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M L Halperin

Publications and source records attributed to M L Halperin.

At least 145 records · Page 8Linked to original sources
PubMed1987

The urine pH: a potentially misleading diagnostic test in patients with hyperchloremic metabolic acidosis.

The purpose of this case report is to illustrate that the urine pH may be a misleading index in the assessment of the normal renal response to metabolic acidosis. On presentation, the patient had a normal anion-gap type of metabolic acidosis; the cause of the acidosis was gastrointestinal bicarbonate loss. Since the urine pH was 6.0 when the patient was acidemic, distal renal tubular acidosis was also suspected. However, since the kidneys generated more than 190 mmol of bicarbonate per day (urine ammonium was 190 mmol/d), reduced renal acid excretion was not the cause of the acidosis. Therefore, the urine pH of 6.0 provided a false clue with respect to a renal cause for the acidosis in this setting; in contrast, the urine anion gap provides more reliable information concerning bicarbonate generation by the kidney.

Acidosis, Renal Tubular↗
PubMed1987

The relationship between the plasma potassium concentration and renal potassium excretion in the adrenalectomized rat.

The purpose of this study was to evaluate the renal mechanisms which lead to a high urine [K+] in adrenalectomized (ADX) rats devoid of aldosterone. By dividing the urine [K+] by the urine to plasma osmolality ratio the [K+] in the cortical collecting duct luminal fluid can be estimated; dividing this value by the plasma [K+] yields an index of the transtubular [K+] gradient (TTKG) in vivo. The TTKG was close to 7 in aldosterone deficient ADX rats while on a normal K+ diet and fell towards unity when amiloride or a low K+ diet was administered to these rats. With a longer time on a low K+ diet, the TTKG was less than 1 in ADX rats. This suggests that K+ was reabsorbed in the medullary collecting duct under these conditions. Hyperkalaemia appears to have an 'aldosterone-like' action in the cortical collecting duct in vivo in the absence of aldosterone in ADX rats. This action of hyperkalaemia permits normal K+ excretion rates despite the absence of mineralocorticoids.

Adrenalectomy↗
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

Renal ammonium production--une vue canadienne.

The purpose of this review is to examine the factors regulating ammonium production in the kidney and to place these factors in the perspective of acid-base balance. Renal ammonium production and excretion are required to maintain acid-base balance. However, only a portion of renal ammonium production is specifically stimulated by metabolic acidosis. One should examine urinary ammonium excretion at three levels: distribution of ammonium between blood and urine, augmented glutamine metabolism, and an energy constraint due to ATP balance considerations. With respect to the biochemical regulation of acid-base renal ammonium production, an acute stimulation of alpha-ketoglutarate dehydrogenase by a fall in pH seems to be important but this may not be the entire story. In chronic metabolic acidosis augmented glutamine entry into mitochondria (dog) or increased phosphate-dependent glutaminase activity (rat) become critical to support a high flux rate. Metabolic alterations, which diminish the rate of oxidation of alternate fuels, might also be important. The above principles are discussed in the ketoacidosis of fasting, the clinically important situation of high rates of renal ammonium production.

Acid-Base Equilibrium↗
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

Plasma glutamine and renal ammoniagenesis in dogs with chronic metabolic acidosis.

The purpose of this investigation was to determine whether the rate of glutamine metabolism in the kidneys of normal dogs and dogs with chronic metabolic acidosis was influenced by the plasma glutamine concentration. Because glutamine is a major renal energy fuel, results were examined at a constant rate of energy or ATP turnover [i.e., per 100 ml glomerular filtration rate (GFR)]. Glutamine extraction per 100 ml GFR was directly proportional to the filtered load of glutamine in normal and acidotic dogs. The slope depicting this relationship was parallel to the filtered load of glutamine; however, in normal dogs it was lower and in acidotic dogs it exceeded the filtered load by approximately 22 mumol/100 ml GFR. With respect to the fate of the nitrogens of the glutamine extracted, alanine and ammonium were produced in normal dogs at a rate nearly equivalent to that of glutamine extracted, whereas ammonium production was almost twofold greater than the rate of glutamine extraction during acidosis. There was a relatively small but constant alanine release over the entire range of plasma glutamine concentrations in these dogs. Furthermore, infusion of glutamine to raise the plasma glutamine concentration twofold during acidosis resulted in an increased rate of glutamine extraction and ammonium production equal to that predicted from the increase in filtered load of glutamine. Therefore, variations of circulating glutamine concentration within the physiological range seem to have an important influence on the steady-state rate of renal glutamine metabolism in normal dogs and in dogs with chronic metabolic acidosis.

