phosphocreatine and Chronic-Disease

Increasing numbers of youth are presenting for psychiatric evaluation with markedly irritable mood plus "hyperarousal" symptoms. Diagnostically homeless in current nosology, the syndrome (as well as its underlying neurobiology) is little understood. To address this problem, we conducted an exploratory proton magnetic resonance spectroscopy (MRS) study in a large sample of youth with chronic, functionally disabling irritability accompanied by hyperarousal, a clinical syndrome known as "severe mood dysregulation" (SMD), which may represent a broad phenotype of pediatric bipolar disorder. Medication-free SMD youth (N=36) and controls (N=48) underwent 1.5 Tesla MRS in four regions of interest. The following three neurometabolites, relative to creatine (Cr), were quantified with LCModel Software: (a) myo-inositol (mI), a marker of intra-cellular second messengers linked to the neurobiology of bipolar disorder; (b) glutamate/glutamine (GLX), a marker of the major excitatory neurotransmitter glutamate; and (c) N-acetyl aspartate (NAA), a marker of neuronal energetics. SMD subjects had significantly lower temporal mI/Cr versus controls. However, this difference did not survive correction for multiple comparisons. Given studies implicating mI in lithium's action in BD adults and youth, further work is necessary to determine potential therapeutic implications of our present finding and how SMD youth differ pathophysiologically from those with strictly defined BD.

Topics: Antimanic Agents; Arousal; Aspartic Acid; Attention Deficit Disorder with Hyperactivity; Bipolar Disorder; Brain Mapping; Cerebral Cortex; Chronic Disease; Creatine; Diagnosis, Differential; Dominance, Cerebral; Double-Blind Method; Glutamine; Humans; Image Processing, Computer-Assisted; Inositol; Irritable Mood; Lithium Compounds; Magnetic Resonance Spectroscopy; Mood Disorders; Phosphocreatine

Chronic heart failure (CHF) is associated with abnormalities of skeletal muscle metabolism. This may be due to impaired oxygen delivery as a result of endothelial dysfunction.. We postulated that ascorbic acid would improve oxygen delivery to exercising muscle and improve skeletal muscle metabolism.. We studied skeletal muscle metabolism using (31)P magnetic resonance spectroscopy in 39 CHF patients. Endothelial function was assessed by changes in pulse wave velocity. Subjects were randomised to receive 4 g ascorbic acid daily for 4 weeks in a placebo-controlled double-blind study.. Ascorbic acid significantly increased phosphocreatine utilization during exercise. In addition, glycolytic ATP synthesis increased in the ascorbic acid group (change in rate of ATP synthesis at 1 min -0.21+/-0.76 with placebo, 2.06+/-0.60 following ascorbic acid; p<0.05). Phosphocreatine and ADP recovery after exercise were not changed. The fall in pulse wave velocity during reactive hyperaemia was increased by ascorbic acid from -6.3+/-2.6% to -12.1+/-2.0% (p<0.05).. These findings suggest that ascorbic acid increased both phosphocreatine utilization and glycolytic ATP synthesis during exercise in patients with CHF implying worsened skeletal muscle metabolism despite improvements in endothelial function.

Topics: Adenosine Triphosphate; Aged; Ascorbic Acid; Chronic Disease; Double-Blind Method; Endothelium, Vascular; Female; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Phosphocreatine; United Kingdom

Cardiac creatine levels are depressed in chronic heart failure. Oral supplementation of creatine to healthy volunteers has been shown to increase physical performance.. To evaluate the effects of creatine supplementation on ejection fraction, symptom-limited physical endurance and skeletal muscle strength in patients with chronic heart failure.. With a double-blind, placebo-controlled design 17 patients (age 43-70 years, ejection fraction < 40) were supplemented with creatine 20 g daily for 10 days. Before and on the last day of supplementation ejection fraction was determined by radionuclide angiography as was symptom-limited 1-legged knee extensor and 2-legged exercise performance on the cycle ergometer. Muscle strength as unilateral concentric knee extensor performance (peak torque, Nm at 180 degrees/s) was also evaluated. Skeletal muscle biopsies were taken for the determination of energy-rich phosphagens.. Ejection fraction at rest and at work did not change. Performance before creatine supplementation did not differ between placebo and creatine groups. While no change was seen in the placebo group compared to baseline, creatine supplementation increased skeletal muscle total creatine and creatine phosphate by 17 +/- 4% (P < 0.05) and 12 +/- 4% (P < 0.05), respectively. Increments were seen only in patients with < 140 mmol total creatine/kg d.w. (P < 0.05). One-legged performance (21%, P < 0.05), 2-legged performance (10%, P < 0.05), and peak torque, Nm (5%, P < 0.05) increased. Both peak torque and 1-legged performance increased linearly with increased skeletal muscle phosphocreatine (P < 0.05). The increments in 1-legged, 2-legged and peak torque were significant compared to the placebo group, (P < 0.05).. One week of creatine supplementation to patients with chronic heart failure did not increase ejection fraction but increased skeletal muscle energy-rich phosphagens and performance as regards both strength and endurance. This new therapeutic approach merits further attention.

Topics: Administration, Oral; Adult; Aged; Cardiac Output; Chronic Disease; Creatine; Double-Blind Method; Heart Failure; Humans; Male; Middle Aged; Muscle, Skeletal; Phosphocreatine; Physical Endurance; Radionuclide Angiography

This study investigated the effects of physical training on skeletal muscle metabolism in patients with chronic heart failure.. Skeletal muscle metabolic abnormalities in patients with chronic heart failure have been associated with exercise intolerance. Muscle deconditioning is a possible mechanism for the intrinsic skeletal muscle metabolic changes seen in chronic heart failure.. We used phosphorus-31 nuclear magnetic resonance spectroscopy to study muscle metabolism during exercise in 12 patients with stable ischemic chronic heart failure undergoing 8 weeks of home-based bicycle exercise training in a randomized crossover controlled trial. Changes in muscle pH and concentrations of phosphocreatine and adenosine diphosphate (ADP) were measured in phosphorus-31 spectra of calf muscle obtained at rest, throughout incremental work load plantar flexion until exhaustion and during recovery from exercise. Results were compared with those in 15 age-matched control subjects who performed a single study only.. Before training, phosphocreatine depletion, muscle acidification and the increase in ADP during the 1st 4 min of plantar flexion exercise were all increased (p < 0.04) compared with values in control subjects. Training produced an increase (p < 0.002) in incremental plantar flexion exercise tolerance. After training, phosphocreatine depletion and the increase in ADP during exercise were reduced significantly (p < 0.003) at all matched submaximal work loads and at peak exercise, although there was no significant change in the response of muscle pH to exercise. After training, changes in ADP were not significantly different from those in control subjects, although phosphocreatine depletion was still greater (p < 0.05) in trained patients than in control subjects. The phosphocreatine recovery half-time was significantly (p < 0.05) shorter after training, although there was no significant change in the half-time of adenosine diphosphate recovery. In untrained subjects, the initial rate of phosphocreatine resynthesis after exercise (a measure of the rate of oxidative adenosine triphosphate [ATP] synthesis) and the inferred maximal rate of mitochondrial ATP synthesis were reduced compared with rates in control subjects (p < 0.003) and both were significantly increased (p < 0.05) by training, so that they were not significantly different from values in control subjects.. The reduction in phosphocreatine depletion and in the increase in ADP during exercise, and the enhanced rate of phosphocreatine resynthesis in recovery (which is independent of muscle mass) indicate that a substantial correction of the impaired oxidative capacity of skeletal muscle in chronic heart failure can be achieved by exercise training.

Topics: Adenosine Diphosphate; Adult; Aged; Cardiac Output; Chronic Disease; Exercise Therapy; Exercise Tolerance; Heart Failure; Humans; Male; Middle Aged; Muscles; Oxygen Consumption; Phosphocreatine

To study the efficacy and safety of exogenous phosphocreatine (EF) in patients with chronic heart failure (CHF).. The all-Russian prospective observational study BYHEART included 842 patients who were treated with EF. Before and after the course of EF therapy, the following studies were conducted: a questionnaire on the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and a clinical condition assessment scale (SHOCK), transthoracic echocardiography with an assessment of the left ventricular ejection fraction, a 6-minute walk test, determination of the level of pro-natriuretic N-terminal peptide (NT-proBNP), glomerular filtration rate. All patients before the course of EF received long-term optimal drug therapy of CHF.. Statistical analysis was carried out in the general group of patients (n=842), as well as in groups of patients A (n=418, the course of treatment of EF is less than 20 g /course) and group B (n=424, the course of treatment of EF is greater than or equal to 20 g/course). The results obtained demonstrate a positive effect of the use of the course of therapy of EF in patients with CHF on the quality of life (QOL), reverse left ventricular remodeling, functional class of CHF, as well as the concentration of NT-pro-BNP, especially in the group of patients who received more than 20 grams of the medication.. The use of EF is a promising pharmacological method of treatment in addition to optimal drug therapy in patients with CHF.. Цель. Изучить эффективность и безопасность экзогенного фосфокреатина (ЭФ) у пациентов с хронической сердечной недостаточностью (ХСН). Материалы и методы. В общероссийское проспективное наблюдательное исследование BYHEART включены 842 пациента, которым проведен курс лечения ЭФ. До курса терапии ЭФ и после проводились следующие исследования: анкетирование по Миннесотскому опроснику качества жизни больных с ХСН (MHFLQ) и шкале оценки клинического состояния, трансторакальная эхокардиография с оценкой фракции выброса левого желудочка, тест 6-минутной ходьбы, определение уровня пронатрийуретического N-концевого пептида (NT-proBNP), скорости клубочковой фильтрации. Все пациенты до курса ЭФ получали длительную оптимальную медикаментозную терапию ХСН. Результаты. Статистический анализ проводился в общей группе пациентов (n=842), а также в группах пациентов А (n=418, ЭФ20 г на курс) и Б (n=424, ЭФ20 г на курс). Полученные результаты демонстрируют положительное влияние курса терапии ЭФ у пациентов с ХСН на качество жизни, обратное ремоделирование левого желудочка, функциональный класс ХСН, а также концентрацию NT-proBNP, особенно в группе больных, получивших 20 г или более препарата. Заключение. Применение ЭФ является перспективным фармакологическом методом лечения в дополнение к оптимальной медикаментозной терапии у пациентов с ХСН.

