DIET AND TISSUE GROWTH : I. THE REGENERATION OF LIVER TISSUE ON VARIOUS ADEQUATE DIETS.

1. The toxicity of chloroform varies according to the diets used in these experiments in the following order of decreasing susceptibility of the animals: high fat > standard > high carbohydrate > high protein diets. 2. On the high fat and high carbohydrate diets there may be a more or less marked proliferation of the endothelium and the connective tissue stroma in the necrotic area producing in some instances scars resembling the picture of an early cirrhosis. 3. On the diets studied, standard, high carbohydrate, high protein, and high fat, the most active and rapid repair is observed on the standard balanced diet. On the high fat diet the reparative process is definitely delayed in comparison with the others. There are only slight differences between the high carbohydrate and high protein diets which suggest but do not conclusively show a more rapid repair with the latter diet.     

BLOOD PLASMA PROTEIN PRODUCTION AND UTILIZATION : THE INFLUENCE OF AMINO ACIDS AND OF STERILE ABSCESSES

When blood plasma proteins are depleted by bleeding with return of the washed red blood cells (plasmapheresis) it is possible to bring dogs to a steady state of hypoproteinemia and a uniform plasma protein production on a basal low protein diet. These dogs are clinically normal. Introduction of variables into their standardized life gives insight into the production of plasma protein. Casein retested as the basal protein in the ration may show high yield of plasma protein, equal to 33 per cent of the protein fed. This equals the potency of liver protein (17 to 33 per cent) and approaches the utilization of plasma protein by mouth (40 per cent). Zein has no effect upon plasma protein regeneration but when it is supplemented with cystine, tryptophane, lysine, and glycine, there is a doubling of the liver basal plasma protein production and a retention of the fed protein nitrogen. Threonine does not modify the above reaction. Liver protein supplemented with cystine, leucine, glutamic acid, and glycine in the basal diet yields double the amount of new formed plasma protein compared with liver alone. This combination is then as potent as plasma protein itself when given by mouth—40 per cent utilization. Tyrosine or lysine, arginine, and isoleucine do not modify the above responses. Methionine is not as effective as cystine in supplementing gelatin and tyrosine to produce plasma protein. Cystine, leucine, and glutamic acid appear to be of primary importance in the building of new plasma protein in these experiments. Plasma protein formation is dependent upon materials coming from the body reserve and from the diet. Given an exhaustion of the reserve store there is very little plasma protein produced during a protein fast (3 to 6 gm. per week). A turpentine abscess does not modify this fasting plasma protein reaction. Homologous plasma given by vein will promptly correct experimental hypoproteinemia due to bleeding. It will maintain nitrogen equilibrium and replenish protein stores. Even during hypoproteinemia plasma protein may promptly pass out of the circulation to supply body needs for protein. Perhaps the most significant concept which derives from all these experiments is the fluidity of the body protein (including plasma protein)—a ready give and take between the protein depots—a "dynamic equilibrium" of body protein.     

The effect of caloric of food on energy intake and body weight in tumor-bearing rats

Anorexia and weigt loss are major problems for cancer patients and are associated with increased cancer morbidity and mortality. The current clinical approach is to encourage high calorie food intake. In the present study, we used an animal model of tumor-induced anorexia to evaluate the effect of feeding a high caloric diet on food and caloric intake and body weight of tumor-bearing rats. Tumor-bearing rats fed a diet containing 4.7 kcal/g reduced the amount of food they ate to equal the caloric intake of rats fed a diet containing 3.7 kcal/g. Body weight and tumor growth were not affected by the diet intervention. These data suggest that energy intake is regulated in tumor-bearing rats as it is in healthy animals, albeit at a lower level. These data have implications for further study of the effects of nutritional supplements on food intake and nutritional status of cancer patients. ©1995 John Wiley & Sons, Inc.     

Role of angiotensin II in dietary modulation of rat late distal tubule bicarbonate flux in vivo.

