Sodium Fate after Sodium Bicarbonate Infusion: Influence of Altered Acid-Base Status.

BACKGROUND: We have previously investigated the fate of administered bicarbonate infused as a hypertonic solution in animals with each of the 4 chronic acid-base disorders. Those studies did not address the fate of sodium, the coadministered cation. METHODS: We examined baseline total body water (TBW), Na+ space, HCO3- space, and urinary sodium and bicarbonate excretion after acute hypertonic NaHCO3 infusion (1-N solution, 5 mmol/kg body weight) in dogs with each of the 4 chronic acid-base disorders. Observations were made at 30, 60, and 90 min postinfusion. Retained sodium that remains osmotically active distributes in an apparent space that approximates TBW. Na+ space that exceeds TBW uncovers nonosmotic sodium storage. RESULTS: Na+ space approximated TBW at all times in normal and hyperbicarbonatemic animals (metabolic alkalosis and respiratory acidosis), but exceeded TBW by ~30% in hypobicarbonatemic animals (metabolic acidosis and respiratory alkalosis). Such osmotic inactivation was detected at 30 min and remained stable. The pooled data revealed that Na+ space corrected for TBW was independent of the initial blood pH but correlated with initial extracellular bicarbonate concentration (y = -0.01x + 1.4, p= 0.002). The fate of administered sodium and bicarbonate (internal distribution and urinary excretion) was closely linked. CONCLUSIONS: This study demonstrates that hypobicarbonatemic animals have a Na+ space that exceeds TBW after an acute infusion of hypertonic NaHCO3 indicating osmotic inactivation of a fraction of retained sodium. In addition to an expanded Na+ space, these animals have a larger HCO3- space compared with hyperbicarbonatemic animals. Both phenomena appear to reflect the wider range of titration of nonbicarbonate buffers (Δ pH) occurring during NaHCO3- loading whenever initial [HCO3-]e is low. The data indicate that the fate of administered bicarbonate drives the internal distribution and the external disposal of sodium, the co-administered cation, and is responsible for the early, but non-progressive, osmotic inactivation of a fraction of the retained sodium.

Fluorescence sensors for lithium ions and small peptides.

Simple but powerful chemosensors were developed by taking advantage of self-assembly processes. First, we will describe a turn-on fluorescent sensor for the pharmacologically important lithium ion. The sensor can be used in purely aqueous solution, and it displays a very high selectivity for lithium over sodium and magnesium ions. It is based on a metallacrown receptor unit, which can be assembled in situ from simple building blocks. Furthermore, we will describe a cross-reactive sensor array for the detection of small peptides. The individual sensors of the array are formed by mixing metal complexes with fluorescent dyes.

Sustained effect of glucose-insulin-potassium on myocardial performance during regional ischemia. Role of free fatty acid and osmolality.

To evaluate the influence of glucose infusate administered with insulin and potassium on left ventricular function during 4 h of ischemia, as well as mechanism of action, four groups of intact anesthetized dogs were studied. Acute regional ischemia was induced with a balloon tip catheter in the left anterior descending artery and infusates were begun after 20 min of ischemia. A threefold increase of plasma glucose concentration was associated with improved left ventricular function during ischemia, compared to animals receiving isovolumic saline. There was a significant decline of left ventricular end-diastolic pressure associated with elevation of stroke volume and ejection fraction to control levels, as determined by indicator dilution. In a separate subgroup studied by cineangiography, shortening of the ischemic anterior wall, after an initial decline, was increased in response to glucose but there was no evidence of extension of injury. Ischemic tissue exhibited a smaller gain of water as well as Na+ per gram dry weight as compared to ischemic controls. On precordial electrocardiogram mapping there was a significant decrease in the sigmaST (sum of ST elevation) as well as NST (number of ST segment elevations), but the reduction of R wave amplitude was not different from controls. To further evaluate long-term effects, eight controls and six treated animals underwent myocardial ischemia and were sacrificed after 4 mo. Calculated area and weight of scar, as well as degree of wall thinning, were similar in both groups. The glucose-treated animals had a significant decrease of plasma FFA in contrast to controls which manifested a significant rise. To examine the postulate that the decrease in FFA was important to therapeutic action, a third group was infused with Intralipid (Cutter Laboratories, Inc., Berkeley, Calif.) and heparin, simultaneously with the glucose infusate, to effect an elevation of plasma FFA during ischemia. Changes in myocardial function and electrolyte composition, as well as precordial electrocardiogram mapping, were similar to that of animals receiving glucose alone. Because serum osmolality was increased approximately 40 mosmol during the glucose infusion, the potential role of hyperosmolality was assessed by infusion of 20% mannitol during acute ischemia in a fourth group. After a transient small increase, there was a moderate decline in function by 4 h, suggesting that the response to glucose is not dependent upon extracellular osmolality. Thus, it is concluded that during the initial hours after the onset of myocardial ischemia the glucose infusate improves ventricular performance without evidence of arrhythmia induction or intensification of ischemic injury. Evolution of irreversible necrosis appears to be delayed rather than prevented under the circumstances of this study.

