THE EXCRETION OF l-MALIC ACID IN RELATION TO THE TRICARBOXYLIC ACID CYCLE IN THE KIDNEY*

Vishwakarma, Pravesh; Lotspeich, William D.

doi:10.1172/jci103816

Cited by 21 publications

(8 citation statements)

References 16 publications

(16 reference statements)

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“…Malate secretion appears established and probably citrate and a-ketoglutarate are secreted under conditions of metabolic alkalosis (27). It is possible that magnesium might accompany such secreted organic acid, or that magnesium complexes formed after the anion reached the urine might interfere with magnesium reabsorption, but present data contribute no direct evidence to evaluation of such possibilities.…”

Section: Effects Of Mercurial Diureticsmentioning

confidence: 55%

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Studies of the Renal Excretion of Magnesium in Man*†

Barker¹,

Elkinton²,

Clark³

1959

J. Clin. Invest.

104

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Magnesium is one of the four principal cations in extracellular fluid, and in intracellular fluid is exceeded only by potassium; yet comparatively little is known about the mechanisms involved in the renal excretion of magnesium. That such is the case must be due to a variety of factors which include difficulties in chemical analysis, the binding by protein of a relatively large portion of the ion in serum, and the formation of soluble complexes which may be handled by the kidney in a different manner from that of the ion. Such difficulties probably account for the relatively few studies to date of magnesium excretion.The experiments reported here involve 70 acute studies in man performed by usual clearance techniques. Renal hemodynamics and excretion rates of magnesium and other electrolytes were observed during multiple control periods and following eight principal experimental procedures. These were intravenous infusions of sodium lactate, sodium bicarbonate, acetazolamide, probenecid, sodium para-aminohippurate (PAH) to tubular saturation, magnesium salts, calcium salts and mercurial diuretics.The data provide a basis for examination of factors likely to affect magnesium excretion and in some instances of probable renal mechanisms involved. The major part of filtered magnesium is reabsorbed by the tubules. The existence of a quantitatively small, but perhaps important, regulatory tubular secretion of magnesium is suggested by certain indirect evidence, but is not settled by present data. In addition to changes in filtered magnesium, consideration is given to possible ef-*Laboratory facilities were aided by grants from the National Heart Institute of the United States Public Health Service fects on tubular magnesium transport of such factors as acid-base balance, possible relation to known active transport systems, specific interionic relationships especially with calcium or potassium, and formation of soluble magnesium complexes. METHODSGeneral. Fifty-three normal men between the ages of 18 and 32 served as experimental subjects for one or more renal clearance studies by standard techniques (4) with bladder catheterization and standard water loading. Control results reported are averages from three or more periods of at least 15 minutes each which followed an equilibration period of at least 45 minutes.Test procedures. The test procedure in each case consisted of the intravenous administration of some electrolyte solution or pharmacological agent. The eight major types of experiments are described below. Additional procedures were carried out to elucidate specific points and will be mentioned in appropriate sections. 1) Sodium lactate, 2.4 mEq. per Kg. body weight, as a hypertonic (0.9 M) solution was given rapidly (10 minutes) in six studies. Whenever results of lactate administration are referred to without qualification in this report it should be understood that these are the studies meant. In four other studies alterations were made in the dosage or time of administration of lactate for comparison wit...

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Section: Effects Of Mercurial Diureticsmentioning

confidence: 55%

“…Another tubular secretory transport system has been recently suggested as involving synthesis and secretion of intermediates of the citric acid cycle (27). Malate secretion appears established and probably citrate and a-ketoglutarate are secreted under conditions of metabolic alkalosis (27).…”

Section: Effects Of Mercurial Diureticsmentioning

confidence: 99%

Studies of the Renal Excretion of Magnesium in Man*†

Barker¹,

Elkinton²,

Clark³

1959

J. Clin. Invest.

104

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“…It is clear that labeled acetate is incorporated into plasma citrate (Table IV), and that this radioactively labeled citrate would be excreted by the kidneys in accordance with the demonstrated effect of pH alterations on the renal clearance of plasma citrate. It is of interest that tubular secretion of malate, another member of the tricarboxylic acid cycle, has been demonstrated (25,26) ; alterations of acid-base balance do not appear to influence the urinary excretion of this intermediate (4).…”

Section: Discussionmentioning

confidence: 99%

Effect of Acute Metabolic Acidosis and Alkalosis on Acetate and Citrate Metabolism in the Rat*

Gordon¹

1963

J. Clin. Invest.

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An enhanced urinary excretion of citrate after administration of alkali and a diminished citrate excretion after administration of ammonium chloride were first observed by Ostberg in 1931 (1). More recently, it has been pointed out that the quantity of citrate excreted in the urine is not a direct consequence of acidification or alkalinization of the urine as believed by Ostberg, but rather is related to systemic pH (2). Hypercitraturia is associated with alkalosis and hypocitraturia with acidosis. This correlation appears to be independent of the mechanism of production of the altered acid-base balance. Thus, urinary citrate is diminished in diabetic acidosis (1, 3, 4), as a result of the intracellular acidosis of potassium depletion (5, 6), and in the metabolic acidosis induced by acetazolamide (2, 7, 8), as well as by administration of NH4Cl, CaCl, and HCl. Increased excretion of citrate in the urine has been observed during respiratory alkalosis (4, 6, 9) as well as during metabolic alkalosis.Two hypotheses have been proposed to explain this effect of altered acid-base balance on urinary citrate excretion. One hypothesis holds that alterations of pH influence the synthesis of citrate and its subsequent secretion by renal tubules (10). This implies that the intracellular pH of the renal tubular cell influences substrate metabolism in the Krebs citric acid cycle with subsequent transport of metabolites from the renal cell into the tubular urine. The second hypothesis, based on data obtained by conventional clearance techniques (11, 12), suggests that acidosis results in an increased renal tubular reabsorption of citrate and alkalosis in a decreased tubular reabsorption of filtered citrate. This would implicate membrane transport as a major mechanism affected by pH changes.It has previously been shown in this laboratory that the urinary citrate is at least in part derived from the blood citrate, since an appreciable portion of intravenously administered citrate-C14 appears unchanged in the urine (13). In the present investigations, a similar experimental approach employing radioactive tracer substances was used to study the mechanism by which acute alterations of acid-base balance influence urinary citrate excretion. These experiments support the second hypothesis, namely, that there is a pH effect on renal tubular reabsorption of filtered citrate. In addition, they provide information bearing on the origin and metabolic fate of the blood citrate in alkalosis and acidosis. MATERIALS AND METHODSFed, female, Sprague-Dawley rats weighing approximately 200 g wevere used. HCl or Na2CO3, 1.5 mmoles, was administered intragastrically in a volume of 3 ml; control animals received 3 ml of water. In all experiments, 0.3 ml of the radioactive compound was injected intravenously as a neutral solution in isotonic saline 30 minutes after administration of the test solution. Animals were restrained in wire cages, and precautions were taken to separate urine and feces during the 3-hour collection period. At the appropriate tim...

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“…Similarly, Buffa & Peters (1949) found that a primary increase of tissue citrate in fluoracetate poisoning was associated with only a slight rise of blood levels. Vishwakarma & Lotspeich (1959) have shown that malate behaves similarly in the dog. They found that the clearance of malate increased after infusions of other organic acids of the Krebs's cycle, from values considerably below the glomerular filtration rate to levels which must have involved tubular secretion of malate.…”

Section: Discussionmentioning

confidence: 98%