearts, treated and untreated, the development of severe cell damage, whenever it occurs, is closely associated with cell swelling, mitochondrial dilation with concomitant appearance of amorphous osmiophilic densities, and abnormalities in and, ultimately disappearance of lysosomes, suggesting that damage to cell membranes is a central event in the progression of reversible injury to irreversible infarction and that protection of membrane integrity should be a reasonable aim in efforts to ameliorate or delay ischemic injury.

Topics: Animals; Chromatin; Coronary Disease; Glycogen; Heart; Hydrolases; Lysosomes; Male; Methylprednisolone; Mitochondria, Heart; Myocardium; Rabbits; Sarcolemma; Time Factors

Potassium-induced cardioplegia was studied in 38 mongrel dogs supported by normothermic cardiopulmonary bypass and subjected to 60 minutes of aortic cross clamping followed by 30 minutes of reperfusion. A study of preischemic and postischemic ventricular function and myocardial high-energy phosphate compounds, lactate, and glycogen showed substantial preservation of high-energy phosphates and ventricular performance when potassium cardioplegia was used. However, the substantial depression in contractility observed following ischemia nad reperfusion suggests that potassium cardioplegia alone does not provide adequate intraoperative protection of the myocardium.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Aorta; Cardiopulmonary Bypass; Constriction; Coronary Disease; Dogs; Glycogen; Heart Arrest, Induced; Lactates; Myocardial Contraction; Myocardium; Phosphocreatine; Potassium

The protective effect of propranolol on ischemic myocardium was studied experimentally and clinically by electron microscope. In an animal experiment, ischemic changes were produced in the posterior papillary muscle of the rabbit following 3, 15, 30 minutes of occlusion of the circumflex coronary artery. Propranolol (0.25 mg/kg) was injected into the left atrial cavity before occlusion of the artery. The posterior papillary muscle was excised and examined by electron microscope. In clinical experience, propranolol (20 microng/kg) was given intravenously to 6 patients who underwent open heart surgery. Transmural left ventricular myocardial biopsy was performed after the anoxic cardic arrest and the material, particularly the subendocardium, was examined by electron microscope. It was shown that propranolol was effective, both in the experiment and in the clinical experience, in preserving ischemic myocardium. The possible mechanisms through which propranolol might act were considered to be (1) indirect effect of altered oxygen supply vs. demand, effect by reducing heart rate and reducing cardiac output due to the drug's function as a beta blocker, (2) direct cellular effect, i.e., reducing myocardial substrate metabolism along with stabilization of cellular structure, and (3) increase collateral circulation to the subendocardium.

Topics: Adolescent; Adult; Animals; Cardiac Surgical Procedures; Coronary Circulation; Coronary Disease; Cytoplasmic Granules; Female; Glycogen; Heart; Humans; Male; Membranes; Microscopy, Electron; Middle Aged; Mitochondria, Muscle; Mitochondrial Swelling; Myocardium; Oxidative Phosphorylation; Oxygen Consumption; Propranolol; Rabbits

Effects of coronary artery ligation on myocardial glycogenolysis were studied in the endo- and epicardial layers of the left ventricular wall in dogs pretreated with 10 or 100 microgram/kg (i.v.) of carteolol, a potent beta-adrenergic blocking agent. Coronary artery ligation was performed by ligating one of the small branches of the left anterior descending coronary artery. In control (saline-pretreated) dogs, an increase in phosphorylase alpha activity and an increase in breakdown of glycogen were observed in both endo- and epicardial layers after coronary artery ligation. In the presence of 10 or 100 microgram/kg of carteolol, however, increases in phosphorylase alpha activity and increase in breakdown of glycogen were not observed in either the endo or epicardial layers. These results indicate that pretreatment of the dog with carteolol inhibits the increase in glycogenolysis caused by coronary artery ligation. Nevertheless, carteolol did not completely inhibit the coronary artery ligation-induced increase in glucose-6-phosphate and lactate levels, and the coronary artery ligation-induced decrease in phosphocreatine level, particularly in the endocardial layers.

Topics: Adenosine Triphosphate; Animals; Coronary Disease; Coronary Vessels; Dogs; Female; Glucosephosphates; Glycogen; Heart Ventricles; Lactates; Levobunolol; Ligation; Male; Myocardium; Phosphocreatine; Phosphorylases

Topics: Amylases; Animals; Coronary Disease; Deoxycholic Acid; Dogs; Egtazic Acid; Glycogen; In Vitro Techniques; Muscles; Myocardium; Phosphorylase Kinase; Sarcoplasmic Reticulum; Tromethamine

Disturbance of the microcirculation produced by the combined injection of the high molecular weight dextran and vasopressin led as soon as the first minutes (5 min) to the intensification of glycolysis. This was testified to by the reduction of glycogen concentration by 19.4 percent, elevation of the phosphorylase "A" activity by 30-36 percent and of the pyruvic acid by 36.9 percent. The ATP, ADP, AMP, and the KP concentration remained unchanged. The observed glycolysis changes can be regarded as the initial metabolic reactions resulting from hypoxia originating in microcirculation disturbances.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Chinchilla; Coronary Disease; Energy Metabolism; Glycogen; Lactates; Microcirculation; Myocardium; Phosphocreatine; Phosphorus; Phosphorylases; Pyruvates; Rabbits

