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M L Halperin

Publications and source records attributed to M L Halperin.

At least 181 records · Page 10Linked to original sources
PubMed1982

A quantitative analysis of renal ammoniagenesis and energy balance: a theoretical approach.

Many theories have been proposed to explain the regulation of renal ammoniagenesis during chronic metabolic acidosis but none of these is entirely satisfactory. Since the activity of each of the enzymes in this pathway greatly exceeds the maximum rate of ammonium production in vivo, even when physiological substrate concentrations are used in this calculation, it follows that ammoniagenesis must be inhibited in the intact animal. We shall present a novel hypothesis for the regulation of the maximum rate of ammoniagenesis which emphasizes the fact that ATP is a product of this pathway and that a limited rate of ATP utilization could control its maximum velocity during chronic metabolic acidosis. To test the validity of our hypothesis, a quantitative analysis of the pathways of ATP production and utilization in the kidney will be reviewed. This approach is similar to one already proposed for the regulation of the maximum rate of ketogenesis in the liver.

Acidosis↗
PubMed1982

Protein wasting due to acidosis of prolonged fasting.

During a total fast in obese subjects, the daily rate of nitrogen excretion undergoes only a small further decline after 2 wk, the excretion rate being about 5 g N/day. At this time, ammonium and urea each constitute about one-half of this excretion. The purpose of this study was to consider two alternative hypotheses: first, that the near plateau in nitrogen excretion represents an irreducible minimum rate of net protein breakdown in order to supply essential organs with calories in the form of glucose; second, that protein breakdown could be further reduced by minimizing the requirement to provide nitrogen for ammonium excretion during the ketoacidosis of fasting. Because ammonium excretion is largely controlled by acid-base balance, 150 mmol of sodium bicarbonate plus 60 mmol of potassium chloride were administered daily to decrease ammonium excretion in eight obese subjects who were totally fasting for more than 14 days. Urine ammonium nitrogen fell with this treatment (from 3.8 +/- 0.4 to 2.0 +/- 0.4 g N/g creatinine). In addition, there was a smaller fall in the rate of urea excretion (from 2.5 +/- 0.2 to 2.1 +/- 0.3 g N/g creatinine) together with a fall in the blood urea nitrogen. Therefore, it appears that ammonium excretion contributes to the negative nitrogen balance of a prolonged total fast, as assessed over a 3-day period of observation, is responsible for about one-third of the net lean body mass loss.

Acidosis↗
PubMed1981

Chronic lactic acidosis in a patient with cancer: therapy and metabolic consequences.

Lactic acidosis is a life-threatening disorder in some cases. Treatment should be directed at the primary cause. Sodium bicarbonate should be added if the acidosis is very severe, or if the rate of hydrogen ion production is very rapid and not controlled. In contrast, with moderate degrees of steady state lactic acidosis and poor dietary intake, the risks of therapy with sodium bicarbonate or dichloroacetate may actually outweigh the benefits in a cachectic patient unless a dietary glucose and/or protein load is given.

Acidosis↗
PubMed1981

Evaluation of the effect of pentobarbitone anaesthesia on the plasma potassium concentration in the rabbit and the dog.

The purpose of these studies was to determine the reasons for the hypokalaemia observed in rabbits studied in our laboratory. The rabbits consumed standard rabbit chow which is rich in potassium and remained in potassium balance. Hypokalaemia was only observed following anaesthesia. A number of additional investigations were undertaken to clarify the mechanisms involved. The hypokalaemia could not be attributed to technical factors, alkalaemia, hyperinsulinaemia or hyperaldosteronism, but seemed to be a function of anaesthesia. This effect of pentobarbitone anaesthesia was not unique to the rabbit, as similar changes also occurred in the anaesthetized dog. The findings reported in this paper have significant implications with respect to the interpretation of plasma potassium concentrations in anaesthetized subjects or animals.

Acid-Base Equilibrium↗
PubMed1981

Sites of ammonia addition to tubular fluid in rats with chronic metabolic acidosis.

The purpose of this investigation was to determine in which nephron segments ammonia was added to or removed from the lumenal fluid of the rat. Ammonium was measured in proximal and distal tubular fluid samples obtained by micropuncture and in collecting duct fluid samples obtained by microcatheterization. Water abstraction was assessed by examining the tubular fluid-to-plasma inulin concentration, (TF/P)In. In normal or acidotic rats, the vast bulk of the final urine ammonium appeared in the proximal tubular fluid samples. Most of this ammonia was lost, however, in transit from the proximal to the distal tubule so that only 20 to 30% of the excreted ammonium was present at the distal site. Ammonia reentered the lumenal fluid primarily in the cortical collecting duct in acidotic rats and in the medullary collecting duct in normal rats. Although the pattern was qualitatively similar in both groups of rats, the absolute quantity of ammonium in each nephron segment of normal rats was about 10 to 20% of that in acidotic animals.

