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Biomedical subjects

A I Arieff

Publications and source records attributed to A I Arieff.

At least 91 records · Page 5Linked to original sources
PubMed1985

Changing concepts in treatment of severe symptomatic hyponatremia. Rapid correction and possible relation to central pontine myelinolysis.

Severe symptomatic hyponatremia (serum sodium level below 120 meq/liter) is often a life-threatening emergency that can result in permanent neurologic damage or death if left untreated. Early recognition and rapid correction to mildly hyponatremic levels by the administration of hypertonic saline are important in order to reduce the potential mortality and morbidity. If the serum sodium level is more than 105 meq/liter, it can be corrected to a value of 125 to 130 meq/liter. However, if the serum sodium level is less than 105 meq/liter, it may be safe to raise the value by only 20 meq/liter. Care should be taken to avoid acute correction to normonatremia or hypernatremia. Moreover, it is also of equal importance to avoid development of hypernatremia in the subsequent days following the correction to mild hyponatremia.

Alcoholism↗
PubMed1985

Captopril-induced hyponatremia with irreversible neurologic damage.

A 61-year-old Chinese-American man with a history of congestive heart failure and hypertension was admitted to the San Francisco Veterans Administration Hospital with confusion, cortical blindness, and generalized flaccidity. Serum sodium level on admission was 114 meq/liter. Administration of captopril had been begun for afterload reduction two weeks before admission with a concomitant fall in serum sodium level from 137 meq/liter to 126 meq/liter in one week. A history of marked thirst with consumption of large volumes of water was reported for over one week prior to hospitalization. Despite correction of the hyponatremia within 24 hours at a rate of 0.9 meq/liter per hour, the patient remained semi-comatose and died four days later with a gastrointestinal bleed. It is suggested that the thirst phenomenon and hyponatremia were caused by the introduction of captopril. This lead to irreversible neurologic damage and death, despite the correction of the serum sodium level.

Captopril↗
PubMed1985

Metabolic effects of sodium bicarbonate in hypoxic lactic acidosis in dogs.

The metabolic effects of NaHCO3 therapy in hypoxic lactic acidosis were evaluated in the anesthetized dog. Hypoxic lactic acidosis was induced by ventilating the dogs with a hypoxic gas mixture of 8% O2/92%N2, resulting in arterial PO2 of less than 30 mmHg, pH below 7.20, bicarbonate less than 12 mM, and lactate more than 7 mM. In this situation lactate accumulates because of overproduction of lactate by gut and carcass in the presence of a diminished capacity of the liver to extract lactate. After the development of hypoxic lactic acidosis the dogs were treated for 60 min with either NaHCO3 or NaCl or had no therapy. Sixty minutes of either treatment resulted in further declines of blood pH and bicarbonate that were similar in all three groups. NaHCO3-treated animals, however, showed an increase in blood lactate that were significantly higher than those treated with NaCl or those that had no therapy. This could be explained by a significantly higher gut lactate production with NaHCO3 therapy than in the NaCl-treated group. Concomitantly NaHCO3-treated animals showed a decrement in liver and gut blood flow that did not occur with NaCl treatment. Only NaHCO3 therapy was associated with a further decrease of liver intracellular pH, which could be attributed to both an increase in the CO2 load to the liver and increased tissue lactate levels, which were not observed with NaCl or no therapy. Additionally, liver lactate extraction was not improved by administration of NaHCO3 or NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1985

Abnormal sodium transport in synaptosomes from brain of uremic rats.

The causes of central nervous system (CNS) dysfunction in uremia are not well known and are not completely reversed by dialysis. This problem was investigated in synaptosomes, which are membrane vesicles from synaptic junctions in the brain. We measured Na uptake under conditions of control, veratridine stimulation, and tetrodotoxin inhibition, in synaptosomes from normal and acutely uremic (blood urea nitrogen, 250 mg/dl) rats. In the control state, maximal Na uptake was 2.2 +/- 0.2 and 1.9 +/- 0.3 nmol/mg of protein in normal and uremic synaptosomes, respectively. With veratridine stimulation, Na uptake was increased by 1.9 and 3.6 nmol/mg of protein in normal vs. uremic rats (P less than 0.001). The increased veratridine-stimulated Na uptake observed in uremia could be due either to increased membrane permeability to Na or decrease in the Na-K ATPase pump activity. To investigate this, we studied the Na-K ATPase pump function by evaluating uptake of K (using rubidium as a tracer), uptake of Na during ATP stimulation, and inhibition of Rb and Na uptake by ouabain. In uremic rats both Rb uptake and ATP-stimulated Na uptake were significantly less than in normals (P less than 0.005). This suggests a defect in the Na-K ATPase pump. Membrane permeability for Na was then evaluated both by measuring initial Na uptake, and with addition of valinomycin. No change in Na uptake pattern was observed with valinomycin, and initial Na uptake was not significantly different in normal versus uremic synaptosomes. These data show that (a) in uremic rats veratridine-stimulated Na accumulation is significantly greater than normal; (b) the increased Na accumulation observed in uremia appears to be due to alterations in Na-K ATPase pump activity; and (c) the altered Na accumulation observed is probably not due to a uremic environment, but may be secondary to a physiologic alteration in synaptosomal function due to the uremic state. These abnormalities may affect neurotransmission and may be associated with the CNS alterations observed in uremia.