[The effect of 1-isoproterenol on monovalent cation transport in activated human lymphocytes]. / Vliianie 1-izoproterenola na transport monovalentnykh kationov v aktivirovannykh limfotsitakh cheloveka.

Potassium (rubidium) influx, sodium and potassium contents, as well as protein contents and 3H-thymidine incorporation have been investigated in quiescent lymphocytes, PHA-stimulated lymphocytes and T-lymphocytes, activated by human recombinant interleukin 2 (IL-2) within 0.5, 24 and 48 h. In quiescent lymphocytes ouabain-sensitive Rb+ influx was diminished by I-isoproterenol and forskolin. Both the cAMP elevating agents decreased the enhancement of ouabain-sensitive and ouabain-resistant Rb+ influxes in PHA-stimulated lymphocytes in 24 and 48 h. The IL-2 activation of T-cells during 24 and 48 h was accompanied by the elevation of Rb+ influxes and Ki content. L-isoproterenol inhibited ouabain-sensitive Rb+ influx in activated T-cells. This inhibition was found to correlate with 3H-thymidine incorporation in cells. Thus, the effects of l-isoproterenol and forskolin on ionic transport in human activated lymphocytes correlated with a well-known cAMP inhibition of lymphocyte proliferation.

Investigation of low ionic strength effect on passive monovalent cation transport through erythrocyte membranes.

Effect of low ionic force on the passive transport of univalent cations through the erythrocyte membranes is considered. It is postulated that this effect is complex and cannot be explained on the basis of electrodiffusion. Data are presented on the already known transport pathways in the erythrocyte membranes for univalent cations. Characteristics of residual cation transport (the "leak" flux) through the erythrocyte membranes also affected by the low ionic force are presented.

[Transport of monovalent cations in erythrocytes after low temperature preservation and treatment with cryoprotective agents]. / Transport odnovalentnykh kationov v éritrotsitakh posle nizkotemperaturnoi konservatsii pod zashchitoi krioprotektorov.

The freezing-thawing of erythrocytes under protection of 1,2-propane diol and glycerol was studied for its effect on the intracellular content of K+,Na+ and state of their passive and active transport. The low-temperature conservation of cells under the effect of penetrating cryoprotectors does not change essentially the content of univalent cations. A significant increase in the Na+ transport is observed with application of the cryoprotective medium on the base of 1,2-propane diol.

Deoxygenation-induced cation fluxes in sickle cells: relationship between net potassium efflux and net sodium influx.

Deoxygenation-induced cation fluxes in sickle cells were studied by measuring net cation movements in ouabain-treated cells. These deoxy cation fluxes were highly dependent on pH, showing inhibition at pH less than 7 and greater than 8 and a maximum at 7.4-7.5. Activation occurred at oxygen tensions around 40-50 torr and fluxes rose sharply as PO2 fell lower. Deoxy K efflux paralleled deoxy Na influx at pH values between 7 and 8, and at all oxygen tensions. Sickle cells were separated by density on Percol-Stractan gradients. Dense cells had lower deoxy cation fluxes of both Na and K than did lighter cell fractions, but in none of the fractionated populations did deoxy K efflux exceed deoxy Na influx. These data demonstrate that deoxy cation fluxes are activated at physiological pH and oxygen tensions and that there are no conditions of pH and PO2 and no cell populations in which cation fluxes induced by deoxygenation contribute directly to net cation loss in sickle cells. Chloride replacement (with nitrate) did not alter deoxy cation fluxes, and deoxy K efflux did not require the presence of external Na (tetramethylammonium replacement). Thus, deoxy cation fluxes do not have the characteristics of a cation-chloride cotransport or cation countertransport system.

[Transport of monovalent cations into erythrocytes of rabbits with experimental hypercholesterolemia: correlation with plasma cholesterol]. / Transport odnovalentnykh kationov v éritrotsitakh krolikov s éksperimental'noi giperkholesterinemiei: korreliatsii s kholesterinom plazmy.

