Lactate-pyruvate Ratio Research Articles

Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock).

The increase in lactate (L) and pyruvate (P) content of arterial blood during experimental and clinical shock states and the extent to which such increases serve as measures of oxygen deficit and irreversible injury were investigated on an empirical basis. A standardized method for production of hemorrhagic shock in the Wistar rat was employed. During a 4-hour bleeding period, oxygen consumption of the rat was reduced to approximately 40% of control value, pH was reduced from 7.39 to 7.08, and a concurrent increase in L from 0.80 to 6.06 m m and in P from 0.07 to 0.18 m m were observed. Cumulative oxygen debt correlated with log L (r = 0.50; P < 0.0005) and both were significantly related to survival. Correlation of cumulative oxygen debt and survival, both with P and with computed values of the lactate pyruvate ratio (L/P) and excess lactate (XL), were of no higher magnitude. Partial correlation analysis demonstrated that neither the measurement of P nor the computation of L/P or XL improved predictability. In 142 patients who presented with clinical manifestation of circulatory shock and of whom 62 survived and 80 died, the best empirical discrimination between survivors and those who died was provided by measurement of L, which failed only 11% of the time. This was confirmed by discriminant function analysis in which the percentage probability of misclassification based on L was 12% whereas this probability increased to 21% with L/P and 19% with XL. The combination of XL and L/P with L failed to improve discrimination. In this series of patients, L served as a sensitive predictor; as L increased from 2.1 to 8.0 m m , the estimated probability of survival decreased from 90 to 10%. These studies corroborate that L alone serves as a reliable indicator, but neither the measurement of P nor the computation of L/P or XL was shown to improve either the reliability of L as a measure of cumulative oxygen debt or its value as a prognosticator of survival during shock states.

The Regulation of Gluconeogenesis: THE EFFECT OF PENT-4-ENOIC ACID ON GLUCONEOGENESIS AND ON THE GLUCONEOGENIC METABOLITE CONCENTRATIONS OF ISOLATED PERFUSED RAT LIVER

Abstract The mechanism of inhibition of gluconeogenesis by pent-4-enoic acid was studied in isolated perfused rat livers. One millimolar pent-4-enoic acid decreased gluconeogenesis from alanine by 80% and ketogenesis from linoleate by 95% and markedly increased the concentration of the gluconeogenic intermediates from lactate to 3-phosphoglycerate and decreased the concentrations of the intermediates from d-glyceraldehyde-P to glucose-6-P. This was associated with a marked decrease in the tissue lactate-pyruvate ratio and only a 20% decrease in the ATP concentration. These data suggest that gluconeogenesis was inhibited at glyceraldehyde phosphate dehydrogenase, probably as a result of decreased NADH generation from fatty acid oxidation. Another point of inhibition was present at pyruvate carboxylase, as indicated by the excessive elevation of the tissue pyruvate concentrations and by the marked decrease of the acetyl-CoA concentrations. The inhibition at pyruvate carboxylase was, however, not rate-limiting. When 8.0 mm ethanol was added after 10 min of prior perfusion with 1.0 mm pentenoic acid, ketone body production remained inhibited while gluconeogenesis from alanine was restored. It was thus possible to maintain relatively normal rates of gluconeogenesis from alanine in spite of almost complete inhibition of long chain fatty acid oxidation. Under these conditions the return toward normal of the lactate-pyruvate ratio showed that ethanol metabolism provided sufficient NADH for restoration of gluconeogenesis. When 8.0 mm ethanol was added after prior perfusion with 1.0 mm pentenoic acid for more than 10 min, the inhibition at glyceraldehyde phosphate dehydrogenase was still reversed, but gluconeogenesis remained inhibited because of inhibition at pyruvate carboxylase because of the decreased acetyl-CoA concentration. In experiments in which ethanol was added after a period of prior perfusion with pentenoic acid, the rate-limiting step for gluconeogenesis appeared to be at pyruvate carboxylase. Since varying rates of gluconeogenesis were obtained depending on the period of prior perfusion with pentenoic acid, it was possible to correlate the rate of gluconeogenesis with the tissue acetyl-CoA concentration. A sigmoidal relationship was obtained with an apparent activation constant for acetyl-CoA of 1.8 x 10-5 m, which agrees well with the value obtained for rat liver pyruvate carboxylase.

