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M L Halperin

Publications and source records attributed to M L Halperin.

At least 73 records · Page 4Linked to original sources
PubMed1997

Hyponatremia in the rat in the absence of positive water balance.

The purpose of this report is to determine the mechanisms that lead to hyponatremia when isotonic saline was the only fluid infused into rats given antidiuretic hormone (ADH), and what might minimize the degree of this hyponatremia. Normal rats were deprived of food and water for the 24-hr study period. They received an infusion of isotonic saline to expand their extracellular fluid (ECF) volume with and without exogenous ADH administration (N = 8 in each of the four groups). Similar studies were also carried out in 32 rats fed a low electrolyte diet for 72 hr before the experiment. An additional control group was fed the low electrolyte diet supplemented with sodium (Na), potassium (K), and chloride (Cl). Hyponatremia developed over 24 hr in rats fed their usual diet if treated with ADH and isotonic saline (fall, 13 +/- 2 mM, P < 0.01). The hyponatremia was caused by negative balance for Na + K salts. Hyponatremia did not develop after the saline + ADH treatment if rats were pretreated for 3 days with a low electrolyte diet. Two factors were required to develop this hyponatremia--generation of electrolyte-free water as a result of the excretion of a large quantity of Na + K salts at a high concentration in the urine, and prevention of the excretion of this electrolyte-free water by ADH. Increasing the avidity for Na reabsorption by the kidney prevented this type of hyponatremia from developing.

Animals↗
PubMed1997

Minimum urine flow rate during water deprivation: importance of the nonurea versus total osmolality in the inner medulla.

Antidiuretic hormone leads to an increase in the permeability for water and urea in the inner medullary collecting duct. Hence, urea may not be an "effective" osmole in the inner medulla during maximal renal water conservation. Accordingly, the purpose of this study was to evaluate whether differences in the rate of urea excretion would influence maximum renal water conservation in humans. In water-deprived rats, the concentration of urea and total osmolality were somewhat higher in the urine exiting the inner medullary collecting duct than in interstitial fluid obtained from the entire papillary tip. Nevertheless, the "nonurea" (total osmolality minus urea in millimolar terms) osmolality was virtually identical in both locations. Chronically fasted human subjects that were water-deprived for 16 h had a lower rate of urea excretion (71 +/- 7 versus 225 +/- 14 mumol/min) and a somewhat lower urine osmolality (745 +/- 53 versus 918 +/- 20 mosmol/kg H2O). Nevertheless, they had identical urine flow rates (0.5 +/- 0.01 and 0.5 +/- 0.02 ml/min, respectively), and their nonurea osmolality also was similar (587 +/- 25 and 475 +/- 14 mosmol/kg H2O, respectively) to the water-deprived normal subjects. The composition of their urine differed in that the principal nonurea osmoles became NH4+ and beta-hydroxybutyrate rather than Na and C1. During water deprivation in normal subjects, the ingestion of urea caused a twofold rise in urine flow rate, a fall in the nonurea osmolality, and a rise in the rate of excretion of nonurea osmoles. The nonurea osmolality of the urine, and presumably the medullary interstitial fluid as well, was inversely related to the urea excretion rate. In chronic fasting, the nature, but not the quantity, of nonurea osmoles changed. The similar minimum urine volume was predictable from an analysis based on nonurea osmole considerations.

Administration, Oral↗
PubMed1997

Effective water clearance and tonicity balance: the excretion of water revisited.

OBJECTIVE: To demonstrate (1) that hyponatremia is usually due to an inappropriately low rate of excretion of electrolyte-free water and (2) that the measure "effective water clearance" (EWC) provides better information about renal defence of the body tonicity than does the classic measure free-water clearance, and to provide the rationale for calculating a "tonicity balance," which involves using water and sodium plus potassium intakes and their renal excretion to reveal the basis for changes in body tonicity. DESIGN: Prospective study. PARTICIPANTS: Four normal subjects with no conditions affecting excretion, 10 patients with advanced congestive heart failure (CHF) and 5 patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). INTERVENTION: Normals and patients were administered a standard water load (20 mL per kg of body weight) during 45 minutes, and blood and urine samples were taken before, during and after the load was given. MAIN OUTCOME MEASURES: Urine and blood sodium and potassium concentrations, osmolar clearance, free-water clearance, electrolyte clearance and EWC. RESULTS: The water load was excreted rapidly by normals, more slowly by patients with CHF, and not at all by patients with SIADH. The EWC was positive in normals and those with CHF, but negative in those with SIADH. In patients with CHF, the EWC, but not the free-water clearance, helped explain why hyponatremia was corrected after the water load was given. CONCLUSIONS: In subjects with abnormal water excretion, the EWC provides the physiologic explanation for the renal role in variations in natremia. The authors propose a bedside evaluation of renal water and electrolyte handling that takes into consideration the role of urinary potassium in body tonicity. Changes in body tonicity can be explained by a "tonicity balance," a calculation in which the source and the net balance of sodium, potassium and water are considered.

