Summary. We performed studies on dogs under hydrated conditions, utilizing the rate of free water formation (CH2o) as an index of the rate of distal tubular sodium transport. Since CH2O could be progressively increased with no evidence of a maximal rate during loading with hypotonic (2.5%) mannitol, it was concluded that there is no limit on distal tubular sodium transport during mannitol loading. In contrast, during hypotonic (0.45%) saline loading CHvo rose initially, but as urine flow (V) exceeded 25% of the filtered load CH2o attained maximal levels (up to 20% of the filtered load) and remained stable as V increased to 50% of the filtered load. It was concluded that saline loading progressively inhibits proximal sodium reabsorption. Initially, the distal tubule absorbs a large fraction of the proximal rejectate and sodium excretion rises slightly. Eventually, an alteration in distal sodium transport appears which culminates in a maximal rate or transport limit. This distal transport limit provoked by saline loading could not be characterized by a classical Tm as seen with glucose and does not seem to be consequent to high rates of flow through the distal tubule. Regardless of the precise nature of this limit, the major increment in sodium excretion develops during saline loading only after saline alters the capacity of the distal tubule to transport sodium.

substantial increase in cell Na, K pump influx was not higher in uremic erythrocytes with high cell Na. When intracellular Na was altered with nystatin (cell Na equal to 120 mmol/liter cell water in both groups), K pump influx was proportional to the number of Na-K pump sites so that the ion turnover rate per pump site was similar in the two groups. Uremic plasma failed to depress K pump influx of normal erythrocytes. The passive net influx of Na in uremic cells with high intracellular Na was not different from that observed in erythrocytes from normal subjects. When erythrocytes were separated by age on Percoll density gradients, the number of Na-K pump sites of the youngest uremic Preliminary reports of this work were presented at

A B S T R A C T To evaluate the effects of glucocorticoids on the Na-K pump in human subjects, we evaluated the intracellular sodium and potassium, 42K influx across and the [3H]ouabain binding to cell membranes of intact human erythrocytes from a group of subjects taking glucocorticoids and a group of normal subjects. Intracellular sodium concentration was lower (7.2±0.4 vs. 10.9+0.2 mmol/liter cell water) and intracellular potassium concentration higher (149.8± 1.5 vs. 137.2±1.2 mmol/liter cell water) in erythrocytes from steroid-treated patients. In spite of a significantly decreased intracellular sodium which normally diminishes ouabain-sensitive 42K influx, the ouabain-sensitive K influx was unchanged in erythrocytes from the steroid-treated group. Maximum [3H]ouabain binding was markedly higher in the steroid-treated group (835±44 vs. 449±11 sites/cell). There was close linear correlation between [3H]ouabain binding and inhibition of K pump, suggesting the specificity of ouabain binding to Na-K pump sites on the cell membrane. Association kinetics for ouabain were similar in the two groups despite the marked difference in the amount of [3H]ouabain binding. External potassium concentration required for half-maximum ouabain-sensitive K influx was identical in the two groups. Thus, the additional Na-K pump sites in the steroid-treated group were qualitatively similar to those in normals. These results suggest that administration of glucocorticoids leads to an increase in the number of Na-K pump sites. The increase in the number of Na-K pump sites may explain the low levels of intracellular sodium and higher cell potassium observed in steroid-treated subjects.

