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M L Halperin

Publications and source records attributed to M L Halperin.

At least 163 records · Page 9Linked to original sources
PubMed1985

Substrate utilization by the distal nephron in dogs with chronic metabolic acidosis: studies with ethacrynic acid.

Glutamine and lactate oxidations provide the bulk of ATP required for sodium reabsorption in the dog kidney during chronic metabolic acidosis. Indirect evidence has suggested that glutamine is oxidized in the proximal convoluted tubule; if this is true, lactate should be the major fuel of the more distal nephron sites. The purpose of these experiments was to determine which substrates were metabolized by the acidotic dog kidney when a significant proportion of sodium chloride reabsorption was inhibited in the thick ascending limb of the loop of Henle. Ethacrynic acid, a loop diuretic, caused the fractional excretion of sodium to increase from 1 to 34%. The glomerular filtration rate declined somewhat, but there was no significant change in the renal blood flow rate. Renal oxygen consumption declined in conjunction with the natriuresis. However, when the data were examined at a constant filtered load of sodium (a constant rate of ATP turnover), there was no reduction in glutamine uptake or glutamine conversion to ATP in the presence of this natriuretic agent. The major change observed concerned lactate metabolism, in the presence of ethacrynic acid, there was no longer a significant rate of lactate extraction. These data are best explained by assuming that glutamine is the fuel of the proximal convoluted tubule of the acidotic dog kidney, whereas lactate oxidation occurs principally in the nephron sites where sodium reabsorption was inhibited by ethacrynic acid.

Acidosis↗
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↗
PubMed1985

Regulation of the maximum rate of renal ammoniagenesis in the acidotic dog.

Metabolism of glutamine results in the net production of ATP; however, cells cannot sustain an ATP production rate greater than their rate of ATP utilization. The purpose of these studies was to determine whether the rate of ATP turnover in the kidney could set an upper limit on renal glutamine metabolism and thereby renal ammoniagenesis. The acidotic dog kidneys extracted glutamine, lactate, citrate, and oxygen from the arterial blood and added ammonium and alanine to the venous blood. Renal glutamine metabolism was responsible for almost all the ammonium production. Renal ATP production was estimated from the rate of oxygen consumption and appeared to be derived roughly equally from the oxidation of glutamine and lactate. There was no apparent renal glucose production from ATP balance calculations and this impression was supported when the inhibitor of gluconeogenesis, 3-mercaptopicolinate, did not inhibit ammoniagenesis. Approximately 90% of the ATP synthesized was utilized to reabsorb sodium. When the amount of ATP utilized for sodium reabsorption in the proximal convoluted tubule (assumed to be 60% of filtered sodium) was compared with the amount of ATP produced from glutamine metabolism, the values were similar despite the fact that the glomerular filtration rate in individual dogs varied more than fourfold. When the quantity of ATP expended for sodium reabsorption was decreased by the infusion of ouabain or by the constriction of one renal artery without reducing glutamine delivery, the kidney lowered its rate of ammoniagenesis to a quantitatively predictable amount.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1985

Regulation of renal ammoniagenesis in the dog with chronic metabolic acidosis: effect of a glutamine load.

We recently emphasized that ATP is an obligatory product of renal glutamine metabolism and that all cells must remain in ATP balance. Based on this, we suggested that the maximum rate of renal ammoniagenesis in dogs with chronic metabolic acidosis may be limited by the rate of ATP utilization in the kidney. Since a large infusion of glutamine led to a twofold increase in renal ammoniagenesis in acidotic dogs, we wished to evaluate the renal metabolic changes that permitted this increment within the constraints of renal ATP balance. A large glutamine infusion did not lead to an augmented rate of ATP hydrolysis because renal oxygen consumption was not increased. Two major metabolic changes could explain this stimulation while maintaining ATP balance: first, ATP production from lactate by the kidney was decreased following the glutamine infusion; second, the metabolic fate of glutamine was changed so that more ammonium per ATP was synthesized (i.e., the rates of amino acid release into the renal vein were markedly enhanced, and gluconeogenesis was now a quantitatively significant process). 3-Mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase, when infused with glutamine, apparently decreased the calculated rate of gluconeogenesis as expected; however, ammonium production did not decline, because the rate of amino acid release increased further, as did the rate of oxygen consumption. Therefore, a large glutamine infusion increased renal ammoniagenesis in dogs with chronic metabolic acidosis while maintaining ATP balance, because ATP production from other substrates was decreased and because the fate of glutamine metabolism was altered in that less ATP was formed per glutamine utilized.