During reperfusion, functional and metabolic recovery of the isolated working rat heart from one hour of ischemia was best in hearts selectively cooled at the onset of the ischemic interval by perfusion with 5 to 10 ml. of 10 degrees C. or 15 degrees C. Krebs-Henseleit buffer. Hearts similarly perfused at 4 degrees C., 20 degrees C. recovered significantly less well or not at all. Immediately after the hour of ischemia and prior to reperfusion, the absolute levels of glycogen and high-energy phosphates were best in the hearts perfused at 4 degrees C. However, metabolic function was best preserved in those perfused at 10 degrees C. and 15 degrees C., as evidenced by rapid recovery of high-energy phosphates and glycogen to control levels compared to metabolic deterioration in the 4 degrees C. group.

Topics: Adenosine Triphosphate; Animals; Cardiac Surgical Procedures; Coronary Disease; Glycogen; Hypothermia, Induced; Myocardium; Perfusion; Phosphocreatine; Rats; Time Factors

The effect of coronary artery ligation on myocardial glyocogenolysis was studied in the endo- and epicardial layers of the left ventricle in dogs pretreated with saline or 1 mg/kg of propranolol. Coronary artery ligation was performed by ligating one of the small branches of the left anterior descending coronary artery. Even after coronary artery ligation, neither increase in phosphorylase activity nor breakdown of glycogen was observed in both layers of ischemic region of myocardium in propranolol-pretreated dogs. These results indicate that pretreatment with propranolol inhibits the increase in glycogenolysis being caused by coronary artery ligation. Propranolol howefer, did not inhibit completely the coronary artery ligation-induced increase in glucose 6-phosphate and lactate and decrease in phosphocreatine in the myocardium, especially in the endocardial layers.

Topics: Adenosine Triphosphate; Animals; Coronary Disease; Coronary Vessels; Dogs; Endocardium; Female; Glucosephosphates; Glycogen; Lactates; Ligation; Male; Myocardium; Pericardium; Phosphocreatine; Phosphorylases; Propranolol

Topics: Animals; Body Weight; Cardiac Output; Coronary Disease; Epinephrine; Glycogen; Heart; Injections, Subcutaneous; Lactates; Muscle Proteins; Myocardium; Organ Size; Perfusion; Rats

Whole-heart ischemia has been induced in isolated working rat heart. The distribution of the reduced coronary flow was even, as judged by 3H-antipyrine autoradiographs. Reducing the coronary flow resulted in myocardial ischemia, as indicated by a lowered tissue content of glycogen, ATP and creatine phosphate and accumulation of lactate. After a reperfusion period of 30 min there was a restoration of glycogen, ATP and creatine phosphate for hearts that were ischemic for 5 and 10 min, with a concomitant normalization of tissue lactate. Hearts that were ischemic for 30 min did not show restoration of high energy phosphates and glycogen. There was a leakage of ASAT, CK and LD in all groups of hearts, suggesting that a release of these enzymes does not necessarily indicate an irreversibly damaged myocardial cell.

Topics: Adenosine Triphosphate; Animals; Aspartate Aminotransferases; Coronary Circulation; Coronary Disease; Creatine Kinase; Glycogen; L-Lactate Dehydrogenase; Male; Myocardium; Perfusion; Rats; Time Factors

The effects of atrial pacing on tissue metabolite levels known to be sensitive to ischemia were examined. Anesthetized dogs were thoracotomized and a pacing electrode was sutured to the right atrium. Pacing at rates of 200 or 250 beats/min (10 animals per group) was performed for 15 min after base-line hemodynamic data had been obtained. At the end of the pacing period, a transmural biopsy was taken, frozen in liquid nitrogen, and sectioned into subepicardial, midmyocardial, and subendocardial layers. ATP, phosphocreatine, lactate, and glycogen were extracted and analyzed. Significant (P less than 0.001) transmural gradients of each of these metabolites existed in the control group. Pacing had no significant (P greater than 0.2) effect on any metabolite from layer to layer at 200 or 250 beats/min. However, indices of heart work (i.e., contractility (dP/dt), stroke work, and stroke volume) demonstrated significant reductions (P less than 0.01) due to pacing, while circumflex artery blood flow increased more than twofold (P less than 0.001) at the highest rate. These data suggest that physiologic autoregulation occurred during pacing and protected the subendocardium from stress-induced ischemic insult.

