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Pulmonary cellular dysfunction in endotoxin shock: metabolic and transport derangements.

Lung cell metabolic and ion transport alterations in endotoxin shock have been studied to elucidate mechanisms of endotoxin-induced pulmonary dysfunction. Glucose oxidation to lactate as well as to CO2 is significantly increased with a decrease in the lung ATP contents. Active Na+ transport is impaired, indicating an increase in lung intracellular fluid. The altered glucose metabolism and active ion transport could potentially contribute to lung edemagenesis in endotoxicosis.

Adenine Nucleotides↗

Preparation of basolateral membranes that transport p-aminohippurate from primary cultures of rabbit kidney proximal tubule cells.

The organic anion p-aminohippurate (PAH) is specifically secreted by the renal proximal tubule. The possibility was examined that the probenecid sensitive PAH transport system (which is involved in this secretory process in renal proximal tubule cells in vivo) is retained in primary cultures of rabbit kidney proximal tubule cells. Significant 3H-PAH uptake into primary cultures of proximal tubule cells was observed. After 10 min, 150 pmole PAH/mg protein had accumulated intracellularly. Given an intracellular fluid volume of 10 microliter/mg protein, the intracellular PAH concentration was estimated to be 15 microM. The initial rate of PAH uptake (when 50 microM PAH was in the uptake buffer) was inhibited 50% by 2 mM probenecid. Intact monolayers also exhibited Na+-dependent alpha methyl-D-glucoside uptake (an apical marker). Basolateral membranes were purified from primary rabbit kidney proximal tubule cell cultures. Probenecid sensitive PAH uptake into the membrane vesicles derived from the primary cultures was observed. The rate of PAH uptake was equivalent to that obtained with vesicles obtained from the rabbit renal cortex. No significant Na+-dependent D-glucose uptake into the vesicles was observed, indicating that primarily basolateral membrane vesicles had indeed been obtained.

Aminohippuric Acids↗

Studies on the extra- and intracellular acid-base status and its role on metabolic depression in the land snail Helix lucorum (L.) during estivation.

The aim of the present study was to examine the acid-base status of extra- and intracellular fluids and its possible role on the regulation of the metabolic rate of Helix lucorum during prolonged estivation. For this purpose, the rate of oxygen consumption for active and estivating snails was determined. The acid-base status was also examined in the hemolymph and tissues from active and estivating snails acclimated at 25 degrees C. In addition, the buffer values of hemolymph and tissues were determined in order to examine whether there is a change in the snails during estivation. The rate of oxygen consumption decreased significantly within the 1st 10 days of estivation from 122.51+/-10 microl.g(-1).h(-1) to 25.86+/-5.2 microl.g(-1).h(-1), indicating a marked decrease in metabolic rate. P(CO2)increased within the 1st 20 days of estivation from 13.52+/-0.68 mmHg to 25.09+/-2.05 mmHg, while the pH of hemolymph (pH(e)) decreased from 7.72+/-0.04 to 7.44+/-0.06. The level of bicarbonates decreased in the hemolymph of estivating snails, indicating a metabolic acidosis, which was moderate in extracellular fluids. In contrast to pH(e), the intracellular pH (pH(i)) was maintained in the tissues of estivating H. lucorum, indicating a regulation of pH(i) despite the developed hypercapnia. According to the results presented here, it seems that the timing of pH(e) changes does not correlate with the timing of metabolic rate reduction in estivating H. lucorum.

Acid-Base Equilibrium↗

Expansion of interstitial fluid is required for full restitution of blood volume after hemorrhage.

Dogs with splenectomy and intact adrenals and adrenalectomized-splenectomized dogs infused with cortisol at a physiologically increased rate restored plasma volume and protein and demonstrated early extracellular hyperosmolality. In contrast, adrenalectomized-splenectomized dogs infused with cortisol at a basal rate did not restore volume or protein after a transient initial phase and did not demonstrate extracellular hyperosmolality. From the foregoing evidence, it is postulated that the second state of restitution of blood volume following hemorrhage proceeds as follows: 1) Hemorrhage and the subsequent increase in plasma cortisol concentration lead to an increase in extracellular osmolality. An osmotic shift of intracellular fluid to the interstitium ensues. 2) The small increase in interstitial fluid volume results in a relatively large increase in interstitial hydrostatic pressure (because of the low compliance of the interstitium), thus accelerating lymphatic movement of interstitial protein to the vascular system. This movement results in a reequilibration of extracellular fluid toward the plasma. 3) The osmotically active agents mobilized by cortisol and hemorrhage do not appear to be glucose, sodium, or potassium. 4) There may be an adrenal factor other than cortisol that is necessary for full restitution of blood volume with 24 hours after hemorrhage.