Acidosis, Renal Tubular↗
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↗
PubMed1981

Studies on the regulation of hydrogen ion secretion in the collecting duct in vivo: evaluation of factors that influence the urine minus blood PCO2 difference.

The purpose of these studies was to clarify the basis of the relationship between the urine bicarbonate concentration and the urine minus blood PCO2 difference in alkaline urine (U-B PCO2) and hence shed light on factors that influence hydrogen ion secretion in the collecting duct in vivo. The U-B PCO2 was used to monitor this latter parameter. In dogs with a normal extracellular fluid (ECF) volume, the U-B PCO2 was not primarily influenced by the urine bicarbonate concentration but rather it was related to the rate of sodium excretion. The U-B PCO2 could be abolished by amiloride when the urine bicarbonate concentration was less than 60 mm. At higher urine bicarbonate concentrations, there was a linear correlation between the U-B PCO2 and the urine bicarbonate concentration in normovolemic dogs given amiloride, but the absolute values were lower than they were in normovolemic animals not treated with amiloride. In the dogs with an expanded ECF volume, the U-B PCO2 was lower than it was in the normovolemic animals, and the U-B PCO2 was nor directly related to the urine bicarbonate concentration and not influenced by the rate of sodium excretion. Amiloride had little influence on the U-B PCO2 under these conditions. These results are interpreted to suggest that the magnitude of collecting duct hydrogen ion secretion is determined primarily by the electrical gradient generated by sodium reabsorption in normovolemic dogs and by the intracellular and lumenal hydrogen ion concentrations when the ECF volume is expanded or when active sodium reabsorption is inhibited by amiloride.

Absorption↗
PubMed1981

Studies on the mechanism whereby acidemia stimulates collecting duct hydrogen ion secretion in vivo.

The purpose of these studies was to elucidate the mechanism whereby collecting duct hydrogen ion secretion was augmented by acidemia. The urine minus blood PCO2 difference in alkaline urine (U-B PCO2) was used to evaluate this parameter. In dogs with a normal ECF volume, the U-B PCO2 factored was high, and there was no significant relationship between the U-B PCO2 factored for the urine bicarbonate concentration and the blood hydrogen ion concentrations unless amiloride, an agent that abolishes the transtubular potential difference, was present. In this latter case, the U-B PCO2 was a linear function of the urine bicarbonate concentration, and the U-B PCO2 factored for the urine bicarbonate concentration was directly proportional to the blood hydrogen ion concentration. To extend the pH range considerably, we used lysine to induce bicarbonaturia in dogs with an expanded ECF volume. Amiloride now caused only a small decrease in the U-B PCO2 at any urine bicarbonate concentration, and furthermore, it did not influence the linear relationship between the U-B PCO2 factored for the urine bicarbonate concentration and the blood hydrogen ion concentration. These results suggests that acidemia stimulates collecting duct hydrogen ion secretion by a mechanism that appears to be independent of the amiloride-sensitive component of the U-B PCO2. We speculate that the mechanism might involve an increased intracellular hydrogen ion concentration during acidemia.

Amiloride↗
PubMed1981

Effect of mineralocorticoids on collecting duct hydrogen ion secretion in the rabbit.

The purpose of this study was to elucidate the mechanism whereby a potassium infusion led to an elevation in the urine minus blood (ohm-B) PCO2 difference in alkaline urine of the rabbit. Rabbits given 9alpha-fluorohydrocortisone 16 h prior to study had a significantly high olm-B PCO2 than control rabbits. However, the ohm-B PCO2 was increased further after potassium infusion. These results suggest that the increased collecting duct hydrogen ion secretion in the rabbit may in part have been induced by mineralocorticoids and in addition been influenced by increasing the potassium concentration.

Acid-Base Equilibrium↗
PubMed1981

Implications of the finding of calcium carbonate in rabbit urine with respect to renal acidification.

Formation of calcium carbonate or carbamino compounds in a bicarbonate solution should generate hydrogen ions and thereby elevate the PCO2 of that solution. The presence of these substances in rabbit urine was established by demonstrating a significantly lower value for urine total carbon dioxide content measured by microgasometry (number of moles) than with the titration technique (number of equivalents). As there was a significant correlation between the calcium and the carbonate contents in the urine, we surmised that most of the carbonate was in the form of a suspension of calcium carbonate. Direct analysis of precipitates from rabbit bladders confirmed this impression. The formation of calcium carbonate in a solution should raise the PCO2 by the reaction: Ca2+ + 2HCO3- leads to CaCO3 + H2CO3 with subsequent dehydration of the H2CO3. In vitro studies demonstrated that the addition of 1 mmol calcium to 1 L of a 200 mM bicarbonate solution raised the PCO2 by approximately 50 mmHg (1 mmHg = 133.322 Pa). However, in vivo measurements of the PCO2 of rabbit urine containing a similar quantity of calcium carbonate revealed that there was no such rise in vivo (urine values = blood values). Therefore, the formation of calcium carbonate should have occurred at an earlier site in the nephron, thereby allowing the PCO2 to diffuse into peritubular capillaries during transit through the nephron.