Topics: Adenosine Triphosphate; Animals; Cardiac Output; Coronary Disease; Dogs; Female; Glycogen; Heart Rate; Heart Ventricles; Lactates; Male; Myocardium; Phosphocreatine; Tachycardia

Topics: Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Electrocardiography; Female; Glycogen; Lactates; Ligation; Male; Microspheres; Myocardium; Phosphocreatine; Potassium; Sodium

Isolated working rat hearts were made ischemic by introducing a one-way aortic ball valve. After the ischemic period the hearts were perfused in a retrograde non-working way for 30 min. Flow rates, glycogen, ATP, and creatine-phosphate went down during the time of ischemia, whereas tissue lactate accumulated. For shorter periods of ischemia these values were normalized but after 30 min of ischemia the hearts seemed to be irreversibly damaged. There was a leakage of GOT, GPT, LDH, and CPK from all hearts when ischemic from 5 to 30 min. Different factors that might be of importance for the degree of ischemic injury were tested. The injury tended to be more severe at higher heart rates. Addition of adrenaline 10(-6)M resulted in excessive myocardial damage. A variation of pH from 7.1 to 7.7 did not alter the effects of the ischemic injury. One group of rats were injected with adrenaline for 8 weeks to simulate chronic stress. When hearts from these rats were made ischemic they were more prone to fail compared to controls. The failing hearts, on the other hand, had a lower leakage of enzymes, possibly due to a less severe myocardial damage. A high mechanical performance and a normal noradrenaline content of the hearts are key factors for the development of myocardial infarction, as indicated by this study.

Topics: Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Glycogen; Heart; Heart Rate; Hydrogen-Ion Concentration; Lactates; Male; Perfusion; Phosphocreatine; Rats

It is proposed that the development of ventricular fibrillation in the context of ischaemic heart-disease and myocardial infarction can be related to accumulation of cyclic adenosine 3',5' monophosphate (A.M.P.) in the ischaemic zone. The known electrophysiological and metabolic actions of cyclic A.M.P. are consonant with the hypothesis, which also provides a framework for the better understanding of the action of antiarrhythmic drugs.

Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Calcium; Coronary Disease; Cyclic AMP; Glycogen; Haplorhini; Lidocaine; Lipid Metabolism; Myocardium; Potassium; Rats; Ventricular Fibrillation

Insertion of a flow pump into the Langendorff retrograde perfusion apparatus has permitted the production of stable, graded ischemia in hearts whose hemodynamic and metabolic response may be evaluated. Ventricular pressures were monitored with a modified balloon and catheter-tip manometer system, and oxygen consumption , lactate and glucose metabolism, and tissue high-energy phosphate stores measured. A 15-min stabilization period in 56 paced hearts was followed by 15 min of either full, 40, 30, 20, or 10% coronary flow, after which the ventricular tissue was freeze-clamped for tissue assay. Tissue creatine phosphate fell progressively from 23.7 in full flow hearts to 9.9 mumol/g dry wt after 90% reduction in flow. This was accompanied by a graded reduction in ATP from 20.3 to 14.0 mumol/g dry wt and a rise in AMP from 1.1 to 2.6 mumol/g dry wt. Tissue lactate rose progressively from 22.3 to 60.1 mumol/g dry wt. Hemodynamic function correlated with coronary flow. This preparation offers an opportunity to study pharmacological and metabolic interventions in ischemic heart disease.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Disease Models, Animal; Glucose; Glycogen; Hemodynamics; In Vitro Techniques; Lactates; Male; Myocardial Contraction; Myocardium; Oxygen Consumption; Phosphocreatine; Rats

Topics: Coronary Disease; Glucose; Glucose Tolerance Test; Glycogen; Humans; Male; Middle Aged

The effects of metabolic accumulation on myocardial metabolism during global heart oxygen deprivation were evaluated in a working in situ swine heart preparation with controlled total coronary blood flow. Myocardial oxygen consumption was depressed to a similar extent by either reducing total coronary flow 60 per cent (ischemia, low coronary perfusion) in 10 swine or by decreasing coronary perfusate PO2 to 30 mm. Hg at normal flows (hypoxemia, high coronary perfusion) in 13 swine. Compared with findings in 13 control hearts, ischemia significantly (p less than 0.05) decreased myocardial oxygen consumption (640 to 390 mumole per hour per gram), glucose uptake (185 to 16 mumole per hour per gram), and free fatty acid consumption (32 to 17 mumole per hour per gram). ttissue levels of glycogen, creatine phosphate, and adenosine triphosphate (tatp) were significantly reduced (p less than 0.005), and tissue lactate, adenosine diphosphate (ADP), and adenosine monophosphate (AMP) were increased (p less than 0.001). During hypoxemia, glucose uptake was increased (240 mumole per hour per gram) and free fatty acid consumption was somewhat less depressed (19 mumole per hour per gram). Creatine phosphate and ATP were higher than with ischemia (p less than 0.01), and lactate, ADP, and AMP accumulations were less (p less than 0.01). Thus, in the period immediately following myocardial oxygen deprivation, inadequate coronary perfusion caused greater metabolic buildup which inhibited myocardial substrate utilization and energy production. High coronary perfusion, even though the perfusate was unoxygenated, was associated with greater preservation of substrate utilization, higher levels of high-energy phosphates, less accumulation of metabolic products, and a longer survival. These data suggest a critical role of coronary perfusion in protecting myocardial metabolism in the immediate period following global heart hypoxia.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Coronary Disease; Disease Models, Animal; Female; Glucose; Glycogen; Heart; Hemodynamics; Hypoxia; Lactates; Male; Myocardial Revascularization; Myocardium; Oxygen Consumption; Phosphocreatine; Swine

Regional ischemia results in infarction even in the presence of residual oxidative metabolism. Although glycolytic flux is relatively inhibited at the level of phosphofructokinase, glucose competes more effectively than does free fatty acid for the residual oxygen supply. Glycogen is not the major energy source until effective collateral flow is virtually zero.