Acidosis↗
PubMed1985

Distal renal tubular acidosis syndromes: a pathophysiological approach.

Ammonium is the most important component of renal acid excretion. A reduced rate of ammonium excretion is the common feature of the group of diseases called distal renal tubular acidosis. We have presented an alternative approach to patients with distal acidification defects based upon the pathophysiology of these disorders. Accordingly, the purpose of this review is to describe a revised classification based on our current understanding of collecting duct hydrogen ion secretion and ammonium addition to the lumen of the distal nephron. We have subdivided these defects into four groups: disorders of the collecting duct proton pump (pump defects); failure to generate and/or maintain an appropriate electrical gradient to favor hydrogen ion secretion (voltage defects); back-leak of hydrogen ions across an abnormally permeable collecting duct membrane (gradient defects), and diminished availability of NH3 in this nephron segment (NH3 defects). These four subtypes can be identified by measuring the urine pH and PCO2 under appropriate circumstances and evaluating the renal excretion of ammonium and potassium.

Acidosis, Renal Tubular↗
PubMed1985

Can marked hyperglycemia occur without ketosis?

The significance of ketosis in this syndrome has been evaluated from several viewpoints. With respect to acid-base considerations (pH, anion gap), ketosis was not very significant. However, with respect to sustained hyperglycemia, the combustion of less glucose than normal by the brain is critical and it is likely that ketone body metabolism plays an important role in this regard. This point can be underscored by a quantitative example. First, assume that the maximum rate of new glucose production in a fasted subject is less than 100 g of glucose per day. Second, since the brain will burn 100 g of glucose per day in a non-ketotic subject, it follows that, even in the absence of glucosuria, there will be a net daily consumption of glucose. Since the hyperglycemic individual has only an extra 100 or so g of glucose, it follows that the blood glucose concentration would approach the renal threshold in several days in the absence of ketosis. Recall that this is a minimum estimate because glucose oxidation in other organs and glucosuria will remove an additional quantity of glucose. Hyperglycemia can only be maintained in the absence of glucose intake if there is a reduced rate of glucose metabolism in the brain. The brain can diminish its rate of glucose catabolism by several mechanisms, including a diminished metabolic rate in the brain and/or the consumption of non-glucose fuels (free fatty acids or beta-hydroxybutyrate) by this organ.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetone↗
PubMed1983

Metabolic acidosis in the alcoholic: a pathophysiologic approach.

The purpose of this paper is to review the acid-base abnormalities in patients presenting with metabolic acidosis due to acute ethanol ingestion and to review the theoretical constraints on ethanol metabolism in the liver. Alcohol-induced acidosis is a mixed acid-base disturbance. Metabolic acidosis is due to lactic acidosis, ketoacidosis and acetic acidosis but the degree of each varies from patient to patient. Metabolic alkalosis is frequently present due to ethanol-induced vomiting. However, it could be overlooked because of an indirect loss of sodium bicarbonate (as sodium B-hydroxybutyrate in the urine). Nevertheless, the accompanying reduction in ECF volume may play an important role in the pathogenesis of alcoholic acidosis because it could lead to a relative insulin deficiency. Treatment of alcohol acidosis should include sodium, chloride, potassium, phosphorus, magnesium and thiamine replacements along with attention to concomitant clinical problems. Unless hypoglycemia is present, glucose need not be given immediately. We feel that insulin should be withheld unless life-threatening acidemia is present or expected. Lastly, alcohol need not be detected on admission to make the diagnosis of this metabolic disturbance. However, when present, it could contribute directly to the lactic, acetic and B-hydroxybutyric acidoses. With respect to the theoretical constraints on ethanol metabolism, it appears that "overproduction" of NADH in the liver is best averted by converting ethanol to B-hydroxybutyric acid.

Acetates↗
PubMed1983

Effect of acute changes in the PaCO2 on acid-base parameters in normal dogs and dogs with metabolic acidosis or alkalosis.