The activities of the Na+, K(+)-pump, Na+, K+, 2Cl- and K+, Cl(-)-cotransports and Na+, Li+ exchange as well as intracellular concentrations of Na+, K+, Mg2+ and cholesterol content in erythrocyte membranes of rabbits with experimental hypercholesterolemia have been studied. The activity of the Na+, K(+)-pump recorded as the ouabain-inhibited component of 86Rb influx is, on the average, by 100% higher than that in control erythrocytes of rabbits fed on a cholesterol-rich diet for 2 months and correlates significantly with the concentration of cholesterol (Ch) and low density lipoproteins (LDL) in the plasma as well as with Na+ concentration in erythrocytes. The activity of the Na+, K+, 2Cl- and K+, Cl(-)-cotransports recorded, correspondingly, as the bumetanide- and furosemide-inhibited component of 86Rb influx, is unobserved in rabbit erythrocytes irrespective of the Ch level in the plasma. The activity of the Na+, Li+ exchange is markedly reduced in erythrocytes of rabbits with hypercholesterolemia and correlates with Ch and LDL levels in the plasma. The K+ and Mg2+ concentrations in erythrocytes do not depend on Ch plasma levels. There was a negative correlation between the intracellular Na+ content with plasma Ch and LDL levels. The Ch content in erythrocyte ghosts is, on the average, identical for both groups of experimental animals.

Anionic mechanisms of zinc uptake across the human red cell membrane.

1. Zinc is taken up into human red cells by two mechanisms that depend upon the presence of anions. One of these requires bicarbonate ions, is inhibited by 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and appears to be catalysed by the anion exchanger. The second occurs in the presence of thiocyanate or salicylate ions and may represent transport of a neutral complex with Zn2+. 2. The initial rate of Zn2+ uptake via the anion exchanger is 64 +/- 13 mumol (10(13) cells x h)-1 microM-1 external Zn2+, in the presence of 5 mM-bicarbonate at pH 7.4 and 37 degrees C (+/- S.D.). This is about 1/250 of the corresponding rate of Pb2+ uptake by the anion exchanger. 3. The variation of transport with Zn2+ concentration, HCO3- concentration and pH suggests that the transported species may be ZnCO3Cl- or Zn(HCO3)Cl.OH-. 4. Zinc efflux could not be observed by either of the above routes. This observation suggests that the intracellular free Zn2+ concentration is below 3 nM.

Intracellular ion metabolism in erythrocytes and uraemia: the effect of different dialysis treatments.

The present report focuses on some aspects of the intra-erythrocytic cation metabolism (e.g. the maximal velocity of the Na+-Li+ countertransport and Na+/K+/Cl- cotransport) in uraemic patients on different dialysis treatments. Patients undergoing dialysis treatment [continuous ambulatory peritoneal dialysis (CAPD) or haemodialysis (HD)] overall showed higher Na+-Li+ countertransport than controls. With regard to Na+/K+/Cl- cotransport, CAPD patients and controls did not differ and both showed, on average, higher values than HD patients. A subgroup of HD patients was studied before and after dialysis. No significant overall changes were detected as a result of the dialysis process with regard to Na+/K+/Cl- cotransport. Na+-Li+ countertransport was significantly reduced by dialysis and a distinctly different response to dialysis was evident according to predialysis values. Patients with high values of Na+-Li+ countertransport showed a significant reduction in this parameter while patients with normal values showed no effect. No distinct association was detected between alteration in either Na+-Li+ countertransport or Na+/K+/Cl- cotransport and the clinical characteristics of the patients. It is concluded that uraemia and/or dialysis influences the maximal velocity of the parameters under investigation. The effect on Na+-Li+ countertransport seems to be similar for both CAPD and HD, while Na+/K+/Cl- cotransport is not altered in CAPD patients.

System y+L: the broad scope and cation modulated amino acid transporter.