Topics: Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Fatty Acids, Nonesterified; Glucose; Glucosephosphates; Glycogen; Glycolysis; Humans; Myocardial Infarction; Myocardium; Oxygen Consumption; Phosphofructokinase-1

Topics: Adenosine Triphosphate; Animals; Coronary Disease; Depression, Chemical; Disease Models, Animal; Dogs; Glucosephosphates; Glycogen; Glycolysis; Heart; Lactates; Myocardium; Nitroglycerin; Phosphocreatine; Phosphorylases

In normothermia, mild, and deep hypothermia the metabolism and the electron microscopic structure were investigated in human and rabbit heart muscle after magnesium aspartate-procaine cardioplegia. In comparison to plain ischaemic arrest splitting of adenine nucleotides and glycogen was significantly reduced in all experiments with the induced cardioplegic arrest. For 40 min at 32 degrees C almost no changes in ultrastructure were seen in heart muscle after induced arrest, while severe and/or irreversible damages were seen in the cell structure of the heart muscle due to plain ischaemic arrest.

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Aspartic Acid; Coronary Disease; Glycogen; Heart Arrest; Heart Arrest, Induced; Heart Ventricles; Humans; Hypothermia, Induced; Magnesium; Microscopy, Electron; Myocardium; Procaine; Rabbits; Resuscitation; Time Factors

In the nonischemic canine left ventricle, levels of glycogen, glucose-6-phosphate (G6P), and lactate, and phosphorylase activity in the endocardial layers were higher than those in the epicardial layers, but the phosphocreatine (PCr) level in the endocardial layers was lower than that in the epicardial layers, and there were no differences in the adenosine triphosphate (ATP) level between the endo- and epicardial layers. Upon ligation of a small branch of the left descending coronary artery, levels of glycogen and PCr decreased, while those of G6P and lactate increased, and the activity of phosphorylase increased. The level of ATP was not affected by the coronary ligation. Thus the coronary ligation accelerated the glycogenolysis and glycolysis in the myocardium without affecting ATP level, and the acceleration in metabolism in the endocardial layers was more rapid and marked than that in the epicardial layers.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Coronary Artery Bypass; Coronary Disease; Dogs; Endocardium; Female; Glucosephosphates; Glycogen; Heart Rate; Ligation; Male; Pericardium; Phosphocreatine; Phosphorylases

The present study was undertaken to determine the involvement of cardiac lyososomes in injury to the myocardium after cardiopulmonary bypass. Twenty conditioned mongrel dogs, weighing 15 to 18 kilograms, were fasted overnight, anesthetized with sodium pentobarbital (30 mg. per kilogram), intubated, and maintained on positive-pressure ventilation. The femoral artery and femoral vein were cannulated for pressure measurements. After median sternotomy, intravenous heparin was administered (3 mg. per kilogram) before the aorta and the superior and inferior venae cavae were cannulated for bypass. Bypass was instituted with a Travenol modular pump and a Bentley pediatric bubble oxygenator and heat exchanger. The ultrastructural effects on the myocardium and the acid phosphatase activity in the left ventricle were compared in dogs exposed to bypass for 1 hour with varying types of myocardial support: perfusion of the coronary arteries, normothermic ischemic arrest, or selective cardiac hypothermia. The morphology of control hearts and hearts fixed after 1 hour of coronary perfusion were similar. The distribution and structure of subcellular lysosomes were the same and showed identical patterns of acid phosphatase activity. Normothermic ischemic arrest was associated with a loss of glycogen stores, disrupted sarcoplasmic reticulum and T tubules, vacuolization and decrease in matrix density of mitochondria, and separation of the intercalated discs. Lysosomal activity was absent except for occasional residual bodies in the nuclear pole zone of the myocardial cells. Selective cardiac hypothermia produced results superior to those from normothermic ischemic arrest. Although these hearts showed proliferation of the lysosomal compartment, the organelles responsible for excitation-contraction coupling were spared.

Topics: Acid Phosphatase; Animals; Cardiopulmonary Bypass; Coronary Disease; Dogs; Extracorporeal Circulation; Glycogen; Heart Arrest; Heart Diseases; Lysosomes; Mitochondria, Muscle; Myocardium; Sarcoplasmic Reticulum; Time Factors

An in situ working swine heart preparation is described in which total coronary perfusion was controlled. At normal rates of coronary flow, oxygen, glucose, and fatty acid utilization were stable for at least a 60-min perfusion period. With a 50% reduction in coronary flow, oxygen and glucose consumption were reduced during 30 min of perfusion and fatty acid extraction was lower at the end of 30 min. Glycogen utilization was increased, but tissue levels of creatine phosphate, ATP, and lactate were similar to those in hearts receiving normal flow. With a 60% reduction in coronary flow, uptake of oxygen, glucose, and fatty acids were further decreased. Tissue levels of high-energy phosphates and glycogen were decreased and ADP, AMP, and lactate increased. Mechanical performance progressively deteriorated in these hearts, and ventricular fibrillation developed after about 20 min (19.8 plus or minus 3.0 min). The data indicate that this preparation is suitable for the study of myocardial metabolism during mild and severe ischemia and may be useful for the evaluation of pharmacological interventions designed for the treatment of myocardial ischemia.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Disease Models, Animal; Energy Metabolism; Fatty Acids; Female; Glucose; Glycogen; Heart; Lactates; Male; Myocardium; Oxygen Consumption; Regional Blood Flow; Swine; Ventricular Fibrillation

