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S Cheema-Dhadli

Publications and source records attributed to S Cheema-Dhadli.

At least 37 records · Page 2Linked to original sources
PubMed1992

Chronic lactic acidosis in a patient with acquired immunodeficiency syndrome and mitochondrial myopathy: biochemical studies.

A 30-yr-old man with acquired immunodeficiency syndrome treated with zidovudine developed biopsy-proven mitochondrial myopathy. Chronic lactic acidosis (lactate, 10 +/- 1 mmol/L) persisted for more than 5 wk. Liver function tests were normal, but the concentration of lactose rose to 16.1 mmol/L when 500 mmol of ethanol was infused. The concentration of lactose rose by only 1.5 mmol/L with maximally tolerated exercise. If this mitochondrial lesion compromised flux through the electron transport system, increased turnover of ATP with exercise should have exacerbated the degree of lactic acidosis because of increased need to regenerate ATP via glycolysis. Two possible explanations will be discussed: first, there was both a rapid rate of production of lactic acid in affected muscles in conjunction and an equally rapid rate of removal by uninvolved organs. Second, there was a low net rate of production of lactic acid in involved muscles despite the exercise.

Acidosis, Lactic↗
PubMed1992

Lactic acidosis, ketoacidosis, and energy turnover: "figure" you made the correct diagnosis only when you have "counted" on it--quantitative analysis based on principles of metabolism.

Three cases are presented to illustrate that quantitative analysis based on physiologic principles can help resolve certain controversies in clinical medicine. For example, in case 1, a patient with severe hypoxia, the rate of production of lactic acid is so high that only restoration of delivery of oxygen is rational therapy. If the degree of hypoxia exceeds 5.6% of demand, dichloroacetate will not lessen the degree of acidosis. Further, even when delivery of oxygen is returned to normal, the rate of fall in lactate and rise in bicarbonate in plasma will be relatively slow. In case 2, a patient with diabetic ketoacidosis, our discussion stresses that the rate of production of ketoacids is not that rapid and that the degree of ketoacidosis is influenced to a major degree by decreasing the rate of oxidation of ketoacids in brain and kidneys. Case 3, a patient with severe hyperglycemia, illustrates that insulin will only promote the oxidation of glucose at a rapid rate once the levels of fatty acids and ketoacids decline to low levels. Accelerated transport of glucose by insulin is only a permissive action for the oxidation of glucose.

Acidosis, Lactic↗
PubMed1991

Can oxygen consumption in blood in vitro be detected by a change in PCO2?

The PO2 measured in a sample of blood can be misleadingly low, owing to consumption of oxygen in vitro in patients with leukemia. The purpose of this study was to determine whether a rise in PCO2 in such blood could be a useful indication of consumption of oxygen in vitro. Because of the non-bocarbonate buffer capacity of blood and the carriage of CO2, mainly as bicarbonate, we reasoned that the rise in PCO2 would be too small to be helpful. Hence the quantitative relationship between the consumption of oxygen and the production of CO2 in blood was determined. Other reactions yielding CO2 (the titration of lactic acid) were monitored. Consumption of oxygen was stimulated in blood of normals in vitro by adding methylene blue (100 mumol/L); in addition, blood from four patients with leukemia was studied without additions. The rate of consumption of oxygen at 22 degrees C was linear over 60 min; the respiratory quotient was close to unity. The rise in PCO2 was small even when the fall in PO2 was 60 mmHg. We conclude that a rise in PCO2 is not a reliable way to diagnose consumption of oxygen in blood in vitro as patients may hyperventilate, making it very difficult to recognize a small rise in PCO2.

Adult↗
PubMed1989

Renal and hepatic aspects of ketoacidosis: a quantitative analysis based on energy turnover.

The central theme explored is that the rate of ATP production cannot exceed its rate of use in any organ or compartment. Thus the rate of ATP turnover exerts an absolute control over the rates in pathways that synthesize it. This is manifested in two major ways: substrate competition for oxidation and the influence of changes in oxygen consumption rate on the rate of fuel oxidation. By direct measurement, the rate of ketogenesis in the liver is as high as 1500 mmol/day during chronic ketoacidosis of fasting. Given the limited ate of hepatic oxygen consumption, ketogenesis and glucose synthesis from amino acids compete as precursors for hepatic ATP synthesis. Thus There is little room to increase the rate of ketoacid production further in these subjects. Energy turnover considerations in the kidney during chronic fasting seem to limit renal NH4+ production. In this case, there is competition between glutamine and ketone bodies as ATP precursors. This aspect may be important in the regulation of lean body mass catabolism of fasting. There is a "trade-off" in maintaining high circulating ketone body concentrations during fasting. The benefit is primarily for the CNS, and the cost is small loss of lean body mass owing to the need for high rates of NH4+ excretion.