Adenosine Triphosphate↗
PubMed1985

Effects of dichloroacetate in the treatment of hypoxic lactic acidosis in dogs.

The metabolic and systemic effects of dichloroacetate (DCA) in the treatment of hypoxic lactic acidosis were evaluated in the dog and compared with the infusion of equal quantities of volume and sodium. Hypoxic lactic acidosis was induced by ventilating dogs with an hypoxic gas mixture of 8% oxygen and 92% nitrogen, resulting in arterial PO2 of less than 30 mmHg, pH below 7.20, bicarbonate less than 15 mM, and lactate greater than 7 mM. After, the development of hypoxic lactic acidosis dogs were treated for 60 min with either DCA as sodium salt or NaCl at equal infusions of volume and sodium. Dogs treated with DCA showed a significant increase of arterial blood pH and bicarbonate, and steady levels of lactate, whereas NaCl resulted in further declines of blood pH and bicarbonate, and rising blood lactate levels. Overall lactate production decreased during therapy with either regimen, but hepatic lactate extraction increased significantly with DCA, while it remained unchanged with NaCl. Tissue lactate levels in liver and skeletal muscle decreased significantly with DCA treatment but were unchanged with NaCl. Additionally, an increase in muscle intracellular pH was observed only in DCA treated dogs. A possible mechanism for the observed actions of DCA might be related to a significant increase in oxygen delivery to tissues. Such an effect was found with DCA administration, but was not observed with NaCl therapy. In conclusion, DCA therapy in hypoxic lactic acidosis has beneficial systemic effects compared with therapy with NaCl. DCA administration is accompanied by increases of blood pH and bicarbonate, a decrease in lactate production, and enhanced liver lactate extraction, and a lowering of tissue lactate levels.

Acetates↗
PubMed1985

Calcium transport abnormality in uremic rat brain synaptosomes.

Brain calcium is elevated in patients and laboratory animals with uremia. The significance of this finding is unclear. We evaluated calcium transport in brain of both normal and acutely uremic rats (blood urea nitrogen = 250 mg/dl) by performing studies in synaptosomes from rat brain cerebral cortex. Synaptosomes are vesicular presynaptic nerve endings from brain that contain mitochondria and are metabolically active. Two mechanisms of calcium transport were evaluated using radioactive 45Ca++ as a tracer. Both mechanisms were evaluated in the absence of exogenously administered parathyroid hormone (PTH). We first evaluated Na+-Ca++ exchange in vesicles that were loaded with NaCl in an external media containing 10 microM CaCl2. Both initial rates of calcium transport and equilibrium levels of calcium accumulation in synaptosomes prepared from uremic rats were significantly greater (P less than 0.005) than in normal. To assess calcium efflux, ATP-dependent calcium uptake (1 mM ATP) was studied in inverted plasma membrane vesicles loaded with KCl. In the uremic synaptosomes, a significant increase (P less than 0.005) in ATP-dependent calcium uptake was observed as compared with the normal. These studies show that (a) Calcium accumulation via the Na+-Ca++ exchanger is increased in synaptosomes prepared from uremic rat brain. (b) Calcium influx into inverted plasma membrane vesicles from uremic rats via the ATP-dependent calcium transport mechanism is increased when compared with normal. (c) The increased calcium accumulation in uremia by both Na+-Ca++ exchange and ATP-dependent calcium transport mechanism appears to be a result of increased synaptosomal membrane permeability to calcium. Both these abnormalities of calcium transport in uremia would tend to increase brain extracellular calcium in vivo. The defects observed in uremia do not appear to be readily reversible, and the relationship to PTH is presently unclear. These abnormalities may affect neurotransmission in the uremic state.

Adenosine Triphosphate↗
PubMed1984

Hyponatremia due to cerebral salt-wasting syndrome. Combined cerebral and distal tubular lesion.