Topics: Adult; Aged; Angina Pectoris; Benzofurans; Benzyl Alcohols; Blood Coagulation; Coronary Circulation; Coronary Disease; Female; Fibrinogen; Glycogen; Heart; Humans; Lipids; Male; Middle Aged; Myocardium; Oxygen Consumption; Vasodilator Agents; Water-Electrolyte Balance

Colloidal lanthanum salts have an average particle size of 40 degrees A; consequently, this electron-opaque marker remains extracellular and does not cross the intact plasma membrane. The affinity of lanthanum for calcium-binding sites on mitochondrial membranes makes it possible to demonstrate loss of plasma membrane integrity at the cellular level in ischemic myocardium. Biopsies were obtained from infarcted, marginal and normal areas 3 1/2 hours after ischemia was produced in 9 anesthetized closed-chest dogs by electrically induced thrombosis of the left anterior descending coronary artery. The tissue was immediately fixed in 4% glutaraldehyde and 0.1 M cacodylate buffer containing 1.3% La(NO3)3, pH 7.4, for 2 hours. In normal control tissue prepared this way the lanthanum tracer, as expected, was confirmed to the extracellular spaces, including, basement membranes, gap junctions and portions of the intercalated discs. Specimens taken near the center of frank infarctions all contained intracellular as well as extracellular lanthanum. Intracellular lanthanum could be seen evenly distributed around lipid droplets and in focal deposits around mitochondria. Only when mitochondria were disrupted did lanthanum gain access to internal sites on mitochondrial membranes. Areas marginal to the infarct contained cells in varying stages of degeneration including many that appeared normal by morphologic criteria alone. Intracellular lanthanum was present in many but not all of the marginal cells in which degenerative changes could be seen. Similarly a few of the cells that appeared morphologically normal contained intracellular lanthanum. The entry of lanthanum into some of these marginal cells and its exclusion from adjacent cells demonstrated that ischemic injury affects the permeability properties of the plasma membrane and independently of other intracellular morphologic changes and that lanthanum can be a sensitive indicator of such alteration in membrane permeability.

Topics: Animals; Binding Sites; Biopsy; Calcium; Cell Membrane; Cell Membrane Permeability; Colloids; Coronary Disease; Dogs; Glycogen; Lanthanum; Membranes; Mitochondria, Muscle; Myocardium; Myofibrils; Sarcolemma

Regional contraction of ischemic anterior and normal lateral left ventricular myocardium was measured with isometric force gauges after 5, 10, 15, and 20 minutes of anterior descending coronary artery occlusion-each followed by 10 minutes of reperfusion. Multiple myocardial biopsies of both regions were taken at these same intervals and examined by electron microscopic techniques. Mean contraction of the ischemic area fell significantly in 15 to 30 seconds and returned to an average of 68, 51, 40, and 28 per cent, respectively, after 5, 10, 15, and 20 minutes of ischemia. Simultaneously, focal morphologic changes were detected after 5 and 10 minutes, were more clear and widespread at 15 minutes, and diffuse and unequivocal at 20 minutes, when return of local contraction was minimal. The changes of myocardial morphology in the ischemic area as seen by electron microscopy were: reduced content of glycogen granules and mitochondrial changes. The latter began to appear at 5 minutes and consisted of swelling, disruption of cristae, and reduction of matrix. This study indicates a qualitative correlation between ultrastructural changes in regionally ischemic myocardium and diminished regional function in the intact heart. At 5 and 10 minutes the mitochondrial changes were focal, requiring multiple samples, while at 15 and 20 minutes they became more widespread, making the occasional sample more representative.

Topics: Animals; Coronary Disease; Disease Models, Animal; Glycogen; Heart; Histocytochemistry; Microscopy, Electron; Mitochondria, Muscle; Mitochondrial Swelling; Myocardial Contraction; Myocardium; Swine; Time Factors

The capacity for recovery of the normothermic left ventricular myocardium from a regional complete ischemia (RCI) was investigated using changes in the myocardial metabolic status (ATP, ADP, AMP, creatine phosphate (CrP), free creatine, glycogen, glucose, lactate) and alterations of the morphology as parameters. In dogs, an area of the anterior wall of the left ventricular myocardium was temporarily deprived completely of its blood supply by 5--7 overlapping ligatures extending into the heart cavity. The metabolites of the adenylic acid-CrP system returned to normal tissue levels after 30 and 60 min of RCI within 14 and 35 days of recovery, respectively; restoration averaged 82% after 100 min, 74% after 140 min, and 38% after 180 min of RCI after 5 weeks of recovery. At the same time glycogen amounted to 163% after 100 min, 114% min, and 65% after 180 min of RCI. The biochemical data correlated well with the structural changes in the affected myocardium, especially with the amount of de- and regenerating heart muscle cells. These obviously were functionally defect and were not comparable with normal structured and functioning heart muscle cells.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Cell Nucleus; Collagen; Coronary Disease; Creatine; Dogs; Female; Glucose; Glycogen; Heart; Heart Ventricles; Lactates; Ligation; Male; Mitochondria, Muscle; Myocardium; Myofibrils; Phosphocreatine; Time Factors; Ventricular Function