Acidosis↗
PubMed1988

Effect of anaesthesia on insulin-induced hypoglycemia in rabbits.

The aim of this study was to determine how anaesthetized rabbits survive much longer than awake rabbits after receiving an insulin overdose. Insulin appeared to act in both groups of rabbits because there was a prompt fall in circulating glucose, free fatty acids, and beta-hydroxybutyrate concentrations. Carbohydrate appeared to be the principal energy source for anaesthetized rabbits because their respiratory quotient approached unity. Although the fall in glycemia was similar in both groups of rabbits, the circulating lactate concentration rose only in the anaesthetized group. This rise in lactate in the initial 60 min after insulin was given could account for most of the fall in glycemia if the source of lactate was the glucose pool. The decline in hepatic glycogen was close to 100 mumol/g liver; this would account for about one-third of the total energy turnover and close to one-half of the measured glucose appearance in these anaesthetized rabbits. As judged from the rate of oxygen consumption, muscle glycogen seemed to supply two-thirds of the fuel to be oxidized in these rabbits. However, only one-third of the lactate released from muscle was first converted to glucose and the remainder was oxidized directly to CO2. Although insulin provided the metabolic setting for a rapid rate of glucose oxidation, this rate appeared to be diminished when the overall rate of oxygen consumption was lower during anaesthesia.

3-Hydroxybutyric Acid↗
PubMed1987

Accelerated loss of lean body mass in fasting rats due to activation of pyruvate dehydrogenase by dichloroacetate.

In order to test the hypothesis that increased pyruvate dehydrogenase (PDH) activity during fasting will result in accelerated loss of lean body mass, we administered sodium dichloroacetate (DCA) intraperitoneally to eight rats during the last three days of a six-day fast, while fasting control rats were given normal saline. DCA treatment resulted in an increased proportion of PDH in the active form in liver (26.5 +/- 4.3% v 13.4 +/- 0.5%, P less than 0.01). During the three-day period of administration, DCA treated rats lost more weight than control animals (42 +/- 2 v 25 +/- 1 g, P less than 0.001) and excreted more nitrogen in the urine (18.1 +/- 1.0 v 6.8 +/- 0.6 mmol/d, P less than 0.001). Calculations from nitrogen balance data suggest that 85% of the increase in weight loss of DCA treated rats over that of control animals was attributable to loss of lean body mass. We conclude that increased flux of pyruvate through the PDH reaction in the DCA-treated animals resulted in increased protein catabolism.

Acetates↗
PubMed1987

Regulation of ethanol metabolism in the rat.

The purpose of these experiments was to examine the factors which regulate ethanol metabolism in vivo. Since the major pathway for ethanol removal requires flux through hepatic alcohol dehydrogenase, the activity of this enzyme was measured and found to be 2.9 mumol/(min X g liver). Ethanol disappearance was linear for over 120 min in vivo and the blood ethanol fell 0.1 mM/min; this is equivalent to removing 20 mumol ethanol/min and would require that flux through alcohol dehydrogenase be about 60% of its measured maximum velocity. To test whether ethanol metabolism was limited by the rate of removal of one of the end products (NADH) of alcohol dehydrogenase, fluoropyruvate was infused to reoxidize hepatic NADH and to prevent NADH generation via flux through pyruvate dehydrogenase. There was no change in the rate of ethanol clearance when fluoropyruvate was metabolized. Furthermore, enhancing endogenous hepatic NADH oxidation by increasing the rate of urea synthesis (converting ammonium bicarbonate to urea) did not augment the steady-state rate of ethanol oxidation. Hence, transport of cytoplasmic reducing power from NADH into the mitochondria was not rate limiting for ethanol oxidation. In contrast, ethanol oxidation at the earliest time periods could be augmented by increasing hepatic urea synthesis.

Alcohol Dehydrogenase↗
PubMed1987

Regulation of urea synthesis by acid-base balance in vivo: role of NH3 concentration.