Anaerobiosis↗
PubMed1981

Selected aspects of the pathophysiology of metabolic acidosis in diabetes mellitus.

Metabolic acidosis with a normal anion gap results from either bicarbonate loss or a urine acidification defect. The bicarbonate loss may be via the gastrointestinal tract or the urine, or may be indirect due to excretion of the sodium and potassium as opposed to the ammonium salts of ketone body anions. Defects in urine acidification in the diabetic have several etiologies: first, hydrogen ion secretion may be decreased because of an intrinsic defect in the hydrogen ion pump (i.e., diseases of the renal medulla); second, there may be a failure to augment hydrogen ion secretion by a favorable electrical gradient (e.g., reduced mineralocorticoids); and third, there may be a failure to generate a favorable chemical gradient to augment hydrogen ion secretion (e.g., reduced urine ammonia). Reduced levels of aldosterone associated with hyporeninemia has been termed type IV RTA, and these patients have specific therapeutic needs.

Anions↗
PubMed1981

Plasma "prorenin"-renin in Bartter's syndrome, cystic fibrosis, and chloride deficiency, and the effect of prostaglandin synthetase inhibition.

In Bartter's syndrome and in other states with ECFV contraction, very high active plasma renin (PRA greater than 78 ng/ml/hr) is associated with an essential absence of prorenin. In patients whose PRA is less than 50 ng/ml/hr, prorenin accumulates significantly. Patients with Bartter's syndrome treated with PG synthetase inhibitors for 1 week respond with a profound drop in renin, together with a rise in prorenin. Thus, in general, highest active renin values coexist with virtually no prorenin, moderately high renins with rising prorenin, and renins "blocked" by PG synthetase inhibitors with highest prorenin levels. Such a reciprocity between prorenin and renin suggests systemic conversion by means of a convertase mechanism apparently susceptible to PG synthetase inhibitors in vivo but not in vitro. It is also possible that these inhibitors suppress in vivo, but not in vitro, renal renin release more than prorenin release, so that the relative level of prorenin increases. This, coupled with decreased conversion to renin, may contribute to the observed elevation of prorenin.

Adolescent↗
PubMed1981

Regulation of energy metabolism in Morris hepatoma 7777 and 7800.

The pathway of fat oxidation in two experimental hepatomas was studied in order to demonstrate that a specific deficit in the energy metabolism of a tumor might contribute to the cachexia of the host. Forty-eight male Buffalo rats were divided into four groups of 12 each. One group was implanted s.c. with Morris hepatoma 7777 and one group was implanted with Morris hepatoma 7800, whereas the other two groups served as controls. All groups were fed standard rat chow diet ad libitum until the tumors reached 2 cm in diameter. The animals were then fasted for 24 hr prior to sacrifice and excision of tumor and liver for assays. During the period of tumor growth, the animals bearing the 7777 hepatoma lost weight, but the weight of the 7800 hepatoma-bearing rats did not differ significantly from that of the control animals. The livers of both groups of animals showed evidence of fatty acid oxidation in vivo and in vitro, and, as expected, during fasting, pyruvate dehydrogenase was inactivated and the rate of fatty acid synthesis was low. A qualitatively similar picture was seen with the better-differentiated 7800 hepatoma. In contrast, the 7777 hepatoma exhibited low levels of fatty acyl coenzyme CoA, no appreciable activity of carnitine palmitoyl transferase and fortified homogenates of the tumor were unable to oxidize palmitate. In keeping with these observations, pyruvate dehydrogenase remained in the active form, and fatty acid synthesis continued unabated in the fasted state in these tumors. Ketone bodies could not be oxidized by fortified homogenates of the liver or by either tumor, probably due to the lack of 3-ketoacid thiotransferase, which was undetectable in these tissues. We hypothesize that flow-through pyruvate dehydrogenase during fasting in Morris hepatoma 7777, occurring as a result of the defect in fat oxidation, contributes to the weight loss of these animals.

Acyl Coenzyme A↗
PubMed1980

Effect of blood pH on distal nephron hydrogen ion secretion.

The purpose o this study was to determine the effect of changes in blood hydrogen ion concentrations on urine acidification. The urine minus the blood PCO2 gradient in alkaline urine was used to monitor distal nephron hydrogen ion secretion. To obtain alkaline urine during acidemia, we induced proximal renal tubular acidosis by lysine. The urine minus the blood PCO2 gradient was evaluated relative to the urine bicarbonate concentration over a range of blood pH values. For any given urine bicarbonate concentration, the urine minus the blood PCO2 gradient was directly related to the blood hydrogen ion concentration. Conclusions. Acidemia stimulates and alkalemia inhibits distal nephron hydrogen ion secretion. Because the slope relating the urine minus the blood PCO2 gradient to the urine bicarbonate concentration was much steeper in urine from acidemic dogs, this change in relationship cannot be explained by a simple chemical equilibrium of the bicarbonate buffer system.

Acid-Base Equilibrium↗