Acid-Base Equilibrium↗
PubMed1987

Renal potassium handling during states of low aldosterone bio-activity: a method to differentiate renal and non-renal causes.

The purpose of this study was to examine renal potassium handling in patients with low aldosterone bio-activity. The patients with a normal renal response to aldosterone were identified by finding both a low plasma aldosterone concentration during hyperkalaemia and a transtubular potassium concentration gradient (TTKG) in the cortical distal nephron of 6 or greater within 4 h after the administration of a physiologic dose of mineralocorticoid hormone. In contrast, patients with a primary renal potassium excretion defect represent a heterogeneous population. In some, the TTKG rose when a pharmacologic but not a physiologic dose of mineralocorticoid was given; others had little renal response to the administration of this hormone. Furthermore, this renal response may be delayed and require more than 24 h to become manifest.

Adrenal Gland Diseases↗
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↗
PubMed1987

Does the kidney 'escape' from the kaliuretic action of mineralocorticoids?

The purpose of this study was to determine if there are renal mechanisms which limit the magnitude of potassium loss during mineralocorticoid-induced hypokalemia. To study the renal effects of mineralocorticoids in vivo, the 'cortical distal nephron' transtubular [K] gradient (TTKG) was calculated by dividing the urine [K] by the urine to plasma osmolality ratio; this in turn was divided by the arterial plasma [K]. Hypokalemia (2.6 +/- 0.1 mM) was induced in rabbits by the daily administration of 5 mg deoxycorticosterone acetate (DOCA) for 9-13 days. Infusion of a K-free isotonic solution into these rabbits resulted in more severe hypokalemia (1.6 +/- 0.1 mM) and a TTKG of 4.3 +/- 0.3. The subsequent infusion of a 60-mM K-containing solution elevated the plasma [K] to 5.1 +/- 0.1 mM and was associated with a significant rise in the TTKG to 5.9 +/- 0.4 (p less than 0.05). A K-free solution was then infused to lower the plasma [K]; when the plasma [K] fell below 4 mM, the TTKG decreased to 4.4 +/- 0.3 (p less than 0.05), and was equal to the preinfusion value. Thus, DOCA-induced hypokalemia diminishes renal K excretion by two mechanisms: first, the lower value for the denominator of the TTKG (the plasma [K]) results in a lower luminal [K] at a given TTKG. Second, the TTKG fell during hypokalemia and thereby decreased the luminal [K] in the cortical distal nephron. Hence the urinary K excretion rate was diminished to a greater extent than that predicted from the fall in the plasma [K] despite continuing mineralocorticoid action.

Animals↗
PubMed1986

The urine anion gap: a clinically useful index of ammonium excretion.

In patients with a normal plasma anion gap type of metabolic acidosis, knowledge of the rate of ammonium excretion can provide valuable information to determine if there is a renal cause for the disorder. Unfortunately, few hospital biochemistry laboratories offer routine determination of the urine ammonium concentration. Data are presented that demonstrate a direct linear relationship between the urine anion gap (Na+ + K+ - Cl-) and the urine ammonium concentration. In a 24-hour urine collection, the relationship is urine ammonium equals -0.8 (urine anion gap) +82 (r = 0.97 p less than 0.01). The applications of this index of ammonium excretion are discussed.

Acid-Base Equilibrium↗
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↗
PubMed1986

Interpretation of the urine electrolytes and osmolality in the regulation of body fluid tonicity.