The purpose of this study was to clarify how changes in acid-base balance influence the rate of urea synthesis in vivo. Since ureagenesis was increased by an ammonium infusion into rats, regulation seemed to be a function of the blood ammonium concentration. The rate of urea synthesis was constant at a fixed rate of ammonium infusion and independent of the conjugate base infused, chloride or bicarbonate. The steady-state blood ammonium concentration was higher in the rats that developed metabolic acidosis. Thus it appeared that regulation was not directly mediated by this ammonium concentration per se. The rate of urea synthesis was also independent of the blood pH. Accordingly, the rate of urea synthesis was examined as a function of the plasma NH3 concentration. The rate of ureagenesis was found to be directly proportional to the plasma NH3 concentration. Assuming that plasma NH3 levels reflect those in mitochondria, the NH3 concentration yielding half-maximal rates of urea synthesis (close to 2 microM) was in the same range as Km for the rate-limiting step in ureagenesis, carbamoyl phosphate synthetase (EC 6.3.4.16). These results suggest that, at a constant ammonium concentration, the decreased rate of ureagenesis caused by a pH fall in vitro could reflect an acidosis-induced decline in the concentration of true substrate (NH3) for this pathway.

Acid-Base Equilibrium↗
PubMed1987

Interaction of insulin with its receptor. I. Possible role of a histidine-arginine interaction.

The interaction of beef and pork insulin with its receptors on rat liver plasma membranes has been studied as a function of pH in tris buffer. The dissociation binding constant decreased from 6.5 to 1.2 nM as the pH was increased from 6.8 to 7.8. Analysis indicated that this was the result of the deprotonation of a single residue with a pK'A of 7.62 at 20 degrees C. The enthalpy change associated with this deprotonation was estimated to be -7,500 cal/mol. On the basis of these parameters it is suggested that this group is a histidine residue on the surface of the insulin receptor. The positively charged group on the insulin molecule which interacts with this histidine was not either of the N-terminal residues, nor the lysine at position B-29; by elimination, it appears to be the B-22 arginine residue.

Animals↗
PubMed1986

Is urea formation regulated primarily by acid-base balance in vivo?

Large quantities of ammonium and bicarbonate are produced each day from the metabolism of dietary protein. It has recently been proposed that urea synthesis is regulated by the need to remove this large load of bicarbonate. The purpose of these experiments was to test whether the primary function of ureagenesis in vivo is to remove ammonium or bicarbonate. The first series of rats were given a constant acid load as hydrochloric acid or ammonium chloride; individual rats received a constant nitrogen load at a time when their plasma acid-base status ranged from normal (pH 7.4, 28 mM HCO3) to severe metabolic acidosis (pH 6.9, 6 mM HCO3). Urea plus ammonium excretions and the blood urea, glutamine, and ammonium concentrations were monitored with time. Within the constraints of non-steady-state conditions, the rate of urea synthesis was constant and the plasma glutamine and ammonium concentrations also remained constant; thus it appears that the rate of urea synthesis was not primarily regulated by the acid-base status of the animal in vivo over a wide range of plasma ammonium concentrations. In quantitative terms, the vast bulk of the ammonium load was converted to urea over 80 min; only a small quantity of ammonium appeared as circulating glutamine or urinary ammonium. Urea synthesis was proportional to the nitrogen load. A second series of rats received sodium bicarbonate; urea synthesis was not augmented by a bicarbonate load. We conclude from these studies that the need to dispose of excess bicarbonate does not primarily determine the rate of ureagenesis in vivo. The data support the classical view that ureagenesis is controlled by the quantity of ammonium to be removed.

Acid-Base Equilibrium↗
PubMed1985

Effect of the blood lactate concentration on renal glutamine metabolism in dogs with chronic metabolic acidosis.

It appears that glutamine and lactate are the principal substrates for the kidney in dogs with chronic metabolic acidosis. Accordingly, the purpose of this study was to determine if a higher or lower rate of renal lactate extraction would influence the rate of glutamine extraction at a constant rate of renal ATP turnover. The blood lactate concentration was 0.9 +/- 0.01 mM in 15 acidotic dogs. However, eight dogs with chronic metabolic acidosis had a spontaneous blood lactate concentration of 0.5 mM or lower. The kidneys of these dogs extracted considerably less lactate from the arterial blood (19 vs. 62 mumol/100 mL glomerular filtration rate (GFR]. Nevertheless, glutamine, alanine, citrate, and ammonium metabolism were not significantly different in these two groups of dogs. Renal ATP balance in acidotic dogs with a low blood lactate could only be achieved if a substrate other than additional glutamine were oxidized in that segment of the nephron which normally oxidized lactate; presumably a fat-derived substrate and (or) lactate derived from glucose was now the metabolic fuel at these more distal sites. When the blood lactate concentration was greater than 1.9 mM, lactate extraction rose to 219 mumol/100 mL GFR. Glutamine, alanine, citrate, and ammonium metabolism were again unchanged; in this case, ATP balance required substrate flux to products other than carbon dioxide, presumably, gluconeogenesis. It appears that renal ammoniagenesis is a proximal event and is independent of the rate of renal lactate extraction.