Adrenal Cortex↗

A pharmacokinetic analysis of long-term administration of rubidium chloride.

When a substance with a long biologic half-life is administered over an extended period with a varying dose schedule, many concerns about safety arise. In the case of rubidium chloride, which has been reported to have antidepressive activity, some of these concerns are related to the potential for unanticipated accumulation in the intracellular fluid, where replacement of more than 40% of the potassium ions is associated with toxicity in animals. A pharmacokinetic model of rubidium distribution, based on a three-compartment system, is in accord with the empirical data from previous human trials. By comparison of predicted with observed plasma rubidium levels, a sudden change in the ratio of intra- to extracellular distribution of rubidium can be detected, and availability of this warning signal of potentially toxic intracellular accumulation can be useful during extended administration.

Animals↗

Variations in plasma sodium concentration in post-operative patients depend on an electrolyte-free water balance, part of a tonicity balance.

BACKGROUND: There is an inverse relationship between changes in the concentration of sodium in plasma (PNa) and intracellular fluid (ICF) volume. Intakes and losses of sodium (Na), potassium (K) and water can be divided into two volumes: isotonic and electrolyte-free water (EFW). Calculations of these volumes assess a tonicity balance, a tonicity imbalance results in a change of PNa: when EFW is added to body fluids, PNa decreases. Moreover, the concept of EFW permits a good understanding of the renal contribution to the defence of body tonicity. PURPOSE: To illustrate that the measurement of a tonicity balance provides the best estimate of changes in PNa in an ICU setting. METHODS: Twenty-two patients were admitted to the Post-Operative Intensive Care Unit. We investigated how well changes in EFW balance correlated with PNa variations and what is the best formula to calculate EFW in this setting. RESULTS: PNa changes depend on EFW balance; there is no significant relationship with other classical factors such as urinary osmolality or Na-free water. CONCLUSION: The utility of a tonicity balance is demonstrated. A formula is derived facilitating at the bedside the prediction of changes in PNa following fluid therapy: PNa2 = [(PNa1.TBW) + balance (Na + K)]/[TBW + balance H2O]. PNa changes can be understood and/or modified exclusively by a careful measurement of intakes and losses of Na, K and water.

Female↗

Nutritional edema in a rat model of protein deficiency: significance of the dietary potassium and sodium content.

The importance of the levels of dietary sodium and potassium in the etiology of gross nutritional edema in a rat model was explored. For this purpose a mineral mixture (EAM) was designed to permit changing the levels of sodium and potassium while maintaining other components of the mixture. The mixture supplied (as % of diet) 0.075 sodium and 0.270 potassium. In study 1 the EAM mixture was found to support adequate growth (approximately 6 g/d) in well-nourished rats. In study 2 the effects of feeding the diet in either agar gel or dry form were explored. The agar gel diet did not aggravate disturbances in body water balance in rats receiving low protein (0.75 and 1.0% lactalbumin) diets for 20 wk. In study 3 the effects of changes in the sodium and potassium content were evaluated with respect to development of edema and body composition. Excessive levels of sodium or potassium (each 493 mg/100 g diet) in the low protein diet (0.5% lactalbumin) increased mortality and the prevalence of gross edema. When dietary sodium and potassium were closer to the estimated requirement for the rat (0.075% and 0.270%, respectively) there was no development of visible edema in protein-restricted rats. Measurements of exchangeable body sodium, total body water and extracellular and intracellular fluid spaces in the animals indicated that fluid and electrolyte changes result largely from dietary protein restriction alone. However, these changes only proceed to a condition of visible edema where an excessive or unbalanced intake of sodium and potassium is superimposed upon protein deficiency.