Electrolytes↗
PubMed1997

[Metabolic alkalosis on the surface but metabolic acidosis in depth].

Our purpose in writing this article is to emphasize the acid-base consequences and total body imbalances which follow the selective depletion of HCl. The initial body balance is an equimolar deficit of chloride and gain of bicarbonate. Within a short period of time, body balance changes; the net deficits are closer to equimolar losses of potassium and chloride. Since the loss of potassium occurred without the simultaneous loss of existing body anions (chloride or phosphate), this negative balance of potassium is accompanied by an equimolar gain of hydrogen ions. Thus when the negative balance is that of KCl, acid-base balance is present but there is a surplus of bicarbonate in the extracellular fluid (ECF) together with an equal surplus of hydrogen ions in another compartment (the intra-cellular fluid (ICF)). Moreover, if the ECF volume is contracted, a more severe degree of acidosis of the ICF may occur due to a higher PCO2 in venous blood. Given the acid-base balance and a deficit of KCl, one should not view this disorder as being "corrected" by saline at any time other than in the acute phase before a large potassium deficit occurs. Sodium chloride should be restricted to repair a deficit of sodium chloride. The emphasis on therapy is obviously to replace the deficit of KCl.

Acidosis↗
PubMed1996

Brain swelling after dialysis: old urea or new osmoles?

The pathogenesis of brain swelling and neurological deterioration after rapid hemodialysis (dialysis disequilibrium syndrome) is controversial. The "reverse urea hypothesis" suggests that hemodialysis removes urea more slowly from the brain than from the plasma, creating an osmotic gradient that results in cerebral edema. The "idiogenic osmole hypothesis" proposes that an osmotic gradient between brain and plasma develops during rapid dialysis because of newly formed brain osmoles. In this review, the experimental basis for the two hypotheses are critically examined. Based on what is known about the physiology of urea and water diffusion across the blood-brain barrier, and empiric observations of brain solute composition after experimental hemodialysis, we conclude that the "reverse urea hypothesis" remains a viable explanation for dialysis disequilibrium and that rapid reduction of a high urea level in and of itself predisposes to this condition.

Animals↗
PubMed1996

Antikaliuretic action of trimethoprim is minimized by raising urine pH.

This study was designed to test the hypothesis that the antikaliuresis caused by trimethoprim could be diminished by alkalinizing the luminal fluid in the CCD, thereby converting trimethoprim from its cationic, active form to an electroneutral, inactive, form. Trimethoprim-induced inhibition of transepithelial Na+ transport was examined in A6 distal nephron cells by analysis of short circuit current. The voltage-dependence of the trimethoprim-induced block of Na+ channels was examined with patch clamp recordings of A6 cells. The antikaliuretic effect of trimethoprim was examined in vivo in rats pretreated with deoxycorticosterone and with NH4Cl to lower urine pH, and in rats also receiving acetazolamide to raise urine pH. We found that the concentration of trimethoprim required to inhibit the amiloride sensitive component of short circuit current by 50% (IC50) was 340 microM (at pH 8.2) and 50 microM (at pH 6.3). The IC50S of protonated trimethoprim were similar (34 microM at pH 8.2 and 45 microM at pH 6.3). The mean time open for the high selectivity, Na+ channel was reduced from 1679 +/- 387 msec to 502 +/- 98 msec with addition of 10-5 M trimethoprim to patch pipette solution at the resting membrane potential (-Vpipette = 0 mV). further decreases in mean time open were observed as -Vpipette was reduced (that is, apical membrane hyperpolarization) to -40 mV (mean time open = 217 +/- 85 msec) and to -80 mV (mean time open = 69 +/- 13 msec). In vivo, trimethoprim caused a > 50% reduction in potassium (K+) excretion due primarily to a fall in the [K+] in the lumen of the terminal CCD. This effect of trimethoprim was markedly attenuated in an alkaline urine induced by acetazolamide. We conclude that it is the charged, protonated species of trimethoprim which blocks epithelial Na+ channels. Increasing urinary pH decreases the concentration of the charged species of trimethoprim and minimizes its antikaliuretic effect.

Animals↗
PubMed1996

What is the impact of potassium excretion on the intracellular fluid volume: importance of urine anions.