Topics: Chronic Disease; Heart Failure; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Phosphocreatine; Quality of Life; Stroke Volume; Ventricular Function, Left

Aim      Improvement of quality of life is one of the most important goals for the treatment of patients with chronic heart failure (CHF). This study searched for ways to increase the efficiency of CHF treatment based on parameters of quality of life in CHF patients during and after the treatment with exogenous phosphocreatine (EP).Material and methods  The effect of a single course of EP treatment on quality of life of patients with functional class (FC) II-IV CHF with reduced or mid-range left ventricular ejection fraction was studied as a part of the all-Russia prospective observational study BYHEART. The presence of FC II-IV CHF and a left ventricular ejection fraction <50 % were confirmed by results of 6-min walk test (6MWT) and findings of echocardiography after stabilization of the background therapy.Results An interim data analysis showed that the course of EP treatment was associated with a significant improvement of quality-of-life indexes as determined by the Minnesota Living with Heart Failure Questionnaire (LHFQ) total score. These indexes significantly increased and remained at a satisfactory level for 6 mos. following completion of the treatment course. Also, the treatment significantly beneficially influenced the clinical condition of patients (heart failure severity scale), results of 6MWT, and the increase in left ventricular ejection fraction.Conclusion      The conclusions based on results of the interim analysis should be confirmed by results of the completed study. Complete results are planned to be published in 2022.

Topics: Chronic Disease; Heart Failure; Humans; Phosphocreatine; Quality of Life; Stroke Volume; Ventricular Function, Left

Hypoxic states of the cardiovacular system are undoubtedly associated with the most frequent diseases of modern time. Therefore, understanding hypoxic resistance encountered after physiological adaptation such as chronic hypoxia, is crucial to better deal with hypoxic insult. In this study, we examine the role of energetic modifications induced by chronic hypoxia (CH) in the higher tolerance to oxygen deprivation.. Swiss mice were exposed to a simulated altitude of 5500 m in a barochamber for 21 days. Isolated perfused hearts were used to study the effects of a decreased oxygen concentration in the perfusate on contractile performance (RPP) and phosphocreatine (PCr) concentration (assessed by (31)P-NMR), and to describe the integrated changes in cardiac energetics regulation by using Modular Control Analysis (MoCA). Oxygen reduction induced a concomitant decrease in RPP (-46%) and in [PCr] (-23%) in Control hearts while CH hearts energetics was unchanged. MoCA demonstrated that this adaptation to hypoxia is the direct consequence of the higher responsiveness (elasticity) of ATP production of CH hearts compared with Controls (-1.88+/-0.38 vs -0.89+/-0.41, p<0.01) measured under low oxygen perfusion. This higher elasticity induces an improved response of energy supply to cellular energy demand. The result is the conservation of a healthy control pattern of contraction in CH hearts, whereas Control hearts are severely controlled by energy supply.. As suggested by the present study, the mechanisms responsible for this increase in elasticity and the consequent improved ability of CH heart metabolism to respond to oxygen deprivation could participate to limit the damages induced by hypoxia.

Topics: Animals; Body Weight; Chronic Disease; Energy Metabolism; Female; Heart; Hypoxia; In Vitro Techniques; Magnetic Resonance Spectroscopy; Mice; Mitochondria, Heart; Myocardial Contraction; Myocardium; Organ Size; Oxygen; Phosphocreatine

Hypoglycemia is common during development and is associated with the risk of neurodevelopmental deficits in human infants. The effects of hypoglycemia on the developing hippocampus are poorly understood. The sequential changes in energy substrates, amino acids and phosphocreatine were measured from the hippocampus during 180 min of insulin-induced hypoglycemia (blood glucose < 2.5 mmol/L) in 14-day-old rats using in vivo(1)H NMR spectroscopy. Hypoglycemia resulted in neuroglycopenia (brain glucose < 0.5 micromol/g). However, the phosphocreatine/creatine (PCr/Cr) ratio was maintained in the physiological range until approximately 150 min of hypoglycemia, indicating that energy supply was sufficient to meet the energy demands. Lactate concentration decreased soon after the onset of neuroglycopenia. Beyond 60 min, glutamine and glutamate became the major energy substrates. A precipitous decrease in the PCr/Cr ratio, indicative of impending energy failure occurred only after significant depletion of these amino acids. Once glutamate and glutamine were significantly exhausted, aspartate became the final energy source. N-acetylaspartate concentration remained unaltered, suggesting preservation of neuronal/mitochondrial integrity during hypoglycemia. Correction of hypoglycemia normalized the PCr/Cr ratio and partially restored the amino acids to pre-hypoglycemia levels. Compensatory neurochemical changes maintain energy homeostasis during prolonged hypoglycemia in the developing hippocampus.

Topics: Animals; Animals, Newborn; Brain Chemistry; Chronic Disease; Energy Metabolism; Glucose; Glutamic Acid; Glutamine; Glycolysis; Hippocampus; Homeostasis; Humans; Hypoglycemia; Infant Nutrition Disorders; Infant, Newborn; Lactic Acid; Magnetic Resonance Spectroscopy; Neurons; Oxidative Phosphorylation; Phosphocreatine; Rats; Rats, Sprague-Dawley

CHF (chronic heart failure) is associated with a prolonged recovery of skeletal muscle energy stores following submaximal exercise, limiting the ability to perform repetitive daily activities.However, the pathophysiological background of this impairment is not well established. The aim of the present study was to investigate whether muscle metabolic recovery following submaximal exercise in patients with CHF is limited by O2 delivery or O2 utilization. A total of 13 stable CHF patients (New York Heart Association classes II-III) and eight healthy subjects, matched for age and BMI (body mass index), were included. All subjects performed repetitive submaximal dynamic single leg extensions in the supine position. Post-exercise PCr (phosphocreatine) resynthesis was assessed by 31P-MRS (magnetic resonance spectroscopy). NIRS (near-IR spectroscopy) was applied simultaneously, using the rate of decrease in HHb (deoxygenated haemoglobin) as an index of post-exercise muscle re-oxygenation. As expected, PCr recovery was slower in CHF patients than in control subjects (time constant, 47+/-10 compared with 35+/-12 s respectively; P=0.04). HHb recovery kinetics were also prolonged in CHF patients (mean response time, 74+/-41 compared with 44+/-17 s respectively; P=0.04). In the patient group, HHb recovery kinetics were slower than PCr recovery kinetics (P=0.02), whereas no difference existed in the control group(P=0.32). In conclusion, prolonged metabolic recovery in CHF patients is associated with an even slower muscle tissue re-oxygenation, indicating a lower O(2) delivery relative to metabolic demands. Therefore we postulate that the impaired ability to perform repetitive daily activities in these patients depends more on a reduced muscle blood flow than on limitations in O(2) utilization.

Topics: Adult; Case-Control Studies; Chronic Disease; Exercise; Female; Heart Failure; Hemoglobins; Humans; Kinetics; Male; Middle Aged; Muscle, Skeletal; Oxygen; Oxygen Consumption; Phosphocreatine

Modular control analysis (MoCA; Diolez P, Deschodt-Arsac V, Raffard G, Simon C, Santos PD, Thiaudiere E, Arsac L, Franconi JM. Am J Physiol Regul Integr Comp Physiol 293: R13-R19, 2007) was applied here on perfused hearts to describe the modifications of the regulation of heart energetics induced in mice exposed to 3-wk chronic hypoxia. MoCA combines 31P-NMR spectroscopy and modular (top down) control analysis to describe the integrative regulation of energy metabolism in the intact beating heart, on the basis of two modules [ATP/phosphocreatine (PCr) production and ATP/PCr consumption] connected by the energetic intermediates. In contrast with previous results in rat heart, in which all control of contraction was on ATP demand, mouse heart energetics presented a shared control of contraction between ATP/PCr-producing and -consuming modules. In chronic hypoxic mice, the decrease in heart contractile activity and PCr-to-ATP ratio was surprisingly associated with an important and significant higher response of ATP/PCr production (elasticity) to PCr changes compared with control hearts (-10.4 vs. -2.46). By contrast, no changes were observed in ATP/PCr consumption since comparable elasticities were observed. Since elasticities determine the regulation of energetics of heart contraction, the present results show that this new parameter may be used to uncover the origin of the observed dysfunctions under chronic hypoxia conditions. Considering the decrease in mitochondrial content reported after exposure to chronic hypoxia, it appears that the improvement of ATP/PCr production response to ATP demand may be viewed as a positive adaptative mechanism. It now appears crucial to understand the very processes responsible for ATP/PCr producer elasticity toward the energetic intermediates, as well as their regulation.

Topics: Adaptation, Physiological; Adenosine Triphosphate; Animals; Chronic Disease; Disease Models, Animal; Elasticity; Energy Metabolism; Female; Heart Rate; Hypoxia; Kinetics; Magnetic Resonance Spectroscopy; Mice; Mitochondria, Heart; Myocardial Contraction; Myocardium; Phosphocreatine; Systems Biology; Ventricular Pressure

Involvement of the prefrontal cortex in schizophrenia has been implicated by neuropsychological, as well as neuropathological and imaging studies. Reductions of N-acetylaspartate (NAA), an in vivo marker of neuronal integrity, have repeatedly been detected in the frontal lobes of patients with schizophrenia by proton magnetic resonance spectroscopy (1H-MRS). In chronic medicated patients, a positive correlation between NAA levels of the prefrontal cortex and cognitive functioning has been observed, but to date, there have been no studies in first-episode neuroleptic-naive patients. In this study, single-voxel 1H-MRS was used to investigate neuronal function of the dorsolateral prefrontal cortex in 15 first-episode and 20 chronic schizophrenic patients. Outcomes were compared to 20 age-matched healthy controls to assess the relationship between prefrontal metabolism and neuropsychological performance. Patients with chronic schizophrenia had significant reductions of NAA, glutamate/glutamine, and choline levels compared to first-episode patients and healthy controls. Furthermore, creatine and phosphocreatine were significantly reduced in both patient groups compared to healthy controls. In the neuropsychological tests, chronic schizophrenic patients performed significantly poorer in the Auditory Verbal Learning Task (AVLT) compared to first-episode patients. In both patient groups, NAA levels of the left frontal lobe significantly correlated with performances in verbal learning and memory. These results corroborate data from recent structural and spectroscopic imaging studies of the frontal lobes in schizophrenia, in which cortical gray matter reductions after onset of symptoms as well as reduced levels of NAA in chronic, but not in first-episode schizophrenic patients have been reported.