Animals↗

Intracellular and extracellular acid-base changes in hemorrhagic shock.

Each of 21 dogs was bled until mean arterial blood pressure fell to 50 torr; this hemorrhagic shock state was then maintained for two hours. During hemorrhagic shock, the blood lactate concentration increased sixfold. The severe metabolic acidosis in arterial blood was partially compensated by a decreased PCO2 caused by increased ventilation. However, in mixed venous blood, the metabolic acidosis was combined with a respiratory acidosis. This hypercapnia in venous blood was indicative of the increased PCO2 in tissues poorly perfused following hemorrhage. The increase in the PCO2 of the femoral venous blood was greater than that in mixed venous blood, suggesting that some tissue beds were better perfused than those of the hind limb during shock. The intracellular lactate concentration of hind limb skeletal muscle was greatly increased in the shock state, and tissue PCO2 rose. Intracellular pH of skeletal muscle was only slightly decreased and bicarbonate concentration was unchanged during this combined metabolic and respiratory acidosis. This capacity of skeletal muscle to maintain a high HCO-3 concentration in intracellular fluid during metabolic acidosis may be an enhanced response of the mechanism responsible for maintaining (HCO-3)i normally at a level approximately ten times that which would be expected if HCO-3 were distributed passively.

Acid-Base Equilibrium↗

Changes in 31P-relaxation times during organ preservation: observations on cold stored human donor livers.

During cold preservation for transplantation the tissue hydration state changes. It is not known whether such changes lead to altered relaxation times of 31P nuclei with potential consequences for the quantification of tissue metabolites. Therefore, 31P spectroscopic and proton T1 relaxometric measurements were performed on 42 isolated human donor livers shortly before implantation. The results demonstrate that 31P T1 relaxation times change during preservation for clinical transplantation, thus quantification of tissue metabolites in cold stored donor livers may be in part dependent on the tissue hydration state. Furthermore, it appeared that changes in tissue hydration state especially affect the physico-chemical characteristics of the intracellular fluid compartment. This study indicates that reliable spectroscopic quantification of tissue metabolites, particularly during sequential spectroscopic measurements in cold stored donor organs is best warranted under fully relaxed conditions.

Adenosine↗

Intracellular potassium in man. A comparison of in vivo and in vitro measurement techniques.

In order to evaluate different methods of estimating intracellular content of potassium, determinations of potassium were made in erythrocytes, in muscle biopsy specimens and in the total body. The total body potassium (TBK) was related to body weight (Bwt), lean body mass (LBM), dry LBM, soft fat-free solids (SFFS), total body water (TBW) and calculated intracellular fluid (ICF). Sixty-two healthy subjects and 80 patients with various diseases and therapy known to influence the potassium metabolism were studied. Statistically significant correlations were found between potassium content in muscle biopsies related to fat-free solids and TBK/Bwt (r = +0.56, P less than 0.05), TBK/LBM (r = + 0.58, P less than 0.01), dry LBM (r = + 0.54, P less than 0.05) and TBK/SFFS (r = + 0.68, P less than 0.01). A correlation was found between muscle potassium related to intramuscular water and TBK/TBW (r = + 0.47, P less than 0.05). No correlations were found between EK and TBK/LBM, TBK/dry LBM or TBK/ICF. Between EK and serum potassium a negative correlation (r = -0.31, P less than 0.05) was found in a group of untreated hypertensives. It is concluded that the quotients of TBK (TBK/LBM, TBK/TBW and TBK/SFFS) might be used in the study of intracellular potassium--at least in the study of patient groups.

Adipose Tissue↗

The hydroxyl-hydrogen ion concentration ratio during hypothermia.

