Ussing (1949) suggested that part of the observed Na efflux in frog muscle might result from a process that he termed 'exchange diffusion', involving a sodium for sodium exchange across the membrane. Thus, if a carrier with a high affinity for Na were confined to the membrane and able to diffuse across it only when it had formed a complex with Na, there would be a continual movement of labelled Na through the membrane without necessarily any simultaneous consumption of energy. If such a mechanism existed, complete removal of Na from the outside of the membrane might be expected to eliminate a substantial fraction of the total efflux of labelled Na, unless the cation substituted for Na+ could also form a complex with the carrier and thus move across the membrane. We therefore investigated the effect on the Na efflux of substituting choline or lithium for the sodium in the external medium, and found that in both cases the efflux was promptly reduced by about half when the sodium in the interfibre fluid was replaced by the foreign cation. This observation clearly warranted further analysis, and the changes in Na efflux were examined for test muscles with altered internal Na concentrations, and at various temperatures. The effect of partial replacement of external Na was also investigated and the resulting changes in Na efflux were compared with the parallel alterations in Na influx. The effect of removing external Na was found to add to that of removing external K, and the relative magnitude of the two effects was studied as a function of the Na content of the muscles.A preliminary report on this work was made at the XX International Physiological Congress (Swan & Keynes, 1956). METHODSMeasurements of sodium fluxes For measurement of effluxes, frog muscles were dissected free and exposed to Ringer's solution containing 4Na for about 3-5 hr. This period was calculated as sufficient for the specific activity of

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From 8 to 15 mM of strong mineral acid per kilogram of body weight may be infused intravenously in the dog over a period of a few hours to produce a severe but non-fatal acidosis. Van Slyke and Cullen (1) showed that only one-sixth of the infused acid is neutralized by blood buffers, five-sixths presumably being neutralized by bicarbonate in interstitial fluid and lymph and by intracellular phosphate and proteinate buffers. Recently, Bergstrom and Wallace(2) have indicated that sodium and potassium on the surface of bone crystals are also available for neutralization of acid.How tissue buffers participate in the neutralization of acid has been investigated by measuring changes in total quantity of extracellular sodium, potassium, bicarbonate, and chloride ions following infusion of hydrochloric acid into nephrectomized dogs. Our preliminary reports (3, 4) were based on experiments in which extracellular fluid volume was approximated by inulin distribution. The observation of a considerable increase in the inulin volume of distribution following infusion of acid led us to compare volumes of distribution of several substances proposed by others as approximations of extracellular fluid volume. This comparison indicated that radiosulfate distribution more closely measures extracellular fluid volume than does inulin in the whole animal (5). Therefore, the experiments on the effects of hydrochloric acid infusion have been repeated using radiosulfate distribution to measure changes in extracellular fluid volume. No definitive publication of the original experiments is contemplated.The results of our recent experiments indicate that when 10 mM of hydrochloric acid per kilogram of body weight are infused into a nephrectomized dog over a period of two hours, 43 per cent of the infused acid is neutralized by bicarbonate 1 Supported by a grant from the American HeartAssociation.originally present in extracellular fluid, whereas 51 per cent is neutralized by a process in which hydrogen ions are exchanged for sodium and potassium ions which diffuse into extracellular fluid probably from cells. Simultaneously a 16 per cent increase in extracellular fluid volume occurs. The results of our earlier experiments using inulin agree qualitatively with each of these findings. The results differ quantitatively for the volume of distribution of inulin is less than that of radiosulfate (5), and in our earlier experiments correction was not made for the slow disappearances of inulin after two to three hours of equilibration.EXPERIMENTAL PLAN Dogs were nephrectomized immediately before an experiment to eliminate renal excretion of acid and to measure more accurately the volume of distribution of radiosulfate. Control values for sodium, potassium, bicarbonate, and chloride in extracellular fluid and in the circulating erythrocyte mass were established three and four hours after nephrectomy. One and one-half and two and one-half hours after the production of a severe metabolic acidosis by hydrochloric acid infusion the total amounts of th...

The volumes of distribution of a number of substances of widely varying molecular size and chemical properties, including sulfate, thiosulfate, mannitol, sucrose, and inulin, have been found to represent 15 to 25 per cent of body weight of man, dog, and other mammals. The apparently equal volumes of distribution of these dissimilar substances has suggested that the distribution of each of these substances measures the same portion of body fluid and has led to efforts to identify this volume of body fluid with the extracellular fluid volume.In a series of individuals, however, there is a considerable range in the fraction of body weight which the volume of distribution of any one of these substances represents. In only a few instances have the distributions of two of these substances been compared simultaneously in the same individual. Schwartz (1) reported a ratio of thiosulfate volume to simultaneously measured mannitol volume of 0.90 (0.87 to 0.96) in four normal dogs, a ratio of 1.02 and 0.98 in two normal human subjects, and a ratio of inulin to simultaneously measured mannitol volume of 0.97 (0.93 to 1.02) in six normal human subjects (2). Walser, Seldin, and Grollman (3) (7) found that the ratio of inulin volume to thiosulfate volume averages 0.79 in five nephrectomized dogs.To determine which, if any, of these substances distribute in equal volumes, the distributions of six substances: radiosulfate, thiosulfate, mannitol, sucrose, raffinose, and inulin, ranging in molecular weight from 96 to 5100 and including two anions, have been compared in nephrectomized dogs. These comparisons have been made under conditions which eliminate or minimize uncertainties regarding: a) extrarenal removal of these substances, b) changing plasma blank, c) completeness of recovery of the injected substance in the urine, and d) upper urinary tract dead space. The volumes of distribution of three of these substances, radiosulfate, thiosulfate, and mannitol, have been found to be equal. Sucrose, raffinose, and inulin volumes are smaller in inverse order to the molecular size of these substances.Volumes of distribution of d-galactose, d-xylose, and l-arabinose have been reported to increase in nephrectomized dogs and rabbits after insulin administration, presumably the result of insulin facilitating transport of these substances across cell membranes (8, 9). The possibility that endogenous insulin release might alter volumes of distribution of the six substances studied has been investigated by observing the effect of intravenous insulin on their volumes of distribution. METHODS

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