The effect of metyrapone on cellular respiration and microsomal drug oxidation

Five mM metyrapone increases the lactate-pyruvate ratio in the perfusion fluid of perfused rat livers by a factor of 9 and in rat liver slices by a factor of 3. Furthermore, it decreases the rate of oxygen uptake of liver slices by 50 per cent. The reduced metabolite of metyrapone also inhibits respiration of liver slices. From these results evidence is taken for an inhibitory effect of metyrapone and its main metabolite on the respiratory chain leading to a change of the redox status of the cell and to an increase of aerobic glycolysis. In mouse liver microsomes the rate of oxygen consumption in the absence of exogenous substrates is not affected by 2 × 10 −4 M metyrapone, although metyrapone in this concentration already inhibits microsomal drug hydroxylation. When the inhibitor SKF 525-A is added oxygen uptake increases, thereby confirming the nature of the inhibitor as a substrate of microsomal hydroxylases. This increase can be diminished by the subsequent addition of 2 × 10 −4 M metyrapone. These results indicate that metyrapone as an inhibitor of drug metabolism acts on the binding of substrates to cytochrome P-450 rather than on microsomal electron transport.

The role of the liver in the development of lactic acidosis in low flow states.

Summary The role of the liver in lactate metabolism in an experimental low flow state induced by cardiac tamponade was investigated in dogs. Arterial and venous lactate, and pyruvate levels and arterio-venous oxygen content differences were measured for the liver, gut, forequarter and hind limbs. Cardiac output and regional blood flows were determined by electromagnetic flow probes. The contribution of the liver to the development of lactic acidosis was found to be variable. When hepatic oxygen consumption was decreased, the liver was documented as the major site of lactate production with an associated increase in the lactate-pyruvate ratio of hepatic venous blood. In some experiments, however, the hepatic oxygen consumption was maintained, or even increased slightly; in these circumstances the liver was, in part, responsible for the development of lactic acidosis by impaired lactate consumption.

Dexamethasone in oligemic shock. Physiochemical effects in monkeys.

It has been established that the anaerobic metabolism in oligemic shock is the product of decreased perfusion through nonvital tissues and is demonstrated by increased blood lactate-pyruvate ratio, and excess lactate as measured by Huckabee.1This is accompanied by a metabolic acidosis. Attempts at preventing this metabolic acidosis have led to the use of vasodilators to increase nonvital tissue perfusion and buffering systems. Neither of these adjuncts attack the biochemical defect which is the anaerobic production of lactic acid and the disassociation of lactic acid to produce the hydrogen ion. Exton and Park2demonstrated that the rate of conversion of lactate to glucose is diminished in perfused livers of adrenalectomized rats, and gluconeogenesis is enhanced when exogenous corticosteroids are instilled in the perfusant. This suggests the possibility that corticosteroid-stimulated gluconeogenesis from lactate may be utilized to decrease the amount of lactate in anaerobic tissue. Furthermore, corticoids in pharmacological

Control of Gluconeogenesis in Liver: III. Effects of L-lactate, pyruvate, fructose, glucagon, epinephrine, and adenosine 3′,5′-monophosphate on gluconeogenic intermediates in the perfused rat liver

The levels of intermediary metabolites in the perfused liver have been measured to determine the location of the rate-limiting step for gluconeogenesis from lactate and the site at which glucagon, epinephrine, and cyclic AMP exert control. The reaction limiting maximum gluconeogenesis from lactate is situated between pyruvate and phosphopyruvate. Glucagon or epinephrine, acting through cyclic AMP, appears to activate a reaction in this portion of the pathway. At less than saturating levels of lactate, the rate of gluconeogenesis is determined by the activities of the above reaction and also of lactate dehydrogenase. The latter step is not under hormonal control. Gluconeogenesis is not limited by the supply of NAD+ or NADH and is virtually independent of the oxidation-reduction potential of the extramitochondrial NAD+-NADH couple as reflected by the lactate-pyruvate ratio of the tissue. The liver has potent mechanisms to restore a displaced oxidation-reduction potential to normal. Glucagon does not stimulate gluconeogenesis or inhibit lactate formation from fructose or dihydroxyacetone. It is suggested that a sparing of pyruvate oxidation or inhibition of the pyruvate kinase reaction is not responsible for the gluconeogenic action of glucagon and that effects, if any, of glucagon on reactions at the level of triose phosphate dehydrogenase, fructose diphosphatase, or glucose 6-phosphatase are of no physiological importance.

The effect of glucagon on fructose metabolism in diabetic and non-diabetic human beings

Glucagon substantially modified the plasma pyruvate and lactate responses to a fructose load in diabetic and non-diabetic human subjects. Addition of glucagon (60 μg. per minute for 30 minutes) at the 60th minute of a fructose infusion was followed by a prompt and complete reversal of the elevation of plasma pyruvate produced by the fructose alone. Lactate concentrations also decreased after glucagon, but the change was much less pronounced, so that the lactate-pyruvate ratio increased. These results appear to indicate that glucagon thwarted hepatic utilization of the carbohydrate load and concomitantly altered intra-hepatic redox potential.