We have reported that overnight fasting stimulates bicarbonate reabsorption (JtCo2) in rat distal tubules. The present in vivo microperfusion studies evaluated the hypothesis that endogenous angiotensin II (AII) mediates this response. Rat late distal (LD) tubules were perfused at 8 nl/min in vivo with a hypotonic solution containing 28 mM bicarbonate. In overnight-fasted rats, LD JtCO2 was significantly higher than in normally fed rats (50 +/- 4 vs. 16 +/- 6 pmol/min.mm, P < 0.05). When overnight-fasted rats were salt-loaded, JtCO2 fell significantly (38 +/- 3 pmol/min.mm, P < 0.05). Conversely, in fed rats ingesting a zero-salt diet, JtCO2 increased three-fold (45 +/- 5 pmol/min.mm, P < 0.05). Enalaprilat infusion (0.25 micrograms/kg body wt, intravenously), in these zero-salt and overnight-fasted rats, reduced LD JtCO2 values to normal. Further, infusion of losartan (5 mg/kg body wt, intravenously), the specific AII AT1 receptor blocker, reduced JtCO2 in overnight-fasted rats by two-thirds (16 +/- 4 pmol/min.mm, P < 0.05). Finally, we perfused 10(-11) M AII intraluminally with and without 10(-6) M losartan: AII increased JtCO2 to 45 +/- 6 pmol/min.mm, equal to the zero-salt flux. This was completely abrogated by simultaneous losartan perfusion. Therefore, these results suggest that AII is an in vivo stimulator of late distal tubule bicarbonate reabsorption.     

Effects of fasting on temporal variations in nephrotoxicity of gentamicin in rats.

Evidence for temporal variations in the nephrotoxicity of low doses of aminoglycosides were recently shown by using specific and sensitive parameters of renal toxicity. The aim of the present study was to evaluate the effect of a short period of fasting on the temporal variations in the renal toxicity of gentamicin. Twenty-eight normally fed (i.e., food and water were available ad libitum throughout the experiment) female Sprague-Dawley rats (weight, 175 to 220 g) and 28 fasted rats (i.e., only water was available during a 12-h fast before and a 24-h fast after gentamicin injection) were used. The animals were synchronized on a 14-h light, 10-h dark cycle (lights on at 0600 h) for 1 week before gentamicin administration. In July 1993, each group of animals was treated with a single intraperitoneal injection of saline (NaCl, 0.9%) or gentamicin (150 mg/kg of body weight) at either the peak (1400 h) or the trough (0200 h) of the previously determined toxicity. On day 1, the 24-h urinary excretion of beta-galactosidase, N-acetyl-beta-D-glucosaminidase, and gamma-glutamyltransferase was significantly higher in normally fed animals treated with gentamicin at 1400 h than in their time-matched controls and in normally fed animals treated at 0200 h (P < 0.01), which had normal levels of these enzymes. By contrast, the urinary excretion of these enzymes was significantly higher in both groups of gentamicin-treated, fasted rats than in their time-matched control groups (P < 0.01), reaching levels similar to those measured in normally fed rats treated at 1400 h. The accumulation of gentamicin was significantly lower in the renal cortex of normally fed rats treated at 0200 h than in rats treated at 1400 h (P < 0.05), but this time-dependent difference was not found in fasted rats treated at 0200 and 1400 h. Immunogold labeling done on ultrathin sections and observed by electron microscopy showed a similar subcellular localization of gentamicin in normally fed and fasted rats treated at either 1400 or 0200 h. These results suggest that the feeding period is of crucial importance in the temporal variations of the nephrotoxicity of gentamicin in rats.     

Role of dietary l-arginine supplementation on serum parameters and intestinal enzyme activities in rats fed an excess-fat diet.

We investigated whether dietary supplementation with L-arginine, the endogenous precursor of nitric oxide, might affect serum parameter levels body weight, food intake and activities of intestinal mucosa enzymes in animals fed with a standard diet or a diet high in saturated fat for 4 weeks. Body weight and food intake were not affected by diet but relative liver weight was higher in animals receiving a high-fat diet. Total cholesterol, LDL-cholesterol and triglyceride levels were higher in both groups fed high-fat diet and dietary L-arginine did not affect these parameters but produced an increase in serum protein levels and a slight decrease in glycaemia. Regarding the intestinal enzyme activities, rats fed a high-fat diet plus arginine showed the lowest intestinal disaccharidase activities.     

FGF21 is an endocrine signal of protein restriction

Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. LP-induced increases in FGF21 were associated with increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the liver, and both baseline and LP-induced serum FGF21 levels were reduced in mice lacking the eIF2α kinase general control nonderepressible 2 (GCN2). Finally, while protein restriction altered food intake, energy expenditure, and body weight gain in WT mice, FGF21-deficient animals did not exhibit these changes in response to a LP diet. These and other data demonstrate that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake.     