Hyponatremia is a common electrolyte abnormality that causes symptoms as a result of swelling of brain cells. We evaluated the impact of a negative balance for sodium (Na) and potassium (K) salts on the intracellular fluid (ICF) volume, emphasizing the role of anions excreted with K. Rats (N = 10) were deprived of food and water for 24 hours. They received half-isotonic saline to expand their extracellular fluid (ECF) volume by 20%; a long acting antidiuretic hormone (DDAVP) preparation was given to prevent the excretion of electrolyte-free water. The concentration of Na in plasma fell from 139 +/- 1 mM to 120 +/- 2 mM 24 hours after the infusion of hypotonic saline (P < 0.01). Since these rats had a small negative balance for water (4 +/- 1 ml), hyponatremia was due to their negative balances for Na (2.2 +/- 0.3 mmol) and K (2.2 +/- 0.1). There were negative balances for Cl (2.4 +/- 0.2 mmol) and phosphate (0.7 +/- 0.05 mmol). Despite the negative balance for NaCl, the ECF volume as assessed by 3H-inulin space was not contracted. In this model for acute hyponatremia, its basis was electrolyte loss, but the ECF volume was not contracted, suggesting that water shifted from the ICF to the ECF. Hyponatremia is associated with cell swelling only if its cause is positive water balance and/or is loss of Na from the ECF. It is critical to examine the urine anions to determine the compartment of origin of particles excreted with K and thereby whether hyponatremia will result in overall expansion or contraction of the ICF volume.

Animals↗
PubMed1996

Alkali therapy extends the period of survival during hypoxia: studies in rats.

The goal of this study was to evaluate whether sodium bicarbonate might be a useful form of therapy for hypoxic L-lactic acidosis; our aim was to determine if alkali could extend the time of survival in this setting. Hypoxia was induced in anesthetized, paralyzed, artificially ventilated rats by lowering inspired O2 to 5.5%, an amount sufficient to develop a severe degree of L-lactic acidosis. Measuring arterial blood gases frequently permitted maintenance of a near-constant arterial O2 content. Three groups of hypoxic rats were studied: first, no infusions (n = 10); second, sodium bicarbonate at a rate equal to H+ production in the no-infusion group (n = 12); and third, a control for the Na load in the second group as NaCl (n = 17). Survival was close to twofold longer in the sodium bicarbonate group. Part of this beneficial effect seemed to be increased anaerobic glycolysis, producing ATP along with L-lactic acid. In addition, there was a large decrease in the metabolic demand (consumption of O2) in the 7- to 15-min period in the sodium bicarbonate group. Rats exposed to hypoxia and infused with NaCl for 15 min or alkali for 15, 27, or 40 min were then returned to room air; all survived for the subsequent experimental period of 150 min. We found that there is both a rationale and experimental evidence for giving sodium bicarbonate to prolong survival during hypoxia.

Acidosis, Lactic↗
PubMed1996

Urea recycling: an aid to the excretion of potassium during antidiuresis.

Urea absorption in the inner medullary collecting duct provides a mechanism to elevate the concentration of urea in the papillary interstitial fluid and thereby permit the excretion of urea with as little water as possible. Urea reabsorption may have another important effect - to aid in the excretion of potassium (K). K excretion depends on two processes: first, factors such as aldosterone which cause the concentration of K in the luminal fluid of the cortical distal nephron to be high and, second, factors which augment the flow rate through those nephron segments. Since, the osmolality of the luminal fluid in the cortical collecting duct (CCD) and plasma are equal when antidiuretic hormone acts, the flow rate in the CCD is dependent on solute delivery. Urea is a major solute in the lumen of the CCD and thereby plays an important role in maintaining the CCD flow rate. Since urea and K are often found in the same foods, having urea help the excretion of K is potentially advantageous. If the excretion of urea was low, the flow rate in the terminal CCD would decline. In this circumstance, the luminal K concentration would have to rise in proportion to the fall in flow rate or there would be a diminished rate of excretion of K and, possibly, hyperkalemia.

Animals↗
PubMed1996

The spectrum of endemic renal tubular acidosis in the northeast of Thailand.