Topics: Adult; Aged; Antipsychotic Agents; Aspartic Acid; Choline; Chronic Disease; Cognition Disorders; Creatine; Dominance, Cerebral; Energy Metabolism; Female; Frontal Lobe; Glutamic Acid; Glutamine; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Mental Recall; Middle Aged; Neurons; Phosphocreatine; Prefrontal Cortex; Psychiatric Status Rating Scales; Reference Values; Schizophrenia; Verbal Learning

Chronic heart failure (CHF) impairs muscle O2 delivery (QO2) and, at a given O2 uptake (VO2), lowers microvascular O2 pressures (PmvO2: determined by the QO2-to-VO2 ratio), which may impair recovery of high-energy phosphates following exercise. Because CHF preferentially decreases QO2 to slow-twitch muscles, we hypothesized that recovery PmvO2 kinetics would be slowed to a greater extent in soleus (SOL: approximately 84% type I fibres) than in peroneal (PER: approximately 14% type I) muscles of CHF rats. PmvO2 dynamics were determined in SOL and PER muscles of control (CON: n= 6; left ventricular end-diastolic pressure, LVEDP: approximately 3 mmHg), moderate CHF (MOD: n= 7; LVEDP: approximately 11 mmHg) and severe CHF (SEV: n= 4; LVEDP: approximately 25 mmHg) following cessation of electrical stimulation (180 s; 1 Hz). In PER, neither the recovery PmvO2 values nor the mean response time (MRT; a weighted average of the time to 63% of the overall response) were altered by CHF (CON: 66.8 +/- 8.0, MOD: 72.4 +/- 11.8, SEV: 69.1 +/- 9.5 s). In marked contrast, SOL PmvO2, at recovery onset, was reduced significantly in the SEV group ( approximately 6 Torr) and PmvO2 MRT was slowed with increased severity of CHF (CON: 45.1 +/- 5.3, MOD: 63.2 +/- 9.4, SEV: 82.6 +/- 12.3 s; P < 0.05 CON vs. MOD and SEV). These data indicate that CHF slows PmvO2 recovery following contractions and lowers capillary O2 driving pressure in slow-twitch SOL, but not in fast-twitch PER muscle. These results may explain, in part, the slowed recovery kinetics (phosphocreatine and VO2) and pronounced fatigue following muscular work in CHF patients.

Topics: Animals; Chronic Disease; Female; Heart Failure; Microcirculation; Muscle Contraction; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Oxygen; Oxygen Consumption; Partial Pressure; Peroneal Nerve; Phosphocreatine; Rats; Rats, Sprague-Dawley

It has been suspected for some time that patients with chronic heart failure (CHF) have abnormal muscle metabolism, so in the present study the muscle metabolism of the arm and leg were compared by (31)P magnetic resonance spectroscopy ((31)P-MRS) to examine the relationship to exercise tolerance.. The study group comprised 13 patients and 11 normal controls. Calf-plantar and forearm-wrist flexion were performed to evaluate the metabolic capacity assessed as the phosphocreatine breakdown rate (PCr-slope) and muscle pH at a submaximal (70% peak) work rate (submax-pH). Exercise of both the arm and leg resulted in an earlier decrease in PCr and muscle pH in patients with CHF compared with controls. There were significant correlations between peak oxygen uptake (peak V(O2)) and the PCr-slope in both limbs in patients with CHF (forearm: r=0.63, p<0.05; calf: r=0.60, p<0.05), but no correlations in normal controls. There was a close correlation between the ventilatory anaerobic threshold (AT) and the PCr-slope in the calf (r=0.85, p<0.01), but not in the forearm in patients with CHF. Submax-pH in both upper and lower limbs was not significantly correlated to peak V(O2) or AT in either patients with CHF or controls.. Although metabolic abnormalities during exercise are seen in both arms and legs, leg muscle abnormalities, in particular, are closely related to systemic exercise intolerance in patients with CHF.

Topics: Arm; Case-Control Studies; Chronic Disease; Energy Metabolism; Exercise Test; Heart Failure; Humans; Hydrogen-Ion Concentration; Leg; Magnetic Resonance Imaging; Muscle, Skeletal; Oxygen Consumption; Phosphocreatine; Phosphorus Isotopes

Extrapyramidal side-effects (EPS), the most frequent and severe side-effects of antipsychotics, sometimes become irreversible and cause severe psychosocial disturbance in patients with schizophrenia. However, the neurobiological basis of EPS has not yet been elucidated. In this study, neurochemical correlates of EPS were examined by 1H-MR spectroscopy (1H-MRS). Sixteen medicated patients with schizophrenia and 15 age-, gender- and parental-socioeconomic-status-matched normal controls were examined using single-voxel 1H-MRS. Absolute concentrations of N-acetyl aspartate (NAA), choline-containing compounds (Cho), creatine/phosphocreatine, myo-inositol, and Glx (glutamate and glutamine) in the left putamen were evaluated. The patient group showed mild EPS and no significant metabolic abnormalities in this region. The more severe drug-induced parkinsonism assessed by the Simpson-Angus Scale, however, significantly correlated with the higher Cho concentration and tended to be correlated with the higher NAA concentration in the patient group. These results suggest a potential of 1H-MRS as a non-invasive monitoring method of neurobiological correlates of EPS associated with neuroleptic treatments in patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Aspartic Acid; Basal Ganglia Diseases; Choline; Chronic Disease; Creatine; Dominance, Cerebral; Energy Metabolism; Female; Glutamic Acid; Glutamine; Humans; Inositol; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neurologic Examination; Parkinson Disease, Secondary; Phosphocreatine; Putamen; Reference Values; Schizophrenia; Schizophrenic Psychology

Proton magnetic resonance spectra (MRS) were acquired from 1.5 x 1.5 x 1.5-cm voxels in the left and right mesial temporal lobes of 20 schizophrenic patients and 20 non-psychiatric comparison subjects. Choline (Cho) to creatine (and phosphocreatine) (Cr(PCr)) ratios were estimated as were the percent gray matter, white matter and CSF contributing to the voxel. The Cho/Cr(PCr) metabolite ratio was significantly lower in the left temporal lobe than in the right temporal lobe for both the schizophrenia subjects and control group. This difference was greater in the schizophrenia subjects. Left temporal lobe gray matter voxel content was significantly higher and white matter content was significantly lower than in the right temporal lobe for both the schizophrenia subjects and control group. This difference was the same for the schizophrenia subjects and control group. Left voxel gray matter and white matter content correlated with Cho/Cr(PCr) metabolite ratios for the schizophrenic subjects but not for the control subjects. No such correlations were noted on the right side. No significant difference was found between Cho/Cr(PCr) in the left temporal lobe or in the right temporal lobe of the schizophrenia subjects vs. the control group.

Topics: Adult; Choline; Chronic Disease; Creatine; Female; Functional Laterality; Humans; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Schizophrenia; Temporal Lobe

The failing myocardium is characterized by reductions of phosphocreatine (PCr) and free creatine content and by decreases of energy reserve via creatine kinase (CK), ie, CK reaction velocity (Flux(CK)). It has remained unclear whether these changes contribute directly to contractile dysfunction. In the present study, myocardial PCr stores in a heart failure model were further depleted by feeding of the PCr analogue beta-guanidinopropionate (GP). Functional and metabolic consequences were studied.. Rats were subjected to sham operation or left coronary artery ligation (MI). Surviving rats were assigned to 4 groups and fed with 0% (n=7, Sham; n=5, MI) or 1% (n=7 Sham+GP, n=8 MI+GP) GP. Two additional groups were fed GP for 2 or 4 weeks before MI. After 8 weeks, hearts were isolated and perfused, and left ventricular pressure-volume curves were obtained. High-energy phosphate metabolism was determined with (31)P NMR spectroscopy. After GP feeding or MI, left ventricular pressure-volume curves were depressed by 33% and 32%, respectively, but GP feeding in MI hearts did not further impair mechanical function. Both MI and GP feeding reduced PCr content and Flux(CK), but here, effects were additive. In MI+GP rats, PCr levels and Flux(CK) were reduced by 87% and 94%, respectively. Although ATP levels were maintained in the GP and MI groups, ATP content was reduced by 18% in MI+GP hearts. Furthermore, 24-hour mortality in GP-prefed rats was 100%.. Rats with an 87% predepletion of myocardial PCr content cannot survive an acute MI. Chronically infarcted hearts subjected to additional PCr depletion cannot maintain ATP homeostasis.

Topics: Adenosine Triphosphate; Animals; Blood Flow Velocity; Body Weight; Chronic Disease; Coronary Circulation; Coronary Vessels; Disease Models, Animal; Guanidines; Heart; Heart Rate; Homeostasis; In Vitro Techniques; Ligation; Magnetic Resonance Spectroscopy; Myocardial Infarction; Organ Size; Phosphocreatine; Phosphorus Isotopes; Propionates; Rats; Rats, Wistar; Survival Rate; Ultrasonography; Ventricular Function, Left

Proton magnetic resonance spectroscopic imaging (1H MRSI) can lateralize the epileptogenic frontal lobe by detecting metabolic ratio abnormalities in frontal lobe epilepsy (FLE). We used 1H MRS to lateralize and localize the epileptogenic focus, and we also sought to characterize further the metabolic abnormality in FLE.. We measured signals from N-acetyl aspartate (NAA), choline-containing compounds (Cho), and creatine + phosphocreatine (Cr) in the supraventricular brain of 14 patients with frontal or frontoparietal epilepsy and their matched controls. The supratentorial brain also was segmented into gray matter, white matter, and cerebrospinal fluid classes. Regional metabolite alterations were compared with localizing and lateralizing results from other examination modalities and with histology from three patients.. Spectroscopy lateralized the epileptogenic focus in 10 patients in agreement with video-EEG and functional imaging. In four patients, spectroscopy showed bilateral, focal metabolic abnormality, whereas video-EEG suggested unilateral or midline abnormality. In the epileptogenic focus, Cho and Cr were increased by 23% and 14%, respectively, and NAA was decreased by 11%, suggesting metabolic disturbances both in the glial and in the neuronal cell pools. Two Taylor dysplasia lesions confirmed by histology and one with radiologic diagnosis showed high Cho and low or normal NAA, whereas two dysembryoplastic neurogenic tumors had normal Cho and low NAA. Contralateral hemisphere NAA/(Cho + Cr) was decreased in FLE, indicating diffusely altered brain metabolism. Segmentation of brain tissue did not reveal atrophic changes in FLE.. Spectroscopy is useful in lateralizing frontoparietal epilepsy and shows promise as a "noninvasive biopsy" in epileptogenic lesions.