A 76-year-old white man was evaluated for a syndrome of hyponatremia, hypotension, and high urinary sodium excretion. There was evidence of inappropriate secretion of antidiuretic hormone and renal salt wasting in the presence of a normal glomerular filtration rate. He had a distal tubular acidification defect and unresponsiveness to standard doses of mineralocorticoids. The renin aldosterone axis was normal, as were thyroid and adrenal function. The patient could not dilute the urine, nor excrete a standard water load. Renal concentrating ability was normal, but there was no additional response to exogenous vasopressin. With modest salt restitution, the patient continued to lose large quantities of sodium in the urine, resulting in severe postural hypotension. Renal biopsy showed normal glomeruli with distinct degeneration of the distal tubules. There was no evidence of an acute inflammatory interstitial nephritis. The patient did not respond to therapeutic doses of mineralocorticoid (fludrocortisone), but treatment with water restriction, increased salt intake, and large doses of mineralocorticoids resulted in a normal serum sodium level and blood pressure. This case falls in the category of "cerebral salt wasting" syndrome. The cause was a combination of idiopathic secretion of antidiuretic hormone and distal tubular degeneration resulting in pseudohypoaldosteronism.

Aged↗
PubMed1984

Uremic encephalopathy: role of brain energy metabolism.

Uremia is associated with decreased brain oxygen consumption in humans and with decreased brain energy consumption in rodent models of acute renal failure. We measured the levels of high-energy phosphates and glycolytic intermediates in the brain of dogs with acute or chronic renal failure. We used methods of rapid brain tissue fixation that trap these labile metabolites at their in vivo levels. Creatine phosphate, ATP, and glucose were normal in the brain of animals with renal failure, indicating a normal brain energy reserve. The brain energy charge, which is the fraction of the total adenine nucleotide pool that contains high-energy phosphates, (ATP + 1/2ADP)/(ATP + ADP + AMP), was also normal despite an 8% decrease in the total adenine nucleotide pool. Mild hypoxia failed to alter the level of any of these metabolites. The brain redox state, (NAD+)/(NADH), was normal to high in acute renal failure, suggesting that oxygen supply was not limiting oxygen consumption. In the face of normal brain energy reserves, energy charge, and redox state, the decreased energy consumption of uremic brain probably results from decreased demand rather than limited supply.

Acute Kidney Injury↗
PubMed1983

Lactic acidosis: current concepts.

Lactic acidosis is now a widely recognized disorder in clinical medicine. Experimental studies during the past decade demonstrate an important role of lactate disposal mechanisms in the pathogenesis of lactic acidosis. Such factors as decreased cardiovascular reserve, inadequate liver perfusion and alterations in liver intracellular pH appear to limit the normally large capacity of the liver to dispose of lactic acid. The continued high mortality of this disorder has led to a re-examination of the conventional, empirical treatment of lactic acidosis with sodium bicarbonate. Available data suggest that alkali may cause or exacerbate the conditions of excessive lactate production, decreased cardiac reserve and inadequate hepatic lactate disposal which exist in this disorder. In contrast, dichloroacetate therapy shows strikingly beneficial results, at least in early experimental studies.

Acidosis↗
PubMed1983

Central and peripheral nervous system effects of chronic renal failure.

Although neurologic dysfunction is a major cause of disability in patients with chronic renal failure, there is little knowledge of the underlying metabolic defect(s). We used a canine model to study the effects of chronic renal failure (CRF: 4 months after 1-7/8 nephrectomy, GFR 11 +/- 2 ml/min) on the composition and function of the nervous system. We also studied the effect of acute renal failure (ARF: 3.5 days after bilateral ureteral ligation) on peripheral nerve composition and function. In dogs with CRF for 4 months intracellular pH of brain and cerebro-spinal fluid (CSF) pH remained normal, despite metabolic acidemia. Osmotic equilibrium of the brain with plasma and CSF (and thus a normal water content) was maintained by almost equivalent increases in brain of urea and idiogenic osmoles (25 mmoles/kg H2O and 23 to 26 mOsm/kg H2O, respectively). Electrolyte concentration in brain tissue water did not change significantly. Calcium content was increased in cortical gray matter and hypothalamus of dogs with CRF, but was normal in the six other regions measured. Functional changes measured by the electroencephalogram were just as severe as those previously seen in dogs with ARF. The motor nerve conduction velocity (MNCV) was normal in dogs with ARF and did not change after up to 6 months of CRF.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Lactic acidosis and the cardiovascular system in the dog.