Dietary fat selectively alters transport properties of rat jejunum.

The influence of dietary fatty acid composition on intestinal active and passive transport function, brush border membrane composition, and morphology was examined in rats. Animals fed a semisynthetic diet high in saturated fatty acids demonstrated enhanced in vitro jejunal uptake of decanoic, dodecanoic, palmitic, stearic, and linoleic acid, as well as cholesterol and chenodeoxycholic and taurochenodeoxycholic acid, as compared with uptake in animals fed a semisynthetic diet high in polyunsaturated fatty acids but equivalent in total content of fat and other nutrients, or as compared with Purina chow. Feeding the saturated fatty acid diet was also associated with reduced jejunal uptake of a range of concentrations of glucose, enhanced ileal uptake of leucine, unchanged uptake of galactose, and lower uptake of decanol. The semisynthetic diets did not alter brush border membrane protein, sucrase or alkaline phosphatase activities, cholesterol, or total phospholipids, although the percentage of jejunal amine phospholipids was higher than in rats fed chow. The morphologic differences between the jejunum and ileum were abolished in animals fed the high polyunsaturated fatty acid diet; in rats fed the high saturated fatty acid diet, there was reduced mean ileal villus height, width, thickness, surface area, cell size, and villus density, as well as reduced mucosal surface area. The changes in jejunal transport were not correlated with the alterations in morphology, unstirred layer resistance, food intake, or body weight gain. It is proposed that small changes in the percentage of total dietary lipids composed of essential and nonessential fatty acids (without concurrent alterations in dietary total fat, carbohydrate, or protein) influence active and passive intestinal transport processes in the rat.     

Protein losing enteropathy associated with Nippostrongylus brasiliensis infestation and its impact on albumin homoeostasis in rats fed two levels of dietary protein

Alterations in plasma albumin concentration and gastrointestinal permeability have been investigated in rats infected with the nematode Nippostrongylus brasiliensis and fed adequate or low protein diets. Infection caused only minor changes in growth and food consumption of well nourished rats but resulted in significant reductions in those fed the low protein diet. Animals in both dietary groups were able to mount an immune response beyond day 10 post-infection (p.i.) which caused expulsion of the parasites, but this was less effective in rats fed the low protein food. Uninfected rats fed the low protein diet had significantly lower plasma albumin concentrations than their well nourished counterparts. Animals of both dietary groups showed a progressive reduction in plasma albumin concentration as the infection developed but values returned towards normal as the parasites were expelled. The reduction in plasma albumin concentration was closely associated with increases in gastrointestinal leakage of plasma protein but losses were far greater in the protein deficiency animals. Beyond day 10 p.i. protein loss decreased in both dietary groups and by day 21 p.i. had returned to normal in well nourished animals but not those fed the low protein diet. Intestinal permeability measured by the lactulose:mannitol ratio technique gave similar results to the protein loss data. Permeability increased as the infection progressed then fell as the worms were expelled but remained above control values in infected protein deficient animals. Overall, animals fed the low protein diet were more severely affected by the parasite than were their well fed counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)     

DIET AND TISSUE GROWTH : V. THE EFFECT OF DIETARY PROTEIN ON THE REMAINING KIDNEY OF ADULT WHITE RATS FOLLOWING A UNILATERAL NEPHRECTOMY.

The effects of the ingestion of diets containing different concentrations of protein on the remaining kidney in adult white rats after a unilateral nephrectomy has been studied. In the animals on the high protein diet (85 per cent casein), actual glomerular and tubular lesions were observed in the kidneys of animals maintained for 90, 120 and 150 days after nephrectomy. In the animals on the standard ration, 18 per cent casein, no significant renal lesions were observed within the experimental period. Spontaneous focal lesions in the kidneys of rats maintained on Sherman''s diets "A" and "B" were inconspicuous at the age of 350 days but became progressively more frequent and were commonly observed after 500 days. The animals on the high protein and standard rations were all under 350 days old at the completion of the experiment. It is suggested that the age factor is of importance in that young animals may have greater powers of adaptation in withstanding the injurious effect of high protein rations. The animals on the high protein ration excreted definitely larger quantities of protein in the urine, and showed a higher incidence of casts in periods roughly corresponding to those in which anatomic lesions were observed than did the rats on the standard diet.     