Topics: Animals; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Extracorporeal Circulation; Glycogen; Heart; Lactates; Mitochondria, Muscle; Mitochondrial Swelling; Myocardium; Myofibrils; Papillary Muscles

Topics: Adenosine Triphosphate; Animals; Coronary Disease; Coronary Vessels; Dipyridamole; Dogs; Glucosephosphates; Glycogen; Lactates; Ligation; Myocardium; Phosphocreatine; Phosphorylases

Transmural gradients in the contents of glycogen triglycerides, and phospholipids were studied in the dog left ventricle with and without 4 hours of left circumflex artery ligation. In control dogs (patent circumflex), an increasing outer to inner glycogen gradient was observed. After 4 hours of ischemia, subepicardial glycogen content was similar to control values, but midventricular and subendocardial stores were nearly depleted, thus indicating a reversal of the control gradient. These changes were seen biochemically as well as by light and electron microscopic techniques. In the present studies, conclusive evidence for a transmural gradient in tissue triglyceride content was not obtained in either control or ligated dogs. However, an approximate three-fold increase in midventricular and subendocardial triglycerides was observed in ischemic hearts. Regional contents of total tissue phospholipids appeared to be similar across the left ventricular wall in both normal and ischemic left ventricles.

Topics: Animals; Coronary Disease; Dogs; Glycogen; Heart; Heart Ventricles; Lipid Metabolism; Microscopy, Electron; Myocardium; Purkinje Cells; Triglycerides

Isolated working rat hearts were made ischemic for 5, 10, and 30 minutes respectively. After the ischemic period, all hearts were perfused in a retrograde nonworking way for 30 minutes. During the 5 first minutes of ischemia, there was a marked fall of cardiac output and coronary flow. A significant release of GOT was seen and this was more marked after longer periods of ischemia. Addition of adrenaline to the perfusate increased the enzyme release. Pacing at 400/minute, high preload, high afterload, acidosis, or alkalosis did not alter enzyme release. Glycogen, ATP and CrP levels were depressed at the end of the ischemic period, but were seen to be rising again during the retrograde perfusion. This study indicates that myocardial tissue may release enzymes without being irreversibly damaged.

Topics: Adenosine Triphosphate; Animals; Aspartate Aminotransferases; Coronary Circulation; Coronary Disease; Creatine Kinase; Glycogen; Hemodynamics; L-Lactate Dehydrogenase; Lactates; Male; Phosphocreatine; Rats

The relationship between coronary flow and adenosine triphosphate ATP production was determined in isolated rat hearts and in situ pigs hearts. The major source of ATP in ischemic hearts was oxidative phosphorylation. Oxidation of glucose accounted for most of the residual oxygen consumption in ischemic hearts when the concentration of fatty acids was low, but at 1.2 mM palmitate fatty acids were oxidized in preference to carbohydrate, as in aerobic hearts. The rates of ATP production from both glycolysis and oxidative metabolism were decreased in proportion to the reduction in coronary flow in oxygen-deficient hearts. Glycolysis was reduced to below aerobic rates when coronary flow was about 0.5 ml/min/g tissue in both rat hearts perfused with bicarbonate buffer and blood-perfused pig hearts. Tissue level of high energy phosphates reflected the rates of ATP production and declined in proportion to the reduction in coronary flow. In addition, tissue lactate and H+ accumulated in proportion to the restriction in flow.

Topics: Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Fatty Acids; Glucose; Glycogen; Glycolysis; Hypoxia; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen Consumption; Palmitates; Perfusion; Rats; Swine

Regional differences in glycogen and triglyceride metabolism were found in the ischemic dog left ventricle. Under these conditions, the subendocardium was characterized by a faster rate of glycogenolysis and the least ability to mobilize tissue triglycerides relative to subepicardial and midventricular zones.

Topics: Animals; Coronary Disease; Dogs; Glycogen; Heart Ventricles; Myocardium; Palmitic Acids; Time Factors; Triglycerides

After local complete ischemia at normothermia of 60, 100, 140, and 180 min duration the status of the adenylic acid-creatine phosphate system in the canine myocardium recovered to 98, 85, 74, and 30 percent of the control values, whereas glycogen was restored even more. In the infarcted myocardium the extent of alterations of the metabolic status was a function of the residual blood flow. Deviations from a regular metabolic status developed if the blood flow dropped below about 35 ml/min/100 gm. This critical flow rate is expected to vary with the energy requirement of the heart, but it is in keeping with results obtained by Rudolph and coworkers (personal communication) who found that patients with a myocardial blood flow below 30 ml/min/100 gm had a life expectancy of less than 1 month. In the nonaffected myocardium, both in experiments with local complete ischemia and in experiments with infarction, the metabolic status was always within normal ranges. This is in contrast to results published by Gudbjarnason (1971/1972) and Gudbjarnason, Puri, and Mathes (1971), who found that in noninfarcted myocardium tissue levels of ATP and creatine phosphate decreased to about 50 percent of the control values and that there was no restoration to normal values within 10 days after infarction.