We have previously reported a high prevalence of endemic renal tubular acidosis (EnRTA) in the northeast of Thailand, and our subsequent studies provided evidence that K deficiency exists in the same region. Since tubulointerstitial damage is associated with K deficiency, we postulate that this might be implicated in the pathogenesis of EnRTA and, if so, that a spectrum of tubulointerstitial abnormalities can be anticipated. In this study we evaluated renal acidification ability in 4 patients and in 11 of their relatives. We used a 3-day acid load (NH4Cl 0.1 g/kg/day) followed by 20 mg oral furosemide and monitored the maximal renal concentrating ability using water deprivation and intranasal 1-deamino-D-arginine vasopressin. The results showed that the subjects could be divided into three groups; normal relatives of the patients, those with suspected renal tubular acidosis, and patients with overt EnRTA who had chronic metabolic acidosis and a low rate of excretion of NH4+. The rate of excretion of K was very low (20 +/- 4 mmol/day) in patients with EnRTA and in their relatives with suspected EnRTA. The transtubular K concentration gradient was also very low in their relatives, especially in patients with suspected EnRTA (2.8 +/- 0.2). With a 3-day NH4Cl load, the rate of excretion of NH4+ was very low in patients with EnRTA (32 +/- 9 mmol/day), and the relatives with suspected EnRTA also had a decreased capacity to excrete NH+4 (50 +/- 14 mmol/day). In contrast, the normal relatives excreted 92 +/- 12 mmol of NH+4/day. The patients with EnRTA could lower their urine pH to less than 5.5 after the acid loading (6.2 +/- 0.3). After furosemide (20 mg), the NH4+ excretion in the patients with EnRTA was lower than in the normal relatives. Moreover, the minimum urine pH in patients with EnRTA did not fall (6.1 +/- 0.2), but there was a fall to 4.8 +/- 0.1 in the patients with suspected EnRTA after furosemide treatment. In conclusion, there was a spectrum of tubulointerstitial abnormalities ranging from suspected to overt distal RTA in a geographic area known to have a high prevalence of K deficiency. K deficiency might be the important pathogenetic factor of EnRTA in the northeast of Thailand.

Acidosis, Renal Tubular↗
PubMed1996

Coexistence of central diabetes insipidus and salt wasting: the difficulties in diagnosis, changes in natremia, and treatment.

Both central diabetes insipidus (DI) and a high rate of excretion of sodium (Na) and chloride (Cl) contributed to the development of polyuria and dysnatremia in two patients during the acute postoperative period after neurosurgery. To minimize difficulties in diagnosis and projections for therapy, two available (but not often used) clinical tools were helpful. First, the osmole excretion rate early on revealed the co-existence of central DI and an osmotic diuresis. The osmoles excreted were largely Na salts; after antidiuretic hormone acted, this electrolyte diuresis caused the urine flow rate to be much higher than otherwise anticipated. Interestingly, part of this saline diuresis occurred when the extracellular fluid volume was contracted. The tool to explain the basis for the dysnatremias was a tonicity balance. Hypernatremia, which developed before treatment of central DI, was primarily a result of a positive balance for Na rather than a large negative balance for water. Moreover, hyponatremia that developed once antidiuretic hormone acted was primarily a result of a negative balance for Na; the urine volume was large and its Na concentration was hypertonic. To prevent a further decline in the plasma Na concentration, either the Na concentration in the urine should be decreased by provision of urea or a loop diuretic while replacing all unwanted water and electrolyte losses; alternatively, the fluid infused should have a similar Na concentration and volume as the urine (infuse hypertonic saline).

Adult↗
PubMed1995

Challenging consults: application of principles of physiology and biochemistry to the bedside. Osmotic diuresis: the importance of counting the number of osmoles excreted.

Polyuria is usually the result of a water diuresis or an osmotic diuresis. Traditionally, the assessment of the extracellular fluid (ECF) volume and the concentration of Na+ in plasma is sufficient to differentiate between the two. We present a case and our approach, which is based on calculations and quantitation of osmoles, to demonstrate the utility of this approach. A patient with diabetes mellitus, human T-cell lymphocyte virus, type 1 (HTLV-1) associated lymphoma, and hypercalcemia presented with marked ECF volume contraction and polyuria. A spot urine osmolality was 567 mOsm/kg H2O in the face of urine output of approximately 6 L/d. The initial diagnosis was an osmotic diuresis. However, a quantitative analysis revealed the enormous number of osmoles could not be accounted for physiologically. Hence, we postulated a water diuresis to be the cause of the polyuria. To confirm this hypothesis, we found that at different times during his hospitalization, the urine specific gravity ranged from 1.005 to 1.022, and urine output varied markedly over 8-h periods. Despite a plasma sodium of 147 mmol/L, the patient did not complain of thirst. Taken together, this suggested the presence of a hypothalamic lesion which caused central diabetes insipidus with variable output of antidiuretic hormone together with a blunted thirst response. Illustration of the utility of a quantitative approach to polyuria is the focus of the discussion.

Chlorides↗