There is a linear relationship between the PaCO2 and blood hydrogen ion concentration in normal dogs, but for theoretical reasons to be discussed, we questioned whether this relationship would apply in animals with metabolic acidosis or alkalosis. To study this in more detail, animals were divided into three groups: normal, metabolically acidotic, and metabolically alkalotic. Following anesthesia and bilateral ureteral ligation, dogs were intubated and ventilated to produce acute steady state PaCO2 values corresponding to the range observed during disease states. Changes in the volume and electrolyte composition of the gastrointestinal fluid and urine as well as the concentration and distribution of lactate were evaluated in all experiments. We observed the previously described linear relationship between the PaCO2 and blood hydrogen ion concentration in normal dogs, but the slope of the regression line differed significantly from those of dogs with metabolic acidosis and metabolic alkalosis. On the other hand, there was a consistent relationship between the ratio of the PaCO2 values, but not the absolute PaCO2, and the change in the plasma bicarbonate concentration over a wide range of PaCO2 values in all groups of dogs. The chemical basis for these observations will be discussed.

Acid-Base Equilibrium↗
PubMed1983

Decreased distal acidification in acute hypercapnia in the dog.

The present studies evaluate the effect of acute hypercapnia on distal nephron H+ secretion (DNH+S) in vivo by means of the urine-blood PCO2 difference (U-B PCO2) in alkaline urine. Bicarbonaturia was induced by either a sodium bicarbonate infusion or L-lysine administration. Our results demonstrate that the U-B PCO2, as a function of the urinary bicarbonate concentration, was significantly lower during acute respiratory acidosis; this effect was not dependent on changes in glomerular filtration rate and/or fractional excretion of sodium, potassium, and chloride. Infusion of the sodium salts of sulfate, a nonreabsorbable anion, did not correct the diminished U-B PCO2. Amiloride caused the U-B PCO2 to fall in normocapnic dogs but not in hypercapnic dogs. When hypercapnia was superimposed in dogs with extracellular fluid volume contraction, there were no changes in the U-B PCO2. This study indicates that acute hypercapnia in the intact dog decreases DNH+S and is compatible with an effect of hypercapnia on the voltage-dependent component of urine acidification. The mechanism appears to be direct rather than secondary to factors that influence the rate of sodium delivery to the distal nephron.

Acidosis, Respiratory↗
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↗
PubMed1982

Metabolism and acid-base physiology.

The purpose of this paper is to review the pathways of hydrogen ion production and removal due to intermediary metabolism. The principal method of analysis employed was one based on a theoretical approach because it is the most accurate and has the broadest application. In the absence of hypoxia and insulin deficiency, carbohydrates and neutral lipids will not make significant contributions to acid-base balance. During normal metabolism, the oxidation of proteins leads to an acid load. The majority of protons are produced from the oxidation of cationic plus sulfur-containing amino acids, whereas they are removed when anionic amino acids are oxidized. Organic anions, if they can be metabolized in vivo, lead to an equivalent degree of proton removal. Small contributions to acid-base metabolism are made by phospholipid and purine oxidations. Special reactions involving calcium contribute to the acid load in that the precipitation of calcium carbonate or phosphate in bone or in the gastrointestinal tract will result in proton liberation. When all of the above are considered, the clinician can make a reasonably accurate estimate of the rate of acid production.

Acid-Base Equilibrium↗
PubMed1982

Role of acidosis in the protein wasting of fasting in the rat and the rabbit.

The purpose of these experiments was to determine if augmented renal ammoniagenesis in chronic metabolic acidosis could increase the negative nitrogen balance during prolonged fasting. To explore this question, rats and rabbits were fasted for up to 10 days because acidosis would markedly augment ammonium excretion in the rat but not in the rabbit. Since the ketoacidosis of fasting was mild in both species (less than 2 mM) and ketonuria virtually absent, a hydrochloric acid load was given to stimulate renal ammoniagenesis. Under these conditions, nitrogen balance was significantly more negative during acidosis in the rat but not in the rabbit. This increment in nitrogen excretion appeared as ammonium with no detectable difference in urea nitrogen excretion. Therefore, it appears that if more nitrogen is excreted as ammonium, net protein breakdown increases to furnish the substrate for ammoniagenesis rather than reducing the excretion of the other nitrogenous waste component urea. The implications of these findings will be discussed.

Acid-Base Equilibrium↗