Topics: Adenosine Monophosphate; Animals; Coronary Disease; Creatine; Disease Models, Animal; Dogs; Glycogen; Heart Ventricles; Lactates; Myocardial Infarction; Myocardium; Phosphocreatine; Time Factors

Topics: Animals; Cardiac Output; Coronary Disease; Disease Models, Animal; Dogs; Edema; Electrocardiography; Endoplasmic Reticulum; Glycogen; Heart; Hypoxia; Microscopy, Electron; Mitochondrial Swelling; Myocardial Revascularization; Myocardium; Myofibrils; Thoracic Arteries

Topics: Adaptation, Physiological; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Coronary Disease; Glycogen; Hypoxia; Male; Myocardium; Phosphates; Physical Exertion; Rats

Topics: Animals; Blood Pressure; Carbon Dioxide; Coronary Disease; Coronary Vessels; Dogs; Electrocardiography; Female; Glucosephosphates; Glycogen; Heart Conduction System; Heart Ventricles; Lactates; Male; Myocardium; Oxygen; Potassium; Sodium; Vascular Resistance

Topics: Animals; Arteries; Blood Glucose; Carbon Dioxide; Carbon Radioisotopes; Collateral Circulation; Coronary Disease; Coronary Vessels; Dogs; Energy Metabolism; Fatty Acids, Nonesterified; Female; Glucose; Glycogen; Lactates; Ligation; Male; Myocardial Infarction; Myocardium; Oxidation-Reduction; Oxygen; Palmitic Acids; Partial Pressure; Pyruvates; Triglycerides; Veins

Topics: Animals; Calcium; Coronary Disease; Endoplasmic Reticulum; Glycogen; Heart; Heart Diseases; Histocytochemistry; Isoproterenol; Male; Microscopy, Electron; Mitochondria; Myocardium; Propranolol; Rats

Topics: Animals; Coronary Circulation; Coronary Disease; Glycogen; Guinea Pigs; Heart Arrest; Microscopy, Electron; Myocardium; Myofibrils; Perfusion; Sarcoplasmic Reticulum

Topics: Animals; Constriction; Coronary Circulation; Coronary Disease; Dogs; Glycogen; Heart Ventricles; Hyperemia; Microscopy, Electron; Mitochondria, Muscle; Myocardial Infarction; Myocardium; Sarcolemma; Swine; Time Factors

Topics: Adaptation, Physiological; Altitude; Carbon Dioxide; Cell Nucleus; Chronic Disease; Coronary Circulation; Coronary Disease; DNA; Genetic Code; Glycogen; Heart; Humans; Hypoxia; L-Lactate Dehydrogenase; Mitochondria, Muscle; Myocardium; Myofibrils; Oxygen Consumption; RNA; Succinate Dehydrogenase

Topics: Animals; Arterial Occlusive Diseases; Coronary Disease; Creatine Kinase; Dogs; Electrocardiography; Glycogen; Hyaluronoglucosaminidase; Myocardial Infarction; Myocardium; Necrosis; Spectrophotometry; Time Factors

Topics: Acid Phosphatase; Animals; Coronary Disease; Coronary Vessels; Dogs; Female; Glucuronidase; Glycogen; Heart Ventricles; In Vitro Techniques; Ligation; Lysosomes; Male; Muscles; Myocardial Infarction; Papillary Muscles; Potassium; Time Factors

Topics: Adult; Aged; Alkaline Phosphatase; Coronary Disease; Female; Glycogen; Humans; Male; Middle Aged; Neutrophils; Peroxidases; Phospholipids

Topics: Adenine Nucleotides; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Blood Sedimentation; Chinchilla; Coronary Disease; Creatine; Glycogen; Heart; Ketoglutaric Acids; Malates; Mast Cells; Microcirculation; Mitochondria, Muscle; Myocardium; Oxidative Phosphorylation; Oxygen Consumption; Phosphocreatine; Pyruvates; Rabbits; Succinates; Transferases

Topics: Animals; Capillaries; Cell Nucleus; Coronary Disease; Electron Transport; Glycogen; Heart; Hypoxia; In Vitro Techniques; Lipid Metabolism; Mitochondria, Muscle; Myocardium; Myofibrils; Oxidative Phosphorylation; Rabbits; Sarcoplasmic Reticulum

Topics: Adult; Aged; Arteriosclerosis; Blood Proteins; Cholesterol; Coronary Disease; DNA; Female; Glycogen; Histocytochemistry; Humans; Intracranial Arteriosclerosis; Leukocytes; Lipids; Lipoproteins; Male; Middle Aged; Neutrophils; Peroxidases; RNA

Topics: Animals; Coronary Disease; Dihydrolipoamide Dehydrogenase; Dogs; Glycogen; Heart Conduction System; Heart Ventricles; Histocytochemistry; Myocardial Infarction; Myocardium; NAD; Purkinje Cells; Rabbits