Topics: Adolescent; Adult; Aspartic Acid; Brain; Child; Child, Preschool; Chronic Disease; Creatine; Electroencephalography; Epilepsy, Frontal Lobe; Female; Frontal Lobe; Functional Laterality; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Monitoring, Physiologic; Neuroglia; Neurons; Parietal Lobe; Phosphocreatine; Videotape Recording

The authors performed a MRSI study of the anterior cingulate gyrus in 19 schizophrenic patients under stable medication and 16 controls in order to corroborate previous findings of reduced NAA in the anterior cingulate region in schizophrenia. Furthermore, correlations between NAA in the anterior cingulate gyrus and age or illness duration have been determined. A decreased NAA signal was found in the anterior cingulate gyrus of patients compared to controls. Subdividing the patient group into two groups depending on medication revealed that the group of patients receiving a typical neuroleptic medication showed a lower mean NAA in comparison to the group of patients receiving atypical antipsychotic drugs. No significant group differences in the creatine and phosphocreatine signal or the signal from choline-containing compounds were found. The NAA signal significantly correlated with age, and therefore, individual NAA values were corrected for the age effect found in the control group. The age-corrected NAA signal in schizophrenia correlated significantly with the duration of illness. The detected correlations of NAA decrease with age and illness duration are consistent with recent imaging studies where progressing cortical atrophy in schizophrenia was found. Further studies will be needed to corroborate a possible favorable effect of atypical antipsychotics on the NAA signal.

Topics: Adult; Antipsychotic Agents; Aspartic Acid; Chronic Disease; Clozapine; Creatine; Female; Gyrus Cinguli; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphocreatine; Reference Values; Risperidone; Schizophrenia; Treatment Outcome

The brain energy metabolism of rats affected by chronic hepatic encephalopathy due to portacaval shunting was monitored by in vivo 31P-nuclear magnetic resonance spectroscopy before and after ammonium acetate administration. With respect to healthy unoperated and to sham operated controls, portacaval shunting decreased the levels of the nuclear magnetic resonance (NMR) visible brain phosphocreatine and nucleoside phosphates, and the intracellular [free Mg(2+)]. Ammonium acetate induced a further decrease of the levels of the NMR detectable phosphocreatine and nucleoside triphosphates and of the [free Mg(2+)], while the PMR spectra of the brain of non-shunted rats did not show any significant change even after treatment with ammonium acetate.

Topics: Ammonia; Animals; Brain; Chronic Disease; Energy Metabolism; Hepatic Encephalopathy; Magnetic Resonance Spectroscopy; Male; Nucleotides; Phosphates; Phosphocreatine; Rats; Rats, Sprague-Dawley

Prolonged atrial fibrillation (AF) results in (ultra)structural remodelling of atrial cardiomyocytes resembling alterations seen in ischemia-induced ventricular hibernation. The mechanisms underlying these changes are incompletely understood. In the present study we explored the hypothesis that a profound imbalance in energy status during chronic AF acts as a stimulus for structural remodelling.. The content of high energy-phosphates and related compounds together with a selected number of mitochondrial enzymes, known to be altered under ischemic conditions, were determined in tissue samples taken from atria of goats in sinus rhythm (SR) and after 1, 2, 4, 8 and 16 weeks of AF maintained by burst pacing. Atrial remodelling was quantified by counting the percentage of cells with >10% myolysis. During AF structural remodelling developed progressively, after 8 weeks about 40% of the atrial myocytes were affected. The concentration of adenine nucleotides and their degradation products did not change significantly during AF. Also the activity of mitochondrial cytochrome c oxidase activity was similar during AF and SR. Mitochondrial NADH-oxidase and proton-translocating ATPase activities were not induced by AF. The tissue content of phosphocreatine decreased during the first week by 60%, but completely recovered between 8 and 16 weeks of AF.. The analysis of adenine nucleotides during AF provided no indication for the development of severe atrial ischemia. This notion is supported by enzyme cytochemical findings. However, AF-induced atrial remodelling was associated with a transient lowering of phosphocreatine content, suggesting an increase in energy demand during the early phase of AF. The subsequent recovery of the phosphocreatine pool indicates restoration of the balance between energy demand and supply in chronically fibrillating atria.

Topics: Adenosine Triphosphatases; Animals; Atrial Appendage; Atrial Fibrillation; Cardiac Pacing, Artificial; Chronic Disease; Creatine; Dogs; Female; Goats; Heart Atria; Immunohistochemistry; Microscopy, Electron; Mitochondria, Heart; Multienzyme Complexes; Myocardium; NADH, NADPH Oxidoreductases; Phosphates; Phosphocreatine; Statistics, Nonparametric

Creatine kinase reaction rates were measured by the magnetisation transfer technique in brains of healthy adult and aged rats and in rats with chronic cerebral ischemia and chronic ethanol intoxication. These measurements indicated that the rate constant of the creatine kinase reaction is significantly reduced in the case of severe chronic cerebral ischemia in aged rats. In the adult rats, during chronic ethanol intoxication after 3 weeks of administration of 3 ml of 30% ethanol once a day via a gastric tube, a significant decrease in the pseudo first-order rate constant k(for) of the creatine kinase reaction was also found. In contrast, mild chronic cerebral ischemia in adult rats produced an increase in the reaction rate 4 weeks after occlusion. At the same time, corresponding conventional phosphorus magnetic resonance spectra showed negligible changes in signal intensities.

Topics: Adenosine Triphosphate; Aging; Alcoholic Intoxication; Alcoholism; Animals; Brain; Brain Ischemia; Chronic Disease; Creatine Kinase; Phosphocreatine; Rats; Rats, Wistar

The usefulness of phosphorus-31 nuclear magnetic resonance spectroscopy (31P NMRS) for detecting heart graft rejection after transplantation has been investigated by several researchers, and it has thus been demonstrated to be a valid technique for detecting acute myocardial rejection. In this study, we investigated the value of 31P NMRS to assess chronic cardiac allograft rejection. Lewis rat hearts were transplanted into the femoral region of F-344 rat recipients which were treated with cyclosporine, 5mg/kg body weight, by a daily intramuscular injection for 30 days beginning on the day of transplantation. The control isografts employed Lewis donors and recipients not given cyclosporine. The ratios of phosphocreatine (PCr) to inorganic phosphate (Pi), beta-adenosine triphosphate (beta-ATP) to Pi, and PCr to beta-ATP were monitored using surface coil 31P NMRS. 31P NMRS was performed 3, 30, and 60 days after transplantation, and the degree of the rejection and arteriosclerosis of the coronary arteries were then assessed histologically. The PCr:Pi and beta-ATP:Pi ratios for the allografts demonstrated a significant decrease on postoperative day (POD) 60 from that on POD 30 (PCr:Pi, P < 0.001; beta-ATP:Pi, P < 0.01). Although a significant difference existed between the isografts and allografts on POD 60 (PCr: Pi, P < 0.01; beta-ATP:P, P < 0.01), no significant difference was found in the PCr:beta-ATP ratio between the allografts and the isografts. On POD 60, the allografts showed significant graft rejection and arteriosclerotic changes in the coronary arteries. These findings therefore demonstrated the effectiveness of 31P NMRS for detecting chronic graft rejection in a rat model.

Topics: Adenosine Triphosphate; Animals; Chronic Disease; Coronary Artery Disease; Coronary Vessels; Cyclosporine; Graft Rejection; Graft Survival; Heart Transplantation; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine; Phosphorus; Phosphorus Isotopes; Rats; Rats, Inbred F344; Rats, Inbred Lew; Transplantation, Homologous

We studied the local relation of muscle perfusion and metabolism in patients with severe chronic heart failure. Alterations of skeletal muscle blood flow and oxidative capacity contribute to exercise intolerance in these patients. The interdependence of both parameters has often been questioned.. With the use of nuclear magnetic resonance, we quantified leg and muscle perfusion during reactive hyperemia in 7 patients with heart failure (New York Heart Association class III and IV) and 7 age-matched control subjects from the difference in longitudinal relaxation rate (1/T1). By using 31P nuclear magnetic resonance spectroscopy, we assessed oxidative metabolism from the creatine rephosphorylation time constant after a short ischemic exercise. Phosphocreatine recovery is slowed (74.6 +/- 11.3 vs 49.9 +/- 13.9 seconds, p = .002) and reactive hyperemic flow is reduced (48.5 +/- 24.9 vs 113 +/- 30.4 mL/100 mL per minute, p = .0005).. By using a totally noninvasive protocol, we demonstrated that reactive hyperemic flow correlates with oxidative capacity in calf muscles from patients with heart failure, showing that exercise performance and local circulatory dysfunction are decreased in parallel in severe heart failure.

Topics: Aged; Chronic Disease; Exercise Tolerance; Heart Failure; Humans; Leg; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Middle Aged; Muscle, Skeletal; Oxidative Phosphorylation; Phosphocreatine; Regional Blood Flow

Several studies have indicated that skeletal muscle is important in determining the exercise capacity of patients with chronic heart failure (CHF). However, this theory has been investigated only in experiments based on local exercise involving a small muscle mass. We investigated skeletal muscle metabolism during maximal systemic exercise to determine whether muscle metabolism limits exercise capacity in patients with CHF. We also studied the relationship between muscle metabolic abnormalities during local and systemic exercise.. Skeletal muscle metabolism was measured during maximal systemic exercise on a bicycle ergometer by a combination of the metabolic freeze method and 31P magnetic resonance spectroscopy in 12 patients with CHF and 7 age- and size-matched normal subjects. We also evaluated skeletal muscle metabolism during local exercise while subjects performed unilateral plantar flexion. Muscle phosphocreatine (PCr) was nearly depleted during maximal systemic exercise in patients with CHF and normal subjects (12.5+/-0.04% and 12.3+/-0.07%, respectively, of initial level). PCr depletion occurred at a significantly lower peak oxygen uptake (peak VO2) in patients with CHF than in normal subjects (CHF, 20.2+/-3.0 versus normal, 31.8+/-3.7 mL . min-1 . kg-1, P<0. 0001). Muscle metabolic capacity, evaluated as the slope of PCr decrease in relation to increasing workload, was correlated with peak VO2 during maximal systemic exercise in patients with CHF (r=0.83, P<0.001). Muscle metabolic capacity during local exercise was impaired in patients with CHF and was correlated with capacity during systemic exercise (r=0.76, P<0.01) and with peak VO2 (r=0. 83, P<0.001).. These results suggest that impaired muscle metabolism associated with early metabolic limitation determines exercise capacity during maximal systemic exercise in patients with CHF. There was a significant correlation between muscle metabolic capacity during systemic and local exercise in patients with CHF.