Acidosis↗
PubMed1982

Theoretical aspects of weight loss in patients with cancer. Possible importance of pyruvate dehydrogenase.

In the analysis of weight loss in cancer patients, consideration must be given to decreased caloric intake, increased caloric expenditure and abnormal losses of calories. When these factors do not adequately explain the degree of weight loss, this may be due to a specific loss of lean body mass, as the caloric density of muscle is much less than that of fat. The key enzyme for the protection of lean body mass in hypocaloric states is pyruvate dehydrogenase (PDH). During fasting, fast oxidation in host tissues leads to inactivation of PDH, preventing irreversible loss of pyruvate precursors which would have to be replaced by protein breakdown. A tumor in which PDH activity remains high in the fasting state would cause loss of lean body mass in the host. This report suggests that this phenomenon may be important in certain patients with cancer cachexia.

Amino Acids↗
PubMed1982

Comparison of glucose and fructose transport into adipocytes of the rat.

The purpose of these studies was to define the properties of the systems that transport hexoses into adipocytes. Glucose appears to enter adipocytes on a single transport system whose maximum velocity is stimulated by insulin and which is competitively inhibited by cytochalasin B, 5-thioglucose, fructose, mannose and 3-O-methylglucose. In contrast, fructose enters adipocytes by at least two separate mechanisms, one an insulin-sensitive transporter (probably the glucose transporter) and the other a mechanism that is insensitive to insulin. The fructose concentration required for half-maximal rates of transport is at least an order of magnitude higher than that for glucose and the maximum velocity of fructose transport is more than double that for glucose.

3-O-Methylglucose↗
PubMed1982

Evaluation of sodium acetate as a source of alkali therapy in an experimental aerobic model of lactic acidosis due to decreased pyruvate oxidation.

An "in vitro" model of one type of lactic acidosis was produced in rat hemi-diaphragms with inhibitors of pyruvate oxidation. In order to obtain this inhibition in the absence of hypoxia, two actions were sought; inhibiting the mitochondrial pyruvate transporter and lowering the rate of pyruvate diffusion into these mitochondria. alpha-Cyano-3-hydroxy cinnamate (CNCM) was utilized because it is a specific inhibitor of the mitochondrial pyruvate transporter. Aminooxyacetate (AOA) was employed because it leads indirectly to inhibition of the entry of cytoplasmic reducing power into mitochondria. As a result of the addition of this latter compound, pyruvate levels fell and this should decrease the rate of pyruvate diffusion into the mitochondria. Glucose was the only substrate provided to this tissue and its entry into the cells was promoted by insulin. The oxidation of U-14C glucose to 14CO2 was significantly reduced in the presence of CNCM and AOA, presumably reflecting the inhibition of pyruvate oxidation. Under these conditions, lactate accumulated and pyruvate fell; however, there was a significant accumulation of lactate plus pyruvate during the incubation period. This "in vitro" lactic acidosis was markedly diminished when acetate was also present. These results are consistent with the hypothesis that provision of an alternate substrate to the TCA cycle for ATP synthesis could lead to a decreased rate of glycolysis and thereby to a decreased rate of lactic acid accumulation in this "in vitro" model of lactic acidosis.

Acetates↗
PubMed1981

A micromethod to measure ammonia.

We have described a simple technique for the measurement of picomoles or nanomoles of ammonium. Samples can be easily processed on the day of an experiment. analysis of 14C-glutamate can be done at a later date by an accurate sensitive and reliable method. We can readily process 50 samples per day. The sensitivity can be increased by using smaller volumes of ammonia-free solutions, prereacting endogenous ammonia with nonradioactive 2-oxoglutarate, and increasing the specific activity of 2-oxoglutarate. The volumes must, however, be very low so as not to diminish the ammonium concentration and thereby limit glutamate formation.

Ammonia↗
PubMed1981

Ammonia addition into the medullary collecting duct of the rat.

The purpose of these studies was to determine if ammonia is added directly to the medullary collecting duct of the rat, and if so, to estimate its quantitative contribution to ammonium excretion. Samples of fluid were obtained along the length of the medullary collecting duct by retrograde microcatheterization. To document net addition of ammonium, we measured the ammonium concentration in tubular fluid by an enzymatic isotope technique, and we calculated the degree of fluid reabsorption from the ratio of the inulin concentration in tubular fluid and plasma. The ammonium concentration corrected for water reabsorption ([NH4+]/[TF/P]In) rose progressively from the beginning to the end of the medullary collecting duct, indicating net ammonia addition to this nephron segment. By calculation, it appears that about 40% of the excreted ammonium reached the urine by direct addition of ammonia to the duct fluid.

Ammonia↗