Fundamental physicochemical characteristics of the acid-base related constituents of extracellular and intracellular fluid spaces of vertebrates in relation to changes in temperature have been reviewed. Emphasis has been placed upon the dissociation constant of water, the solubility constant of CO2, the dissociation constant of histidine imidazole, the hydroxyl-hydrogen ion ratio, the protein charge state and the alpha-imidazole regulation concept. Because pN and pKIm change in parallel when temperature varies, the OH/H ratio and the alpha-imidazole value for any sample of blood or plasma held anaerobically in vitro are invariant with changing temperature, since a constant CO2 content is maintained. Thus, when blood or plasma cools, pH increases and PCO2 decreases, but relative alkalinity and the protein charge state remain constant. These responses are solely the consequence of physical constants, that is, equilibrium constants and gas solubility, changing with temperature. In vivo, the set of PCO2 is established in each poikilothermic species by its normal ventilatory pattern designed to maintain constant CO2 content. Regulation in vivo in poikilotherms consists of adjustments of ventilation per unit metabolism (VA/VCO2) appropriate to every temperature. When the ventilatory and renal mechanisms of human beings are suppressed by anesthesia and hypothermia, their extracellular and intracellular responses mimic those of poikilotherms. Clinical management of hypothermia in humans requires ventilatory control using oxygen-augmented room air without added CO2 monitored by pH measurements of arterial blood warmed anaerobically to 37 degrees C. Finally, the need for new techniques to measure intracellular pH as temperature is lowered and some areas for further investigation are suggested.

Acid-Base Equilibrium↗

Origins of [H+] changes in exercising skeletal muscle.

This brief review describes the main physicochemical factors that contribute to increases in intracellular hydrogen ion concentration ([H+]i) in mammalian skeletal muscle during high intensity exercise. High intensity exercise results in changes in the three main independent physicochemical variables: PCO2, the strong ion difference ([SID]), and total concentration of weak acids and bases ([Atot]), within the intracellular fluid compartment of contracting muscle that result in increased [H+]i. The decrease in [SID] contributes 62% to the increase in [H+]i, due to decreased [K+]i and increased [lactate]i; the decrease in phosphocreatine ([PCr2-]i) exerts an alkalinizing effect. The increase in [Atot], resulting primarily from increases in inorganic phosphate and creatine as a result of PCr2- breakdown, contributes 19% to the increase in [H+]i. An increase in the apparent proton dissociation constant (KA) for [Atot] contributes 7% to the increase in [H+]i. PCO2 is a relatively poor effector of changes in [H+]i, such that a 50-mmHg increase in PCO2 contributes only 12% to the increase in [H+]i during high intensity exercise.

Acid-Base Equilibrium↗

Evaluation of leg edema using a multifrequency impedance meter in patients with lymphatic obstruction.

To evaluate quantitatively local edema, electrical tissue impedance in the leg was measured with a multifrequency impedance meter in 10 patients without edema and in 10 other patients with lymphedema after hysterectomy for uterine cervical cancer (Groups 1 and 2, respectively). Equivalent resistivity of extra- and intracellular fluid (RE, RI, respectively) and the ratio RI/RE were calculated. The difference in mean RE between Groups 1 and 2 was significant (p less than 0.05). In four patients in Group 1 and nine in Group 2, simultaneous measurements were carried out on both legs. The differences between mean RE and RI/RE in Group 2 were significant (p less than 0.05, p less than 0.025, respectively). In these 13 patients, correlation coefficients between the ratio of cross-sectional areas of both legs, and both RE and RI/RE were -0.614 (p less than 0.05) and 0.805 (p less than 0.001), respectively. The results suggest that RE and RI/RE could be used as sensitive indicators of local edema.

Adult↗

Internal potassium balance and the control of the plasma potassium concentration.

The plasma potassium concentration is determined both by external potassium balance and by the distribution of potassium between extracellular and intracellular fluid compartments, i.e., "internal potassium balance." Whenever external potassium balance is altered, the resultant change in the plasma potassium concentration is strongly influenced by concomitant alterations in internal potassium balance. Several factors alter internal potassium balance independently of changes in external balance. Acid-base disturbances produce shifts of potassium into or out of cells, but attempts to quantify these effects are not likely to be clinically useful. Hypertonicity produces a shift of potassium out of cells. Several hormones (insulin, aldosterone, catecholamines, glucagon, and growth hormone) may have roles in internal potassium balance. Digitalis and succinylcholine, by producing efflux of potassium from cells, may cause hyperkalemia. Potassium is released from skeletal muscle during exercise, causing an increase in the plasma potassium concentration. The periodic paralyses are associated with well-defined transient alterations in internal potassium balance.