Topics: Adult; Cardiac Output, Low; Chronic Disease; Exercise; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Phosphocreatine; Physical Endurance; Reference Values

Creatine kinase reaction rates were measured by magnetisation transfer technique in the brain of healthy adult and aged rats and in the rats with mild or severe chronic cerebral ischemia. These measurements indicated that the rate constant of the creatine kinase reaction is significantly reduced in the case of chronic brain ischemia in aged rats. In contrast, occlusion of both carotid arteries in adult rats produced a slight increase in the reaction rate 4 weeks after occlusion. At the same time, corresponding conventional phosphorus magnetic resonance spectra showed negligible changes in signal intensities.

Topics: Aging; Animals; Brain; Brain Ischemia; Chronic Disease; Kinetics; Nuclear Magnetic Resonance, Biomolecular; Phosphocreatine; Phosphorus; Rats; Rats, Wistar

To study how neuronal cells are affected by development of chronic cerebral vasospasm after subarachnoid hemorrhage (SAH), the changes in neuronal metabolites during development of vasospasm were evaluated by in vivo localized proton magnetic resonance spectroscopy (MRS) in primates.. SAH was produced by introduction of a blood clot around the right middle cerebral artery and the right side of the circle of Willis. MRS experiments were performed before SAH and on Days 7 and 14 after SAH. Multislice magnetic resonance images were obtained to locate the volume of interest (1.0 cm3) in the bilateral parietal regions. The peak areas for choline compounds, the sum of creatine and phosphocreatine, and N-acetyl-aspartate were calculated.. Angiograms revealed approximately 50% reduction of vessel caliber for the right main cerebral arteries on Day 7. Magnetic resonance imaging revealed no apparent cerebral infarction, even in the spasm-side hemisphere. MRS revealed a significant (P < 0.05) reduction of the N-acetyl-aspartate/creatine and phosphocreatine ratio on Days 7 and 14 and a significant increase in the choline/creatine and phosphocreatine ratio on Day 7, in the spasm-side parietal region. In the sham-operated animals, there were no significant changes in these ratios in the bilateral parietal region on Days 7 and 14 after the operation.. The results suggested that the development of cerebral vasospasm after SAH caused ischemic injury in a subpopulation of neuronal cells, even when no apparent cerebral infarction was shown. Proton MRS may be useful to evaluate how neuronal cells are affected by the ischemic insult during development of vasospasm in clinical situations.

Topics: Animals; Aspartic Acid; Brain; Brain Ischemia; Cerebral Angiography; Cerebrovascular Circulation; Choline; Chronic Disease; Cognition Disorders; Creatinine; Energy Metabolism; Female; Ischemic Attack, Transient; Macaca fascicularis; Magnetic Resonance Imaging; Neurons; Phosphocreatine; Subarachnoid Hemorrhage

We quantified the concentration of metabolites observed by proton MRS using the tissue water signal as an internal standard. A phantom containing known concentrations of NAA (10 mM) and Cr (5 mM) was used for the study of methodological accuracy. Clinical utility was evaluated by the measurement of patients with severe stenosis or obstruction of the unilateral internal carotid artery. The concentration of tissue water was compensated using a proton-density weighted image measured with a water bag attached to the head. The calculated concentrations of NAA and Cr in the phantom were 9.2 mM (SD: 1.2) and 5.6 mM (SD: 0.7), respectively. On the ischemic side of the brain, the concentrations of NAA and Cr were lower than on the opposite side, but the concentration of choline (Cho) was almost the same on the two sides. The NAA/Cr ratio showed no statistically significant differences between the two sides, because the concentration of Cr was shown to be decreased in the ischemic area. We consider that quantitative evaluation of proton MRS might reveal changes in single metabolites clearly, thereby facilitating understanding of the results of proton MRS.

Topics: Aspartic Acid; Brain; Brain Ischemia; Chronic Disease; Creatine; Humans; Magnetic Resonance Spectroscopy; Phantoms, Imaging; Phosphocreatine; Sensitivity and Specificity

To study the mechanisms of limited exercise capacity and skeletal muscle energy production in male patients with congestive heart failure.. Muscle biopsy study.. Skeletal muscle metabolic response to maximal bicycle exercise was studied in 10 patients with chronic congestive heart failure (ejection fraction 0.22 +/- 0.05; peak oxygen consumption, VO2 15.1 +/- 4.9 ml.min-1.kg-1) and in nine healthy subjects (peak VO2 33.5 +/- 6.7 ml.min-1.kg-1). Activities of skeletal muscle enzymes were measured from the vastus lateralis muscle of 48 patients (ejection fraction 0.24 +/- 0.06, peak VO2 17.4 +/- 5.4 ml.min-1.kg-1) and 36 healthy subjects (peak VO2 38.3 +/- 8.4 ml.min-1.kg-1).. Although blood lactate levels were lower in patients than in healthy subjects (2.2 +/- 0.3 vs 5.2 +/- 0.6 mmol.l-1; P < 0.001) at peak exercise (96 +/- 11 W for patients and 273 +/- 14 W for controls), skeletal muscle lactate was similarly elevated (25.6 +/- 3.2 vs 22.7 +/- 2.7 mmol.kg-1) and creatine phosphate was equally depressed (P < 0.02) to low levels (7.0 +/- 1.9 vs 6.7 +/- 0.9 mmol.kg-1). The muscle ATP decreased by 21% (P < 0.05) and 8% (P < 0.01) in the patients and controls, respectively. Activities of rate limiting enzymes of the citric acid cycle (alpha-ketoglutarate dehydrogenase) and oxidation of free fatty acids (carnitine palmitoyltransferase II) were 48% and 21% lower than in controls, but the mean phosphofructokinase activity was unchanged in congestive heart failure.. It seems that the main limiting factor of exercise performance during heavy exercise is the same in congestive heart failure and healthy subjects, a high rate of skeletal muscle lactate accumulation and high-energy phosphate depletion. In congestive heart failure, the low activity of aerobic enzymes is likely to impair energy production and lead to lactate acidosis at low workloads.

Topics: Adenosine Triphosphate; Adult; Chronic Disease; Epinephrine; Exercise; Exercise Test; Exercise Tolerance; Heart Failure; Humans; Lactates; Male; Middle Aged; Muscle, Skeletal; Norepinephrine; Phosphocreatine

Proton spectra in the regions of the right and left basal ganglia were studied in 14 medicated patients with chronic schizophrenia using proton magnetic resonance spectroscopy (1H MRS). Ratios of N-acetyl-aspartate (NAA) to choline-containing compounds (Cho) were significantly reduced in the bilateral basal ganglia regions compared to normal subjects. The relative level of Cho was increased in the left basal ganglia region in comparison to normal subjects. This finding suggests the presence of disturbances in phospholipid metabolism in the basal ganglia. The level of NAA was decreased in the bilateral basal ganglia regions, which may indicate neuronal dysfunction. The 1H MRS study demonstrated dysfunctions in the basal ganglia regions in medicated patients with chronic schizophrenia.

Topics: Adult; Aspartic Acid; Basal Ganglia; Basal Ganglia Diseases; Brain Mapping; Choline; Chronic Disease; Creatine; Dominance, Cerebral; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neurocognitive Disorders; Phosphocreatine; Protons; Psychiatric Status Rating Scales; Schizophrenia

To evaluate clinicohemodynamic effect of neoton (exogenic phosphocreatine) given in an intravenous course, the drug was added to standard scheme in 53 patients with chronic cardiac failure (6.0 g/day i.v. drip for 5 days or 3.0 g/day for 10 days). 20 control patients received standard therapy alone. A course neoton produced an increase in the ejection fraction, a reduction in end-diastolic and end-systolic left ventricular volumes. It is recommended to include neoton in the scheme of chronic cardiac failure treatment in the dose 3.0 g/day for 10 days.

Topics: Cardiotonic Agents; Chronic Disease; Diuretics; Drug Administration Schedule; Drug Therapy, Combination; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Phosphocreatine; Treatment Outcome

To address the problem of the pathogenesis of diabetic neuropathy, rats were made diabetic by alloxan administration, and sciatic nerves were sampled for electrolyte and water content and levels of selected carbohydrates and intermediates in energy metabolism at 3, 6, and 26 weeks. Significant increases were seen in the nerve content of glucose, sorbitol, and fructose. Decreases of myo-inositol were not statistically significant. Glucose-6-phosphate was increased at all times; fructose-1,6-bisphosphate was elevated at 6 and 26 weeks. Nerve ATP and phosphocreatine levels were both increased concomitantly, as was the energy charge. Nerve lactate levels increased only at 26 weeks when plasma lactate levels were also high. Plasma ketone bodies were elevated throughout the 26-week experimental interval. It is postulated that ketone bodies were being used as alternative metabolic fuels in diabetic nerve, thereby causing inhibition of pyruvate oxidation and increased aerobic production of lactate. Increased plasma ketone body levels could also inhibit hepatic lactate uptake. There was no other evidence for hypoxia/ischemia. Lactate:pyruvate ratios did not differ from control values at any time in these ketotic hypoinsulinemic animals. Five major hypotheses have been proposed to explain the pathogenesis of diabetic neuropathy: 1) hypoxia/ischemia, 2) hyperglycemic pseudohypoxia, 3) myo-inositol deficiency, 4) fructose and polyol accumulation and osmotic disequilibrium, and 5) nonenzymatic glycation of macromolecules by fructose and glucose. The data obtained in this study seem to fit best with hypotheses 4 and perhaps 5.

Topics: Acute Disease; Adenosine Triphosphate; Animals; Carbohydrate Metabolism; Chronic Disease; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Electrolytes; Energy Metabolism; Fructose; Glucose; Male; Peripheral Nervous System Diseases; Phosphocreatine; Polymers; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Sorbitol

The benefit of cardioplegic cardiac arrest for the protection of immature myocardium is controversial. We therefore investigated the efficacy of (1) topical hypothermia alone, (2) slow cooling by coronary perfusion hypothermia, and (3) cardioplegic cardiac arrest for the protection of isolated immature rats hearts (28 days) during 8 hours of global ischemia at 10 degrees C. The study was conducted in hearts from rats that were kept hypoxemic by lifelong exposure to simulated high altitude. Left ventricular function, endothelial function, the metabolic status, and the extent of myocardial injury were all assessed. Topical hypothermia provided superior protection in hypoxic hearts, with recovery of the maximum developed left ventricular pressure by 70.6% +/- 18.0% (mean +/- standard deviation) of its preischemic value (p < 0.01 versus slow cooling and versus cardioplegic protection). The same pattern of recovery was observed among control hearts. The degree of recovery of endothelial function after sole topical hypothermia measured 54% +/- 36% in hypoxic hearts and 62% +/- 37% in control hearts, but was not recordable in any of the other groups. Creatine kinase leakage and the myocardial high-energy content did not differ significantly among any of the groups. Rapid cooling by topical hypothermia alone provides superior protection in chronic hypoxic, immature rat hearts versus the protection conferred by slow cooling. St. Thomas' Hospital cardioplegic solution II does not afford additional protection. Endothelial injury caused by cold asanguineous perfusates, including cardioplegia, interferes with the recovery of vascular function, which, in turn, may limit mechanical function.