Effect of assisted circulation of the left heart (synchronized arterial counterpulsation) on coronary circulation and myocardial oxygen metabolism

The basic principle of Synchronized Arterial Counterpulsation (SAC-P), as described by Clauss in 1961, appears to be both simple and sound on first inspection. If the blood is removed from the aorta just before and during ventricular systole, the resistance against which the left ventricle must eject can be reduced. The same volume of blood is then returned during ventricular diastole, possibly raising the aortic diastolic pressure and aiding the peripheral perfusion, particularly the coronary perfusion. Controversy, however, continues regarding the effect of this procedure. In the previous studies on assisted circulation, the authors satisfactorily demonstrated favorable hemodynamical changes during SAC-P, but it was thought that only hemodynamical study could not fully clarify its effect on the myocardium. Therefore, so as to assess the effect of SAC-P, the author has attempted to investigate the changes in the coronary hemodynamics and oxygen metabolism of the myocardium induced by SAC-P and to evaluate its effect in aspect of the myocardial oxygen metabolism. In order to prove the effect of this procedure, such parameters as the coronary sinus blood flow, coronary vascular resistance, exchange of oxygen, lactate and pyruvate between the aortic blood and the myocardium, lactate-pyruvate ratio (L/P ratio), myocardial excess lactate (XL) and redox potential (ΔEh) were determined. Lactate and pyruvate are of interest in the myocardial metabolism for two reasons: (1) The myocardium is the main mammalian tissue known to be capable of utilizing lactate as a substrate for energy production; and (2) lactate and pyruvate hold an important position in relation to anaerobic metabolism. Myocardial excess lactate (XL) and redox potential (ΔEh), calculated by the arterio-venous concentration of the two substrates, have been considered as the indicators of cellular oxygenation and are used quantitatively as a measure of anaerobic rate in myocardial metabolism. Thus, the author has attempted to find out the most useful of all parameters measured, in order to estimate the effect of SAC-P on the myocardium with rapidity and accuracy. The pump used in this study was a Davol Heart Pump Model 8500, which was connected to a cannule inserted into the aortic root through the brachiocephalic artery or the abdominal aorta. After pericardiotomy the catheters for the pressure-measurement and the blood sampling were inserted into the left ventricle and the aorta.

Lactate-pyruvate ratio and its relation to oxygen pressure in arterial, coronarvenous and femoralvenous blood.

Lactate-pyruvate ratio and its relation to oxygen pressure in arterial, coronarvenous and femoralvenous blood.

Biologic responsiveness to environmental stimuli in schizophrenia

Evidence has previously been presented that a plasma factor, measured by the chicken-cell lactate-pyruvate ratio method, is at a higher level in the blood of schizophrenic subjects than control subjects after exercise. The present study examined the question of whether this difference was also present after a cold pressor test or 80 reaction time trials.

Conflict between treatment and science on a research ward investigating schizophrenia.

The biological aspects of schizophrenia have been under study at the Lafayette Clinic since 1956. Previous publications described the isolation of a factor in the plasma of schizophrenic patients. The factor is identified using a chicken-cell lactate-pyruvate (L/P) ratio method. Studies have shown that schizophrenic patients can be significantly differentiated from non-schizophrenic subjects. Work has continued on the identification of the factor and on the regulation of the factor. Attempts are being made at relating behavioural attributes to some aspects of the biochemical measures. A sizeable population of subjects for these studies has been required, as well as a hospital ward. Northville State Hospital made available an adequate ward and an area sufficient for the research laboratory. The hospital ward is described. Criteria for the selection of schizophrenic patients are outlined as follows: sex, age, weight, central nervous system factors, intelligence potential, disease factors, drug factors, somatic treatment factors, duration and characteristics of illness. The selection of control subjects has always posed a problem; and at one stage of investigation, ‘trusties’, obtained through the Michigan State Department of Corrections, were utilized. The management of patients and controls is described. Discussion deals with the more serious problems encountered in the administration of this ward, including: 1) evidence of friction between staffs of a state hospital and a research clinic; 2) difficulties in obtaining a satisfactory ward physician who could willingly co-operate with both staffs; 3) feelings of nursing staff regarding patient care; 4) the unexpected difficulties encountered in the management of ‘trusties’ used as control subjects; and 5) additional efforts to help the members of the state hospital staff concerned feel that they are definitely essential for the success of the project.