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Endoplasmic Reticulum; Glycogen; Heart Conduction System; Mitochondrial Swelling; Myofibrils; Perfusion; Rats; Sinoatrial Node; Time Factors

Topics: Animals; Biomechanical Phenomena; Carbon Dioxide; Carbon Isotopes; Coronary Circulation; Coronary Disease; Culture Techniques; Diet, Atherogenic; Dietary Fats; Glucose; Glycogen; Heart; Lactates; Lipids; Male; Myocardium; Palmitic Acids; Perfusion; Pyruvates; Rats

Topics: Acridines; Animals; Autolysis; Autopsy; Cardiomegaly; Clinical Enzyme Tests; Coronary Disease; Death, Sudden; Diagnosis, Differential; Forensic Medicine; Glycogen; Humans; Hydrogen-Ion Concentration; Microscopy, Fluorescence; Myocardial Infarction; Myocardium; Oxidoreductases; Staining and Labeling; Swine

Topics: Acid Phosphatase; Alkaline Phosphatase; Capillaries; Coronary Disease; Coronary Vessels; Dihydrolipoamide Dehydrogenase; Electron Transport Complex IV; Esterases; Glycogen; Heart Conduction System; Heart Neoplasms; Histocytochemistry; Humans; Hypertension; Lipase; Methods; Myocardial Infarction; NAD; NADP; Regional Blood Flow; Succinate Dehydrogenase

Topics: Coronary Disease; Diagnosis, Differential; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type I; Glycolysis; Heart Failure; Histocytochemistry; Humans; Hypokalemia; Lactates; Myocardium; Potassium; Rheumatic Heart Disease

Topics: Adenine; Adenine Nucleotides; Animals; Coronary Disease; Dogs; Glycogen; Heart Arrest; Hypoxanthines; Myocardium; Nucleosides; Potassium Chloride; Rabbits; Transferases; Xanthines

Topics: Animals; Catecholamines; Coronary Disease; Denervation; Dogs; Ethanolamines; Glucosyltransferases; Glycogen; Glycolysis; Guinea Pigs; Heart; In Vitro Techniques; Lactates; Methods; Models, Chemical; Myocardial Infarction; Myocardium; Norepinephrine; Rabbits; Rats; Reserpine; Synaptic Transmission; Tritium; Tyramine

Topics: Animals; Coronary Disease; Coronary Vessels; Dogs; Glycogen; Glycosaminoglycans; Histocytochemistry; Myocardium; Necrosis; Thoracic Arteries

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Blood Glucose; Carbohydrate Metabolism; Coronary Disease; Dogs; Glycogen; Histocytochemistry; Lactates; Myocardium; Oxygen Consumption; Phosphocreatine; Phosphorus; Polarography; Pyruvates

Topics: Animals; Coronary Disease; Endoplasmic Reticulum; Glycogen; Hypoxia; Lipids; Microscopy, Electron; Mitochondria, Muscle; Myocardium; Rats; Ribosomes

Topics: Animals; Coronary Disease; Dogs; Freezing; Glucosyltransferases; Glycogen; Heart Arrest, Induced; Myocardium; Rabbits; Rats

Topics: Animals; Arteriosclerosis; Cholesterol; Coronary Disease; Female; Glycogen; Histocytochemistry; Male; Methods; Microscopy, Polarization; Myocardium; Rabbits

Topics: Animals; Blood Flow Velocity; Blood Pressure; Cardiac Catheterization; Coronary Disease; Dogs; Extracorporeal Circulation; Female; Glucose; Glycogen; Heart; Heart Ventricles; Male; Methods; Myocardium; Oxygen

Topics: Animals; Coronary Disease; Glycogen; Humans; Hypoxia; Lactates; Muscle, Smooth; Myocardium; Pyruvate Oxidase; Rats

Topics: Animals; Calcium; Coronary Disease; Dogs; Electrons; Glycogen; Histocytochemistry; Ischemia; Microscopy; Microscopy, Electron; Mitochondria; Pathology; Research

Topics: Animals; Coronary Disease; Dogs; Glycogen; Glycosaminoglycans; Histocytochemistry; Myocardium; Thoracic Arteries

Topics: Animals; Blood Flow Velocity; Chlorides; Coronary Disease; Dogs; Glycogen; Myocardial Infarction; Myocardium; Phosphorus; Potassium; Research; Sodium; Ventricular Fibrillation; Water-Electrolyte Balance

Topics: Adenosine Triphosphatases; Carbohydrate Metabolism; Coronary Disease; Glycogen; Ischemia; Metabolism; Muscle Proteins; Myocardium; Proteins; Research

Topics: Coronary Disease; Electron Transport Complex IV; Electrons; Fluorescence; Glycogen; Heart Diseases; Histocytochemistry; Humans; Hypoxia; Isoproterenol; Lipids; Microscopy; Microscopy, Electron; Microscopy, Fluorescence; Mitochondria; Myocardial Infarction; Myocardium; Necrosis; Pathology; Rats; Research; Succinate Dehydrogenase

Topics: Animals; Coronary Disease; Coronary Occlusion; Dogs; Glycogen; Heart; Myocardium