Topics: Adenosine Triphosphate; Animals; Bicarbonates; Blood Gas Analysis; Calcium Chloride; Cardioplegic Solutions; Cell Hypoxia; Chronic Disease; Creatine Kinase; Endothelium, Vascular; Fetal Heart; Heart Arrest, Induced; Heart Function Tests; Hypothermia, Induced; In Vitro Techniques; Magnesium; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Oxygen Consumption; Phosphocreatine; Potassium Chloride; Rats; Rats, Wistar; Sodium Chloride; Time Factors; Ventricular Function, Left

The dynamics of the changes in myocardial phosphorylated compound contents (inorganic phosphate: Pi; phosphocreatine: PCr; ATP) induced by 10(-6)M isoprenaline administration was studied, using 31P-NMR spectroscopy, in hearts isolated from rats adapted for three weeks to normobaric hypoxia (10% of oxygen). When compared with the behaviour of control hearts, the inotropic response to Ca2+ and isoprenaline was larger in the hearts from hypoxic rats, while the oxygen consumption was similar. During administration of isoprenaline, a decrease in the myocardial contents of high energy phosphates (ATP and PCr) and an accumulation of Pi was observed in both groups. After action of isoprenaline, the hearts from hypoxic animals showed significant overshoot of PCr, that was not seen in hearts from normoxic rats. The mechanisms of these alterations are analysed and the phosphocreatine overshoot, as well as the increased rate pressure product to oxygen consumption ratio, are assumed to indicate more efficient energy conversion in the heart from animals adapted to chronic hypoxia.

Topics: Acclimatization; Adenosine Diphosphate; Adenosine Triphosphate; Adrenergic beta-Agonists; Animals; Chronic Disease; Female; Heart; Hypoxia; Isoproterenol; Kinetics; Magnetic Resonance Spectroscopy; Myocardial Contraction; Myocardium; Oxygen Consumption; Phosphates; Phosphocreatine; Rats; Rats, Wistar; Reference Values; Time Factors

To determine whether the depression of cerebral bioenergetic metabolism caused by chronic subdural hematomas can account for neurologic dysfunction and whether the degree of metabolic depression may be useful for clinical assessment and therapy.. Sixteen patients who had chronic subdural hematomas with hemiparesis and/or mental disturbances underwent phosphorous 31 MR spectroscopy before and 10 to 14 days after surgery. Phosphorous 31 MR spectroscopy was also performed on 5 patients who had chronic subdural hematomas with only slight headaches who were treated by conservative therapy and on 10 healthy volunteers.. The peroperative phosphocreatine-to-inorganic phosphate ratio (2.10 +/- 0.36) improved to normal values (2.69 +/- 0.44) after evacuation of hematomas. This improvement was accompanied by complete disappearance of hemiparesis and/or mental disturbance. Brain tissue pH also improved from 7.07 +/- 0.11 to 7.205 +/- 0.13 after surgery. On the other hand, patients who had chronic subdural hematomas with only slight headaches had the same phosphocreatine-to-inorganic phosphate ratio and brain intracellular pH as healthy volunteers.. The phosphocreatine-to-inorganic phosphate ratio may be useful for determining when to operate on patients with chronic subdural hematomas and to assess the efficacy of treatment.

Topics: Acid-Base Equilibrium; Adolescent; Adult; Aged; Aged, 80 and over; Brain; Chronic Disease; Energy Metabolism; Female; Hematoma, Subdural; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neurologic Examination; Phosphates; Phosphocreatine; Postoperative Complications

The hemodynamic effects of acute and long-term administration of creatine phosphate were studied in 23 patients with heart failure (NYHA classes II and III) under stabilized treatment. Acute creatine phosphate (5 g i.v.) induced a significant increase of the ejection fraction (FE) and of other parameters of cardiac contractility. Once these improvements of cardiac contractility were obtained by acute treatment, further significant increases in cardiac function were observed if treatment was continued for six days, i.e. telesystolic diameter and volume, as well as parietal stress were significantly reduced, and ejection fraction and shortening fraction were significantly increased. Creatine phosphate treatment has a favourable influence on the hemodynamics of patients with an obvious contractility deficit and chronic ischemia of the myocardium.

Topics: Acute Disease; Aged; Cardiomyopathy, Dilated; Chronic Disease; Drug Evaluation; Echocardiography; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Ischemia; Phosphocreatine

Fatigue and lethargy, common symptoms in uraemia, have been attributed to many factors. To assess possible bioenergetic contributions to this, we examined the forearm muscle of five patients in end-stage renal failure using 31P-magnetic resonance spectroscopy. There was a small increase in the ratio of intracellular inorganic phosphate to ATP in resting muscle, suggesting an increased cytosolic phosphate concentration. During exercise, increased phosphocreatine breakdown was accompanied by rapid intracellular acidification and an increase in calculated lactic acid accumulation in the muscle of the uraemic subjects, suggesting glycolysis dominating over oxidative phosphorylation as a source of ATP. After exercise, the half-time of phosphocreatine (PCr) recovery was longer in the uraemic subjects, suggesting diminished mitochondrial function. The initial rate of PCr resynthesis was not significantly decreased, but when account was taken of the high cytosolic ADP concentration (which drives mitochondrial oxidative ATP synthesis) the calculated maximum oxidative capacity was significantly reduced in the uraemic subjects. Thus there was evidence of mitochondrial dysfunction in uraemia due either to limitation of oxygen supply, reduced mitochondrial content, or an intrinsic mitochondrial defect. This resulted in increased phosphocreatine depletion and increased glycolytic ATP production during exercise and there was partial compensation of the mitochondrial abnormality by increased ADP concentration. In three of these patients studied after elevation of haemoglobin with erythropoeitin (from 8 to 12 g/dl), initial phosphocreatine breakdown and lactic acid accumulation during exercise were normalized, while exercise duration and calculated maximum oxidative capacity remained significantly abnormal. This suggests that anaemia contributes to these metabolic abnormalities but does not fully explain them.

Topics: Adenosine Triphosphate; Aged; Anemia; Chronic Disease; Energy Metabolism; Exercise; Humans; Hydrogen-Ion Concentration; Kidney Failure, Chronic; Lactates; Lactic Acid; Male; Middle Aged; Muscles; Phosphocreatine; Uremia

Magnetic resonance imaging and spectroscopy were performed in several types of muscular disorders. In acute stages, 31P spectra showed remarkable changes compared with normals, and T2-weighted MR images were most sensitive in delineating the pathology. Fatty degeneration of muscle in chronic diseases yielded high contrast in T1-weighted MRI and could be quantified by 1H-MRS including the chemically selective determination of proton T1 values. In order to evaluate true abundance rations of phosphorus metabolites, 31P relaxation times T1 of muscle were measured by localized inversion recovery.

Topics: Acute Disease; Adenosine Triphosphate; Adipose Tissue; Adult; Body Water; Chronic Disease; Energy Metabolism; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Phosphates; Phosphocreatine; Polymyositis

To determine whether cardiac hypertrophy secondary to chronic renovascular hypertension is associated with altered in vivo myocardial metabolism, phosphorus-31 nuclear magnetic resonance saturation transfer techniques were used to study creatine kinase (CK) kinetics in six chronically hypertensive dogs with moderate cardiac hypertrophy and eight control dogs. The forward rate constant of CK and the flux of phosphocreatine to adenosine triphosphate were determined in both groups of dogs before and during norepinephrine administration (1 microgram/kg per min), used to increase heart rate x systolic blood pressure (rate-pressure product), cardiac output and oxygen consumption. Baseline and norepinephrine-induced changes in rate-pressure product, cardiac output and oxygen consumption were similar in both groups of dogs, as were baseline forward rate constant and flux of phosphocreatine to adenosine triphosphate. However, the norepinephrine-induced changes in forward rate constant and flux were significantly less in hypertensive than in control dogs (p less than 0.05) even though changes in hemodynamic and functional variables were similar in both groups. These data demonstrate that moderate myocardial hypertrophy is associated with altered CK kinetics, which do not appear to affect the heart's ability for global mechanical recruitment at this stage in the hypertensive process. It is possible that the changes in myocardial enzyme kinetics may contribute to diastolic dysfunction previously reported in this model and may be a precursor for ultimate development of heart failure if hypertension is maintained for prolonged periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Cardiomegaly; Chronic Disease; Creatine Kinase; Disease Models, Animal; Dogs; Echocardiography; Epinephrine; Heart; Hypertension, Renovascular; Kinetics; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine; Phosphorus Radioisotopes

High-energy phosphate levels were measured in the canine cerebral artery during chronic vasospasm. Subarachnoid hemorrhage and vasospasm were induced by percutaneous injections of autologous venous blood into the cisterna magna. Narrowing of the artery was confirmed by angiography 7 days later. Levels of adenosine phosphates (adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP)), guanosine phosphates (guanosine triphosphate (GTP) and guanosine diphosphate (GDP)), and creatine phosphate (CrP) in the basilar artery were quantified using high-performance liquid chromatography. The total creatine (Crtotal) content was measured by a spectrophotometric method after acid hydrolysis of CrP. Levels of ATP, GTP, and CrP were markedly reduced in the spastic arteries, and ratios of ATP:ADP, GTP:GDP, and CrP:Crtotal were significantly decreased. The results indicate a serious disturbance in the energy metabolism that takes place in the cerebral artery during chronic vasospasm.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Cerebral Arteries; Chronic Disease; Dogs; Female; Guanosine Diphosphate; Guanosine Triphosphate; Ischemic Attack, Transient; Male; Phosphates; Phosphocreatine; Subarachnoid Hemorrhage

A study was performed to determine quantitatively the alterations in phosphorus metabolite concentrations and pH in regions of the human brain damaged by chronic stroke. Image-guided phosphorus-31 magnetic resonance spectroscopy was performed on the brains of eight healthy subjects and six patients with cerebral infarction of more than 3 months duration. Phosphorus metabolite concentrations in infarcted regions were reduced 8%-67%. Significant decreases occurred in phosphomonoester (PME), phosphodiester (PDE), and adenosine triphosphate (ATP) concentrations, while inorganic phosphate (Pi) and phosphocreatine (PCr) concentrations showed smaller, nonsignificant decreases. The PCr/ATP ratio was significantly increased, while the ATP/Pi ratio was somewhat lower. The phospholipid ratio PDE/PME was also significantly increased, while the ratios of phospholipid (PME, PDE) to phosphate (PCR, Pi) metabolites were significantly decreased. The pH of the infarcted region indicated significantly more alkalinity than in the normal brain. The results suggest that chronic stroke is associated with significant changes in brain metabolite concentrations and pH that are different from those reported for other brain diseases.