Blood Lactate and Pyruvate in Pulmonary Insufficiency

Blood lactate and pyruvate levels and lactate-pyruvate ratios were determined in 20 patients with severe hypoxemia due to pulmonary insufficiency, 18 patients having arterial oxygen tensions (pO2) lower than 50 mm. of mercury, and 8 having tensions lower than 40 mm. of mercury. Most of the patients had normal lactate levels and lactate-pyruvate ratios in spite of severe hypoxemia, and there was no correlation between pO2 or oxygen content and raised levels. All but 1 patient with an elevated lactate level and lactate-pyruvate ratio had a disorder of systemic circulation with hypotension. On the other hand, failure of the right side of the heart with cor pulmonale did not lead to hyperlactatemia. In the resting state generalized tissue hypoxia and increased anaerobic metabolism are seldom due to clinical hypoxemia per se. When present, increased anaerobic metabolism is related to a systemic circulatory disorder, with resultant inadequate tissue perfusion.

Lactate-pyruvate ratio in surgically produced chronic hypoxemia in dogs

Lactate-pyruvate ratio in surgically produced chronic hypoxemia in dogs

Circulatory and ventilatory responses to postprandial exercise

The circulatory and ventilatory responses to postprandial exercise were studied in normal men and compared with the fasting responses. The findings were as follows: (1) Exercising cardiac output was not affected by the meal. (2) The heart rate was faster during postprandial exercise. (3) The duration of systolic ejection was decreased out of proportion to the faster rate after the meal. (4) No significant change in arterial pO 2, pH, or O 2 uptake was found in postprandial exercise when compared with fasting exercise. (5) The lactate-pyruvate ratio was significantly increased during exercise after a meal. It is concluded that the changes found can be best explained by a postprandial decrease in effective blood volume, an increase in myocardial inotropic state, and an alteration in the distribution of cardiac output.

Carbohydrate metabolism during fasting and hibernation in the ground squirrel.

Biochemical levels of glycogen, lactate and pyruvate determined in liver, skeletal muscle and cardiac muscle of control, fasting and hibernating groups of ground squirrels were compared. During fasting liver glycogen increased, as compared to the control, apparently as a result of glycolysis in both skeletal and cardiac muscle. The lactate-pyruvate ratio in both types of muscle greatly favored lactate. Therefore, it is possible that the formation of a ‘lactate pool’ by muscle supplies the glycogenetic needs of the liver at this time. In hibernation both liver and cardiac muscle showed increases in glycogen over control values. Possibly, this may subsequently serve as a source of energy for arousal. Lactate and pyruvate during hibernation decreased in all tissues studied due to a low metabolic rate slowing the process of glycolysis. However, the ratio between the two compounds remained within the control range. The data suggest that the mechanism of carbohydrate metabolism during fasting differs from that during hibernation.

Studies on obesity. II. Blood pyruvate and lactate curves in obese and normal subjects after ingestion of glucose.

Renewed interest in the metabolism of the obese patient has been revinced by several investigators, and reviews on the subject have been published during the last year. Since pyruvic acid is one of the key breakdown products in the intermediary metabolism of protein, fat and carbohydrate, it was thought that changes in the level of blood pyruvate in response to ingestion of glucose might provesignificant. Such a study was carried out on a group of 15 obese patients by Taylor and McHenry, but the results were not statistically different as compared to those in the control group (1). However, since pyruvic acid is so readily reduced to lactic acid, it was considered that such investigations should include determination of blood lactic-acid levels, and that the lactate-pyruvate ratio would give further information as to any deviations in the metabolism of obese subjects as compared to normal ones. Contrary to Taylor and McHenry's view, we theorized that either pyruvic or lactic acid levels would be higher than in the normal, and that there would be a delay in the return to fasting levels. This could be due to the obese person having difficulty in oxidizing pyruvic acid as rapidly as the normal person via the tricarboxylic-acid cycle, with a consequent increase in the concentration of pyruvic and/or lactic acid after ingestion of glucose.

The metabolism of lactate and pyruvate in children with congenital heart disease.

Venous blood lactic acid and pyruvic acid concentrations and lactate-pyruvate ratio were studied in 42 normal adults, 16 normal children and 18 children with congenital heart disease. There was elevation of resting values in children as compared with adults, but no significant change of values of resting children with congenital heart disease as compared with normal children. Following a standard exercise test, children with patent ductus arteriosus showed a time curve comparable to normal children, but children with cyanotic heart disease showed a persisting elevation of all values. The lactate-pyruvate ratio varied inversely with calculated mean capillary blood pO 2 .