1. Lactic acidosis is a clinical syndrome characterized by metabolic acidaemia (pH less than 7.25) and hyperlactaemia (lactate greater than 5 mmol/l). Many patients with type B lactic acidosis have no evidence of tissue hypoxia or myocardial dysfunction when first evaluated. Although it is considered that cardiac dysfunction is secondary to the systemic effects of lactic acidosis, the reverse may sometimes be true. To evaluate this possibility, studies were carried out in 43 dogs consisting of a control group and three groups which had hyperlactataemia and metabolic acidaemia related to either: (1) phenformin infusion; (2) hepatectomy; (3) lactic acid infusion. Serial studies of cardiac function, as well as measurements of GFR (glomerular filtration rate) and hepatic portal vein (HPV) blood flow, were carried out. 2. In dogs infused with phenformin for 99 min, the arterial pH, lactate, bicarbonate, heart rate and mean blood pressure (BP) were normal. However, there was significant deterioration (P less than 0.01) in several indices of cardiac function, including the peak positive dP/dt, cardiac output, LVEDP (left ventricular end-diastolic pressure) and percentage extraction of oxygen and lactate by the heart. After 3 h of phenformin, the blood lactate exceeded 5 mmol/l and there were further significant decrements (P less than 0.01) in cardiac output, LVEDP and dP/dt, as well as BP and heart rate. In dogs subjected to hepatectomy, the decrement in cardiac output was similar to that with phenformin infusion. However, in animals infused with lactic acid, despite a similar blood pH and lactate, cardiac output was unaffected. Although percentage myocardial oxygen extraction declined in phenformin-infused animals, there was a concomitant increase in coronary sinus blood flow such that myocardial oxygen utilization was probably unaltered. 3. Thus, in certain types of experimental type B lactic acidosis, myocardial dysfunction may be a primary event, with other associated systemic manifestations being secondary.

Acidosis↗
PubMed1983

Metabolic effects of dichloroacetate in diabetic dogs.

In fasted, diabetic dogs treated with dichloroacetate (DCA) (300 mg X kg-1 X h-1 iv), we determined the relative contributions by skeletal muscle and gut to the supply of precursors used for hepatic gluconeogenesis. The total production of lactate and alanine by skeletal muscle and gut decreased from 2,370 to 1,160 mumol X kg-1 X h-1 during treatment with DCA. Hepatic uptake of these substrates decreased from 1,040 to 435 mumol X kg-1 X h-1, and blood glucose decreased from 370 +/- 18 to 279 +/- 22 mg/dl (P less than 0.001). DCA treatment decreased the skeletal muscle production of both lactate and alanine to 40% of control, whereas gut production was decreased to only 72% of control levels. Hepatic uptake of the two substrates decreased in proportion to the change in blood levels because fractional hepatic extraction was unaltered. The effects of DCA on the interorgan metabolism of plasma amino acids showed that diminished availability of alanine for hepatic gluconeogenesis was compensated in part by increased release of other gluconeogenic amino acids from muscle and gut. Gut uptake of glutamine appeared unchanged, but most of its metabolic end products were released in greater amounts by DCA treatment, suggesting enhanced glutamine degradation. These results in fasted, diabetic dogs indicate that 1) DCA treatment lowers blood glucose in part by limitation of gluconeogenic substrate supply from skeletal muscle and gut, and 2) DCA has complex and diverse effects on the interorgan metabolism of plasma amino acids.

Acetates↗
PubMed1982

Uremic encephalopathies: clinical, biochemical, and experimental features.

Patients with renal failure may manifest a variety of neurologic disorders. Patients with chronic renal failure who have not yet received dialytic therapy may develop a symptom complex progressing from mild sensorial clouding to delirium and coma, with tremor, asterixis, multifocal myoclonus, and seizures. After the institution of adequate maintenance dialysis therapy, patients may continue to be afflicted with more subtle nervous dysfunction, including impaired mentation, generalized weakness, and peripheral neuropathy. These central nervous system disorders are referred to as uremic encephalopathy. The dialytic treatment of end-stage renal disease has itself been associated with the emergence of two distinct, new disorders of the central nervous system; dialysis dysequilibrium and dialysis dementia. The dialysis disequilibrium syndrome consists of headache, nausea, muscle cramps, obtundation, and seizures, and is a consequence of the initiation of dialysis therapy in some patients. Dialysis dementia is a progressive, generally fatal encephalopathy which affects patients on chronic hemodialysis. There are at least three different forms of dialysis encephalopathy: sporadic, epidemic; and that associated with renal disease in children. In addition to the foregoing neurologic diseases which are specifically related to uremia and/or dialysis, a number of other neurologic disorders occur with increased frequency in patients with end-stage renal disease on chronic hemodialysis. These include subdural hematoma, electrolyte disorders, vitamin deficiencies, drug intoxication, hypertensive encephalopathy, and acute trace element intoxication. Renal transplantation is associated with a variety of central nervous system infections, reticulum cell sarcoma, and central pontine myelinosis. The present manuscript will review the clinical, structural, and biochemical components of those neurologic disorders which are peculiar to the uremic state and its treatment with dialysis.