Effect of Dietary Medium-Chain Triacylglycerol on Serum Albumin and Nitrogen Balance in Malnourished Rats

The present study was examined the therapeutic effect of medium-chain triacylglycerol (MCT) in protein-energy malnutrition (PEM). Wistar rats were fed low protein diet containing 70 g/kg of long-chain triacylglycerol (LCT) or MCT for 31 days. The serum albumin concentration in rats fed MCT diet (2.88 ± 0.04 g/dl) were significantly higher compared with those fed LCT diet (2.72 ± 0.04 g/dl) at day 31. Nitrogen balance was higher in rats fed MCT diet (54.1 ± 2.3 mg/day) compared with those fed LCT diet (45.4 ± 2.4 mg/day) during d 10–12. These results suggest that MCT effectively elevates serum albumin concentration and improves nitrogen balance in malnourished rats.     

Positive effects of an oral supplementation by Glisodin,a gliadin-combined SOD-rich melon extract,in an animal model of dietary-induced oxidative stress

We investigated the potential protective effects of two antioxidant molecules: Glisodin, a gliadin combined copper-zinc superoxide dismutase SOD (Cu,Zn SOD)-rich melon extract, SOD is a known enzyme that has been best studied as a regulator of antioxidant defence, and an antioxidant agent N-acetylcysteine (NAC). Glisodin, given orally to rats fed a chow diet, as 180 U/d during 2 weeks in a preconditioning treatment, and then for 8 weeks, combined to a high fat/high fructose diet (HF/HFr), had more positive effects than NAC (100 mg/d), not only on oxidative stress parameters, but also on features of the metabolic-syndrome. DNA oxidative damages, lipid peroxidation, and fasting glycaemia were lower in rats receiving Glisodin than in those supplemented by NAC. In addition, insulin sensitivity was improved and mesenteric fat was significantly lower in rats fed the Fr/Fe diet plus Glisodin than in animals fed NAC supplementation.These data suggest potential beneficial effects of oral Glisodin supplementation in preventing metabolic alterations related to the metabolic syndrome.     

Dietary supplementation with conjugated linoleic acid does not improve nutritional status of tumor-bearing rats.

Tumor necrosis factor-alpha (TNF) is an immunoregulatory cytokine that plays a major role in tumor-induced anorexia and weight loss. Conjugated linoleic acids (CLA) are naturally occurring isomers of linoleic acid that, when added to the diet, improve food intake and body weight in mice injected with TNF. The purpose of the present study was to examine the effects of a diet supplemented with 0.5% CLA on the nutritional status of rats implanted with the Morris 7777 hepatoma. Body weight, food intake, serum levels of insulin-like growth factor, and splenocyte synthesis of TNF were not different in tumor-bearing animals fed CLA versus the control diet. However, insulin levels were increased in both tumor-bearing and control animals given CLA. The 0.5% CLA did not improve the nutritional status nor alter TNF synthesis in hypophagic tumor-bearing rats. The biological significance of increased insulin levels in animals given CLA remains to be determined.     

BLOOD PLASMA PROTEIN GIVEN BY VEIN UTILIZED IN BODY METABOLISM : II. A DYNAMIC EQUILIBRIUM BETWEEN PLASMA AND TISSUE PROTEINS

Large amounts of normal blood plasma can be given intravenously to normal dogs over several weeks without causing any significant escape by way of the urine. There appears to be no renal threshold for plasma protein even with high plasma protein concentration (9.7 per cent). Dogs receiving sugar by mouth and plasma by vein can be kept practically in nitrogen equilibrium and it would seem that the injected protein must be utilized by the body. If this can happen in this emergency we may suspect that normally there is a certain amount of "give and take" between body protein and plasma protein. Plasma protein fed by mouth under identical conditions shows the same general reaction as noted with plasma by vein but the urinary nitrogen is a little higher and suggests that the injected protein is utilized a little more completely to form new protein. The difference may be explained as due to deaminization in the case of protein by mouth. During fasting periods the blood plasma proteins are used up and the total circulating protein may even decrease to one-half the normal level. The plasma protein concentration changes but little and the significant change is a shrinkage of plasma volume. All these facts point to a dynamic equilibrium between tissue protein and plasma protein depending upon the physiological needs of the moment. In the absence of food protein the body can use material coming from one body protein to fabricate badly needed protein material of different character.     