The properties are discussed of system y+L, a broad scope amino acid transporter which was first identified in human erythrocytes. System y+L exhibits two distinctive properties: (a) it can bind and translocate cationic and neutral amino acids, and (b) its specificity varies depending on the ionic composition of the medium. In Na+ medium, the half-saturation constant for L-lysine influx was 9.5 +/- 0.67 microM and the inhibition constant (Ki) for L-leucine was 10.7 +/- 0.72 microM. L-Leucine is the neutral amino acid that binds more powerfully, whereas smaller analogues, such as L-alanine and L-serine interact less strongly (the corresponding inhibition constants were Ki,Ala, 0.62 +/- 0.11 mM; Ki,Ser, 0.49 +/- 0.08 mM). In the presence of K+, the carrier functions as a cationic amino acid specific carrier, but Li+ is able to substitute for Na+ facilitating neutral amino acid binding. The effect of the inorganic cations is restricted to the recognition of neutral amino acids; translocation occurs at similar rates in the presence of Na+, K+ and Li+. The only structural feature that appears to impair translocation is bulkiness and substrates with half-saturation constants differing by more than 100-fold translocate at the same rate. This suggests that translocation is largely independent of the forces of interaction between the substrate and the carrier site. System y+L activity has been observed in Xenopus laevis oocytes injected with the cRNA for the heavy chain of the 4F2 human surface antigen. 4F2hc is an integral membrane protein with a single putative membrane-spanning domain and it remains to be clarified whether it is part of the transporter or an activator protein.

Stomatocytosis, abnormal platelets and pseudo-homozygous hypercholesterolaemia.

A 13-yr-old girl with congenital haemolytic anaemia associated with pseudo-homozygous hypercholesterolaemia is described. The erythrocyte morphology showed 50-80% stomatocytes, but no abnormality of membrane lipid or protein composition or of cation transport was detected. The platelets were reduced in number, abnormally large and showed reduced adhesion. Successful treatment of the hypercholesterolaemia did not influence the stomatocytosis.

Analysis of BP response and Ca2+ metabolism using the saturation kinetics model.

The provision of supplemental dietary calcium (dCa) lowers blood pressure (BP) in the spontaneously hypertensive rat (SHR). Whether calcium's antihypertensive effects can be expressed in the presence of potentially hypertensinogenic nutrients is not known. Furthermore, the amount of dCa required to attenuate hypertension in the SHR remains undetermined. Along with establishing the effects of dCa on BP under conditions of a high Na+ intake, we sought to define the lowest dose of dCa associated with the greatest attenuation in arterial pressure in the young SHR. Thirty-five 6-wk-old SHR were fed one of five diets containing either 0.1, 0.25, 0.5, 1.0, or 2.0% dCa. All diets contained 1.0% Na+. The rates of change (delta) in body weight, BP, and serum ionized calcium were determined between 6 and 20 wk of age. Bone density (BD) was measured only at 20 wk of age. The data were analyzed using the saturation kinetics model. Results indicate that the half-maximal dose (K50) of dCa needed to lower pressure is 0.67 +/- 0.18%, which is higher than the K50 for weight (0.23 +/- 0.18) and BD (0.36 +/- 0.22). It is concluded that supplemental dCa lowers BP despite a high Na+ intake. Furthermore, a dose of approximately 1.5 dCa is sufficient to attenuate the rate of hypertension in the young growing SHR.

The membrane defect in hereditary stomatocytosis.

Hereditary stomatocytosis and allied conditions represent a series of diseases in which abnormal movements of univalent cations across the plasma membrane play an important part in cellular disease. The primary problem lies not in the active transporters but in the basal permeability of the membrane, which is always increased, and the extent of the increase correlates with the cellular dysfunction. A number of structural abnormalities have been described in these membranes, but the most consistent and convincing is the deficiency of a hitherto uncharacterized integral membrane protein of molecular weight 31 kDa in the severe, 'overhydrated' form of the disease. The true function of this protein remains enigmatic, but its deficiency in this condition indicates that it may have a role in the regulation of cation transport.

The monovalent cation "leak" transport in human erythrocytes: an electroneutral exchange process.

The mechanism of the "ground permeability" of the human erythrocyte membrane for K+ and Na+ was investigated with respect to a possible involvement of a previously unidentified specific transport pathway, because earlier studies showed that it cannot be explained on the basis of simple electrodiffusion. In particular, we analyzed and described the increase in the (ouabain+bumetanide+EGTA)-insensitive unidirectional K+ and Na+ influxes as well as effluxes (defined as "leak" fluxes) observed in erythrocytes suspended in low-ionic-strength media. Using a carrier-type model and taking into account the influence of the ionic strength on the outer surface potential according to the Gouy-Chapman theory (i.e., the ion concentration near the membrane surface), we are able to describe the altered "leak" fluxes as an electroneutral process. In addition, we can show indirectly that this electroneutral flux is due to an exchange of monovalent cations with protons. This pathway is different from the amiloride-sensitive Na+/H+ exchanger present in the human red blood cell membrane and can be characterized as a K+(Na+)/H+ exchanger.