Topics: Adenosine Triphosphate; Adult; Aged; Alkalosis; Brain; Cerebral Infarction; Chronic Disease; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphocreatine; Phospholipids; Phosphorus

The calf muscle metabolism of 7 patients with stable chronic respiratory failure (PaO2 below 65 Torr) was studied using 31P NMR spectroscopy. NMR spectra were acquired at rest, during the course of 360 pedal movements at 20, 35 and 50% of the maximal voluntary contraction (MVC) and during recovery. Eight normal aged-matched subjects served as a control group. In resting muscle, no significant differences were observed between both groups as regards intracellular pH, inorganic phosphate/phosphocreatine (Pi/PCr) and beta-ATP/PCr + Pi + phosphomonoester (PME) ratios. Although effective power outputs were similar for both groups at each work level, patients exhibited a higher Pi/PCr ratio than healthy controls (3.19 +/- 1.01 vs 0.49 +/- 0.05 at 50% MVC; p less than 0.01) and a lower pHi (6.65 +/- 0.11 vs 7.06 +/- 0.02 at 50% MVC; p less than 0.01). Moreover, PCr resynthesis during recovery was slower in patients than in control subjects (t1/2 PCr = 1.26 +/- 0.30 vs 0.47 +/- 0.05 min; p = 0.01). These results suggest impairment of aerobic capacity in a non-ventilatory working muscle, probably due to hypoxemia in patients with chronic respiratory failure.

Topics: Adenosine Triphosphate; Aged; Animals; Chronic Disease; Humans; Lung Diseases, Obstructive; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Phosphates; Phosphocreatine; Phosphorus Radioisotopes; Respiratory Insufficiency

Osmotic injury induced by rapid correction of severe chronic hyponatremia has been implicated in the development of central pontine myelinolysis. Organic osmolytes known previously as "idiogenic osmoles" accumulate intracellularly to protect cells from osmotic injury. We investigated the changes of these organic osmolytes as well as electrolytes in the brain during the induction and correction of chronic hyponatremia. Using 1H-nuclear magnetic resonance spectroscopy and HPLC, we found that in rats with chronic hyponatremia (3 d, serum sodium = 109 +/- 3 meq/liter), brain concentrations of myoinositol (41%), glycerophosphorylcholine (45%), phosphocreatine/creatine (60%), glutamate (53%), glutamine (45%), and taurine (37%) were all significantly decreased compared with control values (percentage control value shown, all P less than 0.01). The contribution of measured organic osmolytes and electrolytes to the total brain osmolality change was 23 and 72%, respectively. With rapid correction by 5% NaCl infusion, significant brain dehydration and elevation of brain Na and Cl levels above the normal range occurred at 24 h. These changes were not seen with slow correction by water deprivation. Reaccumulation of most organic osmolytes except glycerophosphorylcholine is delayed during the correction of hyponatremia and is independent of the correction rate of serum sodium. It is concluded that: most of the change of brain osmolality in chronic hyponatremia can be accounted by the changes in organic osmolytes and brain electrolytes; and rapid correction of hyponatremia is associated with an overshoot of brain sodium and chloride levels along with a low organic osmolyte level. The high cerebral ion concentrations in the absence of adequate concentrations of organic osmolytes may be relevant to the development of central pontine myelinolysis.

Topics: Animals; Body Water; Brain; Chronic Disease; Creatinine; Demyelinating Diseases; Electrolytes; Hyponatremia; Magnetic Resonance Spectroscopy; Male; Osmolar Concentration; Phosphocreatine; Pons; Rats; Rats, Inbred Strains

The current study investigated the relationship between duration of outlet obstruction, magnitude of bladder mass, and functional dysfunction on the rabbit urinary bladder. Following the production of obstruction with the "cuff model", bladder wet weight increased to twice control weight within one week, and then slowly to four times control weight by one month, and remained at this level for the six month period. Bladder capacity decreased significantly by one week but returned to control volumes by one month. The in vitro ability of the bladder to empty in response to field stimulation and bethanechol decreased significantly in the one and two week obstructed bladders and remained decreased for six months. One of the major observations of this study was the relatively large variation of bladder weight and histology observed for the one to six month obstructed rabbits. Although the bladders with mild mass increase (less than 3 gm./kg. body weight) had normal distribution of urothelium and muscular elements, the bladders with moderate mass increase (3 to 6 gm./kg.) had thick extrinsic connective tissue deposits and the bladders with severe mass increase (greater than 6 gm./kg.) had thick extrinsic and intrinsic connective tissue deposits and muscular degeneration. The percentage occurrence of mild, moderate and severe mass increase was approximately the same (58%, 30% and 12%, respectively) for the one, three, and six month groups. The bladders with mild mass increase had normal bladder capacities and increased pressure responses to field stimulation and bethanechol. The bladders with moderate-to-severe mass increase showed enlarged bladder capacities and had progressively smaller pressure responses. As the magnitude of bladder mass increased, the ability of the bladder to empty in response to field stimulation and bethanechol decreased proportionally. We conclude that the functional impairment of the bladder is related to the amount of extrinsic and intrinsic connective tissue and the degree of muscle degeneration.

Topics: Adenosine Triphosphate; Animals; Bethanechol; Bethanechol Compounds; Chronic Disease; In Vitro Techniques; Male; Organ Size; Phosphocreatine; Rabbits; Urinary Bladder; Urinary Bladder Neck Obstruction

In acute and subacute hydrocephalus periventricular oedema is most prominent. At these stages of hydrocephalus, the free water content is increased and the bound water content, to the contrary, significantly decreased in the periventricular white matter. The bioenergetic state is also altered. In the chronic stage the ratio of free-to-bound water content returns to a level near the control value, leading to a decrease of periventricular oedema by formation of alternative pathways of CSF absorption. The bioenergetic state was slightly altered at this stage.

Topics: Acute Disease; Animals; Body Water; Brain; Chronic Disease; Dogs; Energy Metabolism; Hydrocephalus; Phosphates; Phosphocreatine

The effects of palmitate on mechanical failure of ischemic hearts were studied in acutely (48-hour) and chronically (6-week) streptozotocin diabetic rats. Coronary flow was reduced by 50% in isolated working hearts perfused at a 15 cm H2O preload and 100 mm Hg afterload by the one-way ball valve model of ischemia. Peak systolic pressure (PSP) and cardiac output (CO) decreased 40% by 4 minutes in control hearts perfused with 11 mM glucose and paced at 280 beats/min, compared with 50% in hearts from acutely diabetic rats. Addition of 1.2 mM palmitate to the perfusate accelerated failure rates, with PSP and CO decreasing 65% and 80% by 4 minutes in control and acutely diabetic rat hearts, respectively. In chronically diabetic rats, mechanical function could not be maintained in palmitate-perfused hearts paced at 280 beats/min, even in the absence of ischemia. If these hearts were paced at 250 beats/min and subjected to ischemia, PSP and CO decreased 90% by 4 minutes, regardless of whether palmitate was added to the perfusate. Under these conditions, PSP decreased less than 10% by 4 minutes in both palmitate- or glucose-perfused control hearts. Etomoxir (10(-9) M), a carnitine palmitoyltransferase I inhibitor, markedly decreased the rate of mechanical failure in both acutely and chronically diabetic rat hearts, in the presence and absence of palmitate. The beneficial effect of Etomoxir on mechanical function did not occur as a result of a decrease in either myocardial long chain acyl-coenzyme A or long chain acylcarnitine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Acyl Coenzyme A; Acyltransferases; Animals; Carnitine O-Palmitoyltransferase; Chronic Disease; Coronary Disease; Diabetes Mellitus, Experimental; Epoxy Compounds; Fatty Acids; Heart; In Vitro Techniques; Male; Myocardium; Phosphocreatine; Rats; Rats, Inbred Strains; Streptozocin; Thiourea

Chronic right ventricular hypertrophy (RVH) has been shown to produce changes in left ventricular diastolic properties but minimal effects on left ventricular systolic function. We studied the effects of chronic pressure overload RVH on left ventricular systolic function before and after reversible hypothermic global ischemia. RVH was induced by pulmonary artery banding (PAB) in newborn piglets (5 to 7 days). At 2 months of age the PAB group (n = 6) and a control group (n = 8) were subjected to cardiac arrest on cardiopulmonary bypass with cold crystalloid cardioplegia (10 degrees C) for 2 hr and were reperfused for 1 hr. Left ventricular function was assessed by a conductance catheter in the left ventricle measuring the end-systolic pressure-volume relationship (Emax). Preischemic and postischemic Emax were the same in the control group (4.1 +/- 0.4 mm Hg/ml before vs 4.1 +/- 0.4 mm Hg/ml after ischemia), but significantly different in the PAB group (4.7 +/- 0.5 mm Hg/ml before vs 2.97 +/- 0.7 mm Hg/ml after ischemia, p less than .05). There also was a marked drop in ATP and phosphocreatine (CP) content in the PAB group during ischemia (ATP, 20 +/- 2 mmol/kg dry wt before vs 10 +/- 2 mmol/kg dry wt after ischemia, p less than .05; PC, 26 +/- 3 mmol/kg dry wt before vs 11 +/- 1 mmol/kg dry wt after ischemia, p less than .05). In the control group there was no change in ATP content and, although CP did drop by end-ischemia, there was complete recovery by 1 hr of reperfusion but minimal CP recovery in the PAB group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Cardiac Volume; Cardiomegaly; Chronic Disease; Coronary Circulation; Heart; Heart Arrest, Induced; Lactates; Lactic Acid; Myocardium; Organ Size; Phosphocreatine; Stroke Volume; Swine

Topics: Acute Disease; Animals; Chronic Disease; Diastole; Energy Metabolism; Guinea Pigs; In Vitro Techniques; Myocardial Contraction; Myocardium; Phosphocreatine; Rats