To evaluate urinary solutes in terms of their effect on body fluid tonicity, it is necessary to consider: whether that solute serves as an effective osmole in terms of ECF-ICF fluid shifts, its ability to accumulate in the body even if it is an osmotically effective particle, and the original number of body particles from which it derived. Thus, urea can be excluded since it is an ineffective osmole and only urine cations and anions need be considered. With respect to the former, one must separate the proportion of dietary versus endogenous potassium in this analysis as their effects differ. With respect to urine anions, urine chloride need not contribute to the loss of 'particles that count' when its excretion is accompanied by ammonium (i.e. equivalent to a bicarbonate gain). Thus, in the example cited at the beginning of this article, the excretion of hyperosmolar urine may not change body fluid tonicity if all the urinary potassium was of dietary origin and all the bicarbonate generated was retained as such. Finally, it is necessary to integrate defence of ECF volume (sodium balance), potassium balance, acid-base balance and intercompartmental fluid shifts to understand the overall renal response to defend tonicity. While there is utility in measuring urinary osmolality (assessment of medullary physiology, ADH action, water abstraction, concentrating power), in situations where body fluid tonicity is deranged, it is necessary to evaluate the urine sodium concentration along with the concentration of other solutes which may serve as effective osmoles in the urine.

Ammonia↗
PubMed1986

Development of a test to evaluate the transtubular potassium concentration gradient in the cortical collecting duct in vivo.

The purpose of these investigations was to develop a noninvasive test to estimate the transtubular potassium concentration gradient (TTKG) and thereby aldosterone action in the late distal convoluted tubule and the cortical collecting duct in patients with disorders of potassium excretion. Experiments were performed in rats under conditions where the ratio of urine to renal venous potassium concentration could reflect this TTKG. A large furosemide-induced diuresis ensured that sodium delivery was adequate and minimized the change in water content during transit through the medullary collecting duct (equal osmolality and TF/P inulin at the base and the tip of the medullary collecting duct). There was no significant potassium reabsorption nor secretion during transit through the medulla as shown by micropuncture and microcatheterization. Thus the potassium concentration in the urine should mirror that in the lumen at the major nephron sites of potassium secretion. The potassium concentration in the renal vein provides the simplest estimate of the cortical peritubular potassium concentration (the mean renal A-V difference for potassium was 1.2 mM); with a very high fractional excretion of potassium, an adjustment can be made to the arterial potassium concentration to correct for the potassium extracted. If the urine/plasma potassium concentration ratio were a quantitative reflection, then the transepithelial potential difference (TEPD) would be close to -40 mV in normal rats. The TTKG fell to unity when amiloride was given, consistent with an abolition of the apparent TEPD in vivo by this drug. Similar results were obtained in non-diuretic rats. The clinical implications of these findings are discussed.

Aldosterone↗
PubMed1986

New clinical approach to evaluate disorders of potassium excretion.

A new clinical approach to patients with disorders of potassium excretion is reported. This approach uses a urinary index, the ratio of potassium concentrations in the urine to vein after adjusting the urine potassium concentration for medullary water abstraction. This index provides a semiquantitative assessment of the apparent transtubular potassium concentration gradient (TTKG) in the major distal nephron segment where potassium is secreted. Three clinical situations are presented where the use of this index provided a better indication of the renal action of mineralocorticoids than did the traditional approach; in each case, the presence of mineralocorticoids was known as drugs with this action were administered. We emphasize that use of this index is restricted to situations where the urine is not hypotonic and distal nephron sodium delivery is not limiting for potassium secretion (greater than 25 mM, twice the sodium concentration required for maximum potassium transport at this nephron site).

Desoxycorticosterone↗
PubMed1985

Lactic acidosis--emphasis on the carbon precursors and buffering of the acid load.

We have compared the capacity of major organs to produce lactic acid from endogenous sources relative to their ability to buffer that proton load. We deduced that the ultimate source for the rapid production of a very large amount of lactic acid must be hepatic and/or muscle glycogen or exogenous glucose, because the quantity of endogenous glucose is quite small and the rate of net protein catabolism is too slow. Of the organs examined, only the liver of fed persons can produce sufficient lactic acid to markedly overwhelm its own buffer capacity plus that of the ECF and other tissues. Moreover, it is important to realize that a fasted (low hepatic glycogen) subject who lacks the stimulus for muscle glycogenolysis can only develop a modest degree of acute lactic acidosis owing to a limited precursor availability; under these circumstances, hypoglycemia and/or localized tissue necrosis could be the major threats to that patient. We present two examples with more chronic lactic acidosis without hypoxia emphasizing that tissue catabolism may be necessary to support high rates of lactic acid production, and we suggest that a high plasma lactate concentration need not be present to observe a large turnover of this metabolite.

Acid-Base Equilibrium↗