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BackgroundAfter ischemia of the CNS, extracellular adenosine 5′-triphosphate (ATP) can reach high concentrations due to cell damage and subsequent increase of membrane permeability. ATP may cause cellular degeneration and death, mediated by P2X and P2Y receptors.Methodology/Principal FindingsThe effects of inhibition of P2 receptors by pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS) on electrophysiological, functional and morphological alterations in an ischemia model with permanent middle cerebral artery occlusion (MCAO) were investigated up to day 28. Spontaneously hypertensive rats received PPADS or vehicle intracerebroventricularly 15 minutes prior MCAO for up to 7 days. The functional recovery monitored by qEEG was improved by PPADS indicated by an accelerated recovery of ischemia-induced qEEG changes in the delta and alpha frequency bands along with a faster and sustained recovery of motor impairments. Whereas the functional improvements by PPADS were persistent at day 28, the infarct volume measured by magnetic resonance imaging and the amount of TUNEL-positive cells were significantly reduced by PPADS only until day 7. Further, by immunohistochemistry and confocal laser scanning microscopy, we identified both neurons and astrocytes as TUNEL-positive after MCAO.ConclusionThe persistent beneficial effect of PPADS on the functional parameters without differences in the late (day 28) infarct size and apoptosis suggests that the early inhibition of P2 receptors might be favourable for the maintenance or early reconstruction of neuronal connectivity in the periinfarct area after ischemic incidents.

The majority of the ouabain-insensitive K influx in human erythrocytes is dependent on the presence of Cl. Recent studies have shown that a portion of the Cl-dependent K influx persists in the absence of external Na (Nao). It has been suggested that this Nao-independent component represents (K + Cl) cotransport, whereas the remainder of the Cl-dependent K influx seen on addition of external Na represents (Na + K + 2Cl) cotransport. In the present studies, the kinetics of Cl-dependent K influx were examined in the presence and absence of external Na, by varying external K and external Cl. Our studies suggest that the Nao-independent Cl-dependent pathway has a relatively low affinity for external K (Km 17-30 mM) in contrast to the high affinity of the Nao-augmented component (Km 3-4 mM). N-ethylmaleimide (NEM) stimulates the maximal velocity of the Nao-independent Cl-dependent K influx achievable without alteration of intracellular solutes but does not alter its Km for external K. In contrast, NEM has no stimulatory effect on the Nao-augmented component. The Cl dependence of the Nao-independent K influx is best described by a relatively flat curve with a mild upward concavity. The kinetic properties of the Nao-independent component of Cl-dependent K transport are very similar to those of the putative (K + Cl) cotransport pathway seen in low-K sheep erythrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of sodium nitrate were compared with sodium chloride loading on transport of electrolytes by the nephron. Maximal levels of free water clearance/clomerular filtration rate (CH2O/GFR) averaged 8.4% with nitrate loading and 14.4% with saline loading. Since ethacrynic acid and chlorothiazide exert their major natriuretic effect in the distal nephron, the increment in Na ad Cl reabsorbed beyond the proximal tubule. The administration of these agents resulted in an increase in fractional sodium excretion (CNa/GFR) of 21.1%, urinary sodium excretion (UNaV) of 1,126 mueq/min, and urinary chloride excretion (UClV) of 848 mueq/min during nitrate loading compared with an increase in CNa/GFR of 37.6%, UNaV of 2,362 mueq/min, and UClV of 2,397 mueq/min during saline loading. The smaller diuretic-induced increment in Na and Cl excretion in the nitrate studies suggests, as do the hydrated studies, that less Cl and Na are reabsorbed in the distal nephron during nitrate than saline loading. At every level of UNaV, fractional bicarbonate reabsorption was higher, urine pH was lower, and urinary potassium excretion (UKV) was higher in the nitrate studies. Thus, compared with saline loading, sodium nitrate decreases chloride and sodium reabsorption in the distal nephron. The higher hydrogen and potassium secretion in the nitrate studies may be consequent to the decreased ability of the distal nephron to reabsorb chloride.

Hypernatremia is usually associated with water depletion. Seven very ill patients developed hypernatremia in association with marked edema during therapy in the hospital. All patients had hypoalbuminemia and azotemia. At the time of hypernatremia, urine output averaged 1880 mL/24 h and urine sodium concentration averaged 59 mmol/L, suggesting that low levels of antidiuretic hormone and/or a diminished effect of this hormone on the nephron may contribute to the pathophysiological mechanism of the hypernatremia. Recognition of this salt- and water-overloaded state should guide therapy.