Using phosphorous nuclear magnetic resonance, we have previously demonstrated that patients with heart failure often exhibit abnormal forearm muscle metabolism during forearm exercise. To determine if this altered metabolism is due to reduced muscle flow, we measured forearm blood flow with plethysmography and forearm muscle inorganic phosphate (Pi), phosphocreatine (PCr), and pH with 31P nuclear magnetic resonance spectroscopy at rest and during mild forearm exercise (0.2, 0.4, and 0.6 W) in 21 men with heart failure and in 12 age-matched normal male subjects. The Pi/PCr ratio was correlated with power output and the slope of this relationship was used as an index of forearm metabolism. At rest, both groups had similar Pi/PCr ratios (normal subjects 0.11 +/- 0.05; patients with heart failure 0.11 +/- 0.03; p = NS) and forearm blood flows (normal subjects 2.9 +/- 1.4 ml/min/100 ml; patients with heart failure 2.6 +/- 1.2 ml/min/100 ml; p = NS). In both groups, exercise resulted in a progressive increase in both Pi/PCr and forearm blood flow as power output increased. However, the patients exhibited a steeper slope of the Pi/PCr-to-power output relationship than did the normal subjects (normal subjects 1.4 +/- 0.6 Pi/PCr U/W; patients with heart failure 3.0 +/- 2.4 Pi/PCr U/W; p less than .03). In contrast, forearm blood flow was similar in both groups during exercise (at 0.2 W, 6.3 +/- 3.3 and 6.8 +/- 3.2 ml/min/100 ml in normal subjects and patients with heart failure, respectively; at 0.4 W, 8.7 +/- 6.5 and 8.3 +/- 3.3; at 0.6 W, 12.8 +/- 7.9 and 12.0 +/- 4.6; all p = NS). Nine of the 21 patients with heart failure had slopes of the Pi/PCr-to-power output relationship above the normal range. These nine patients also had forearm blood flows comparable to flows observed in the normal subjects. These data indicate that forearm muscle metabolism during forearm exercise is altered in a subpopulation of patients with heart failure. This metabolic alteration does not appear to be due to decreased muscle blood flow, suggesting that other mechanisms, such as alterations in mitochondrial population or substrate utilization, may be responsible.

Topics: Adult; Aged; Chronic Disease; Energy Metabolism; Exercise Test; Forearm; Heart Failure; Hemodynamics; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Phosphates; Phosphocreatine; Plethysmography; Time Factors

Nine patients with chronic iliac vein obstruction and venous claudication were investigated. Intramuscular pressure was measured in the anterior tibial and the deep posterior compartments in both legs at rest and during exercise. The pressures were significantly higher in the leg with iliac vein obstruction (39 +/- 10 mm Hg) than in the contralateral leg (26 +/- 12 mm Hg) at rest as well as during exercise (60 +/- 16 mm Hg and 41 +/- 15 mm Hg, respectively) in the deep posterior compartment. Similar changes were observed in the anterior tibial compartment. Muscle water content was higher (P less than 0.01) in the obstructed leg and contributes to the explanation for the high intramuscular pressure in this leg. Muscle blood flow, adenosine triphosphate, phosphocreatine, and lactate were determined in the gastrocnemius muscles at rest and at exercise. Muscle blood flow, measured with the 133xenon clearance technique, was lower in the obstructed leg (17.5 ml/min, 100 gm) than in the control leg (28.1 ml/min, 100 gm) during exercise. Lactate increased more (P less than 0.05) in the obstructed leg. It is suggested that pain in venous claudication is caused by the high intramuscular pressure, and therefore fasciotomy may be useful in the treatment of this disorder.

Topics: Adenosine Triphosphate; Adolescent; Adult; Aged; Blood Pressure; Chronic Disease; Female; Humans; Iliac Vein; Intermittent Claudication; Lactates; Lactic Acid; Leg; Male; Middle Aged; Muscles; Phosphocreatine; Venous Insufficiency; Venous Pressure

The kinetics and factors regulating alanine and glutamine formation and release were investigated in skeletal muscle preparations from control and experimentally uremic rats. These preparations maintained phosphocreatine and ATP levels in vitro which closely approximated levels found in vivo. Alanine and glutamine release from uremic muscle were increased 45.8 and 36.0%, respectively, but tissue levels were unaltered. The increased release of alanine by uremic muscle was not accounted for by decreased rates of medium alanine reutilization via oxidation to CO(2) or incorporation into muscle protein. The maximal capacity of added amino acids such as aspartate, cysteine, leucine, and valine to stimulate net alanine and glutamine formation was the same in uremic and control muscle. Epitrochlearis preparations were partially labeled in vivo with [guanido-(14)C]-arginine. On incubation, preparations from uremic animals showed a 54.6% increase in the rate of loss of (14)C-label in acid precipitable protein. Correspondingly, these same uremic preparations showed a 62.7% increase in (14)C-label appearance in the acid-soluble fraction of muscle and in the incubation media. Insulin decreased alanine and glutamine release to an extent threefold greater in uremic than in control preparations, and increased muscle glucose uptake approximately threefold in all preparations. Although basal rates of [4,5-(3)H]leucine incorporation into protein were decreased 25% in uremic muscles as compared with control muscles, insulin stimulated [(3)H]leucine incorporation nearly equally in both preparations. These data demonstrate increased alanine and glutamine production and release from skeletal muscle of chronically uremic rats. This increase appears to derive in part from an enhancement of net protein degradation which could be caused by an acceleration in the breakdown of one or more groups of muscle proteins, or by an inhibition of protein synthesis, or by both processes. The increased alanine and glutamine formation and release in uremia appears not to result from an insensitivity to insulin action. The implications of these findings for an understanding of the abnormal carbohydrate metabolism of uremia are discussed.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Alanine; Amino Acids; Animals; Carbohydrate Metabolism; Chronic Disease; Glutamine; In Vitro Techniques; Insulin; Muscle Proteins; Muscles; Phosphocreatine; Rats; Uremia

1. The concentration of metabolites in intercostal and quadriceps muscle, and pulmonary function, were studied in twelve patients with chronic obstructive lung disease and acute respiratory failure before, during and after standardized treatment at an intensive care unit. The findings were compared with those obtained in hospitalized patients of comparable age with non-pulmonary diseases. 2. On admission, when the patients had marked hypoxaemia, hypercapnia and acidosis, the concentrations of ATP and creatine phosphate were low in both intercostal and quadriceps muscle, particularly the latter. The lactate concentration was increased in relation to control values but glycogen did not differ significantly. 3. In response to therapy, the Pa,CO2 and the patient's acidosis decreased, the vital capacity increased and lung mechanics improved along with the clinical condition. At the same time there were significant increases in the concentrations of ATP, creatine phosphate and glycogen in intercostal and quadriceps muscles, to values similar to, and for glycogen in excess of, those found in control subjects. Lactate concentration fell significantly during treatment. 4. In view of the low initial muscle concentrations of ATP and creatine phosphate in the patients, it is suggested that dysfunction of the respiratory muscles may be an important component of respiratory failure. Moreover, the concentration of energy-rich compounds in muscle rose significantly as the patients responded to treatment, which emphasizes the importance of adequate nutritional therapy in this disorder.

Topics: Acute Disease; Adenosine Triphosphate; Aged; Chronic Disease; Female; Glycogen; Humans; Intercostal Muscles; Lactates; Lung Diseases, Obstructive; Male; Middle Aged; Muscles; Phosphocreatine; Respiratory Function Tests; Respiratory Insufficiency

Subcellular fractions in hearts from rats with severe acute uremia (24 hours after total nephrectomy) and moderate chronic uremia (2 weeks after five sixths nephrectomy) were studied and compared with preparations from acute and chronic sham-operated rats, respectively. Calcium- and magnesium-sensitive actomyosin adenosine triphosphatase (ATPase) activities were normal in both groups. Acute uremia was associated with a significant depression of sarcolemmal Na+,K+ ATPase activity. Calcium transport by fragmented sarcoplasmic reticulum was also depressed in the presence and absence of oxalate in acute uremia. Mitochondrial calcium transport and adenosine triphosphate (ATP) and creatine phosphate (CP) concentrations were normal in these animals. Chronic uremic animals showed no abnormal subcellular mechanisms. These data suggest a direct effect of acute uremia on some membrane functions in myocardial cells. The discrepancies observed between acute and chronic uremic groups may be due to a different degree of uremic state. The observation of depressed calcium transport by fragmented sarcoplasmic reticulum (FSR) in acute uremic hearts which were previously shown to have increased contractile reserve suggests that studies of calcium transport in FSR may not always truly reflect the contractile capacity of the heart.

Topics: Actomyosin; Acute Disease; Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Biological Transport, Active; Calcium; Chronic Disease; Male; Mitochondria, Muscle; Myocardial Contraction; Myocardium; Phosphocreatine; Potassium; Rats; Sarcoplasmic Reticulum; Sodium; Uremia

Topics: Adenosine Triphosphatases; Adolescent; Adult; Chronic Disease; Creatine Kinase; Enteritis; Female; Humans; Intestinal Mucosa; Male; Middle Aged; Phosphocreatine

Topics: Aged; Alcohols; Cardiac Complexes, Premature; Chronic Disease; Coronary Disease; Electrocardiography; Female; Heart Diseases; Humans; Male; Middle Aged; Myocardial Infarction; Phosphocreatine; Tachycardia

Topics: Aged; Cardiac Complexes, Premature; Chronic Disease; Coronary Disease; Electrocardiography; Female; Heart Diseases; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Phosphocreatine; Tachycardia

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Body Temperature Regulation; Child; Chronic Disease; Female; Humans; Male; Phosphocreatine; Phosphorus; Pyelonephritis

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiac Output; Chronic Disease; Creatine; Disease Models, Animal; Dogs; Elasticity; Heart; Heart Failure; Heart Rate; Heart Ventricles; Muscle Contraction; Myocardium; Oxygen Consumption; Pacemaker, Artificial; Phosphocreatine; Statistics as Topic; Tachycardia

Topics: Acute Disease; Animals; Brain Chemistry; Carbon Dioxide; Chronic Disease; Glutamates; Hydrogen-Ion Concentration; Hypercapnia; Ketoglutaric Acids; Lactates; Male; Phosphocreatine; Pyruvates; Rats; Time Factors

Topics: Acute Disease; Adenosine Triphosphate; Animals; Blood Glucose; Brain; Carbohydrate Metabolism; Carbon Monoxide Poisoning; Chronic Disease; Female; Glycogen; Lactates; Phosphocreatine; Pyruvates; Rats

Topics: Adult; Alcoholic Intoxication; Alcoholism; Aspartate Aminotransferases; Chronic Disease; Creatine Kinase; Humans; Male; Middle Aged; Phosphocreatine