Acid-Base Imbalance↗

Acidosis and contractility of heart muscle.

The contractility of heart muscle is sensitive to small and physiological changes of extracellular pH. The reduction of contractility associated with an acidosis is determined by the fall of pH in the intracellular fluid. The function of many organelles within the cardiac cell is affected by hydrogen ions. The tension generated by isolated myofibrils at a fixed calcium concentration is reduced at low pH. The dominant mechanism for the reduction of contractility in whole tissue is competitive inhibition of the slow calcium current by hydrogen ions. The reduction of the slow calcium current is similar when the same fall of developed tension is induced by acidosis or by a reduction of extracellular calcium concentration. Measurement of tissue pH with fast-responding extracellular electrodes show that, in myocardial ischaemia, tissue acidosis develops at the same time or only seconds before the onset of contractile failure. Much of the reduced contractility can be accounted for by the severity of the acidosis. Although a mild acidosis can delay or prevent damage to the myocardium from ischaemia or hypoxia, a severe acidosis is not beneficial and may even cause tissue necrosis.

Acidosis↗

A simulation study on transcellular fluid shifts induced by hemodialysis.

A computer-based model has been developed to predict the changes in serum sodium, urea concentration, and osmolality as well as transcellular fluid distribution which occur during hemodialysis. Sodium and urea transfers across the dialyzer membrane and transcellular fluid shifts in response to the sodium transfer were modeled assuming that only sodium and its accompanying anions are important as effective osmotic substances in extracellular fluid. Model predictions were consistent with values measured in five patients who were studied on hemodialysis at three different dialysate sodium concentrations equal to 7% below and 7% above the predialysis serum concentration. The measurements and model predictions indicate that serum sodium concentration decreases and intracellular fluid volume increases in dialyses with dialysate Na+ concentration used in conventional hemodialysis, whereas serum sodium concentration increases and intracellular volume decreases in high sodium dialyses. An analysis of model predictions indicates that a reasonable estimation of total body water and the intracellular to extracellular volume ratio enables us to accurately predict the magnitude of transcellular fluid shifts induced by hemodialysis as well as the postdialysis serum sodium concentration and osmolality.

Blood Urea Nitrogen↗

Lithium ions increase action potential duration of mammalian neurons.

During Lucifer Yellow staining of mammalian neurons, intracellular recording revealed a prolongation of the action potential that is probably the result of leakage of lithium ions into the intracellular fluid. In experiments on dorsal root ganglion neurons intracellular iontophoresis of lithium ions also broadened the action potential. Cadmium, a calcium channel blocker, shortens the lithium-evoked wide actions potentials. The present experiments do not reveal whether lithium directly enhances inward calcium current, or whether a block of outward rectification allows calcium currents to increase the action potential duration.

Action Potentials↗

Effects of cadmium exposure on volume regulation in the lugworm, Arenicola marina.

Effects of hypo-osmotic stress and Cd (cadmium) exposure, applied singly or in combination, on volume regulation were investigated in Arenicola marina, the common European lugworm. In short-term experiments, the combined exposure to Cd and hypo-osmotic stress mainly affected the worm's capacity for regulating the coelomic fluid volume without significantly affecting the regulation of intracellular fluid volume. Exposure to Cd increased the worm's sensitivity to hypo-osmotic stress noted as increased mortality compared to the mortality in groups exposed only to Cd or hypo-osmotic stress. In long-term Cd exposure experiments, the capacity for coelomic fluid volume regulation was affected even at constant external osmolarity and the tissue water concentration decreased slightly. The results could not be explained by changes in Apparent Water Permeability (AWP) as Cd did not significantly affect this. The glycogen content of the chloragogenous tissue did, however, increase during long-term Cd exposure suggesting a metabolic effect. The results demonstrate that two stressors, each without serious effects when applied alone, may have fatal effects when applied in combination. The kind of osmotic stress applied in these experiments is common in many biotopes inhabited by the lugworm. The severe effects of the combination with Cd exposure indicate that classical ecotoxicology testing could conceivably underestimate the toxicity of chemical compounds due to not considering combined effects of natural and anthropogenic stressors.

Journal Article↗