Aluminum↗
PubMed1982

Systemic effects of NaHCO3 in experimental lactic acidosis in dogs.

Lactic acidosis is characterized by metabolic acidosis due to accumulation of H+ ions from lactic acid with blood lactate of at least 5 mM. The standard treatment is intravenous NaHCO3, with resultant mortality in excess of 50%. Despite the high mortality, the metabolic and systemic effects of NaHCO3 used in the treatment of lactic acidosis have not been extensively studied. The present experiments in diabetic dogs were designed to address these questions. Dogs with phenformin-induced lactic acidosis (blood lactate above 5 mM, arterial pH below 7.20) were treated with equimolar amounts of either NaCl or NaHCO3 or received no therapy. Intravenous NaHCO3 resulted in a decline of cardiac output and intracellular pH (pHi) of liver and erythrocytes, whereas treatment with NaCl did not. With NaHCO3 but not with NaCl infusion gut lactate production increased almost stoichiometrically, with no change in arterial pH or bicarbonate but with a doubling of lactate. Bicarbonate also resulted in a decrease of hepatic portal vein blood flow. The mean survival time and percent mortality were similar in NaCl- vs. NAHCO3(-) treated animals. Although both groups lived longer than did animals receiving no therapy, the differences were not significant. Thus, treatment of experimental lactic acidosis with either NaCl or NaHCO3 or with no therapy results in no change of blood pH and bicarbonate and in a similar mortality. In terms of systemic effects, however, NaHCO3 results in significant decrements of liver and erythrocyte pHi, hepatic portal vein blood flow, and cardiac output and in significant increments of gut lactate production, whereas NaCl does not. The data suggest that the rationale for therapy of lactic acidosis with NaHCO3 should probably be reevaluated.

Acidosis↗
PubMed1982

Treatment of lactic acidosis with dichloroacetate in dogs.

Lactic acidosis is a clinical condition due to accumulation of H(+) ions from lactic acid, characterized by blood lactate levels >5 mM and arterial pH <7.25. In addition to supportive care, treatment usually consists of intravenous NaHCO(3), with a resultant mortality >60%. Dichloroacetate (DCA) is a compound that lowers blood lactate levels under various conditions in both man and laboratory animals. It acts to increase pyruvate oxidation by activation of pyruvate dehydrogenase. We evaluated the effects of DCA in the treatment of two different models of type B experimental lactic acidosis in diabetic dogs: hepatectomy-lactic acidosis and phenformin-lactic acidosis. The metabolic and systemic effects examined included arterial blood pH and levels of bicarbonate and lactate; the intracellular pH (pHi) in liver and skeletal muscle; cardiac index, arterial blood pressure and liver blood flow; liver lactate uptake and extrahepatic splanchnic (gut) lactate production; and mortality. Effects of DCA were compared with those of either NaCl or NaHCO(3). The infusion of DCA and NaHCO(3), delivered equal amounts of volume and sodium, although the quantity of NaHCO(3) infused (2.5 meq/kg per h) was insufficient to normalize arterial pH. In phenformin-lactic acidosis, DCA-treated animals had a mortality of 22%, vs. 89% in those treated with NaHCO(3). DCA therapy increased arterial pH and bicarbonate, liver pHi and cardiac index, with increased liver lactate uptake and a fall in blood lactate. With NaHCO(3) therapy, there were decrements of cardiac index and liver pHi, with an increase in venous pCO(2) and gut production of lactate. Dogs with hepatectomy-lactic acidosis were either treated or pretreated with DCA. Treatment with DCA resulted in stabilization of cardiac index, a fall in blood lactate, and 17% mortality. NaHCO(3) was associated with a continuous decline of cardiac index, rise in blood lactate, and 67% mortality. In dogs pretreated with NaCl, mortality was 33%, but all dogs pretreated with DCA survived. Dogs pretreated with DCA also had lower blood lactate and higher arterial pH and bicarbonate than did those pretreated with NaCl.Thus, in either of two models of type B experimental lactic acidosis, treatment with DCA improves cardiac index, arterial pH, bicarbonate and lactate, and liver pHi. The mortality in dogs with type B lactic acidosis was significantly less in DCA-treated animals than in those treated with other modalities.

Acetates↗