Effect of fasting on temporal variation in the nephrotoxicity of amphotericin B in rats

Evidence for temporal variation in the nephrotoxicity of amphotericin B was recently reported in experimental animals. The role of food in these variations was determined by studying the effect of a short fasting period on the temporal variation in the renal toxicity of amphotericin B. Twenty-eight normally fed and 28 fasted female Sprague-Dawley rats were used. Food was available ad libitum to the fed rats, while the fasted animals were fasted 12 h before and 24 h after amphotericin B injection to minimize stress for the animals. Water was available ad libitum to both groups of rats, which were maintained on a 14-h light, 10-h dark regimen (light on at 0600 h). Renal toxicity was determined by comparing the levels of excretion of renal enzyme and the serum creatinine and blood urea nitrogen (BUN) levels at the time of the maximal (0700 h) or the minimal (1900 h) nephrotoxicity after the intraperitoneal administration of a single dose of dextrose (5%; control group) or amphotericin B (50 mg/kg of body weight; treated group) to the rats. The nephrotoxicities obtained after amphotericin B administration at both times of day were compared to the nephrotoxicities observed for time-matched controls. In fed animals, the 24-h urinary excretion of N-acetyl-beta-D-glucosaminidase and beta-galactosidase was significantly higher when amphotericin B was injected at 0700 and 1900 h. The excretion of these two enzymes was reduced significantly (P < 0.05) in fasting rats, and this effect was larger at 0700 h (P < 0.05) than at 1900 h. The serum creatinine level was also significantly higher (P < 0.05) in fed animals treated at 0700 h than in fed animals treated at 1900 h. Fasting reduced significantly (P < 0.05) the increase in the serum creatinine level, and this effect was larger in the animals treated at 0700 h. Similar data were obtained for BUN levels. Amphotericin B accumulation was significantly higher (P < 0.05) in the renal cortexes of fed rats than in those of fasted animals, but there was no difference according to the time of injection. These results demonstrated that fasting reduces the nephrotoxicity of amphotericin B and that food availability is of crucial importance in the temporal variation in the renal toxicity of amphotericin B in rats.     

Chronic Exposure to the Herbicide, Atrazine, Causes Mitochondrial Dysfunction and Insulin Resistance

There is an apparent overlap between areas in the USA where the herbicide, atrazine (ATZ), is heavily used and obesity-prevalence maps of people with a BMI over 30. Given that herbicides act on photosystem II of the thylakoid membrane of chloroplasts, which have a functional structure similar to mitochondria, we investigated whether chronic exposure to low concentrations of ATZ might cause obesity or insulin resistance by damaging mitochondrial function. Sprague-Dawley rats (n=48) were treated for 5 months with low concentrations (30 or 300 µg kg⁻¹ day⁻¹) of ATZ provided in drinking water. One group of animals was fed a regular diet for the entire period, and another group of animals was fed a high-fat diet (40% fat) for 2 months after 3 months of regular diet. Various parameters of insulin resistance were measured. Morphology and functional activities of mitochondria were evaluated in tissues of ATZ-exposed animals and in isolated mitochondria. Chronic administration of ATZ decreased basal metabolic rate, and increased body weight, intra-abdominal fat and insulin resistance without changing food intake or physical activity level. A high-fat diet further exacerbated insulin resistance and obesity. Mitochondria in skeletal muscle and liver of ATZ-treated rats were swollen with disrupted cristae. ATZ blocked the activities of oxidative phosphorylation complexes I and III, resulting in decreased oxygen consumption. It also suppressed the insulin-mediated phosphorylation of Akt. These results suggest that long-term exposure to the herbicide ATZ might contribute to the development of insulin resistance and obesity, particularly where a high-fat diet is prevalent.     

PROTEIN CONSUMPTION AND THE RESTORATION OF LOST ORGAN TISSUE

1. At all levels of immediate protein consumption, from almost none to excessive amounts, the degree of growth of the single kidney, suprarenal, and ovary left after removal of one of each of these organs is the same up to 5 days after the operation. 2. On a 1 per cent protein diet there is no growth of the remaining organs after the first 5 days. 3. On diets containing from 10 per cent to 57 per cent of protein there is no definite relation between the level of protein consumption and the rate and degree of growth from 5 to 40 days after the operation. 4. When rats are given a 1 per cent protein diet for 10 days before the operation a continuation of this diet reduces the initial growth of the remaining organs and leads to a cessation of growth after the first 2 days.     

Carbohydrate metabolism in pregnancy: VI. Plasma fuels, insulin, liver composition, gluconeogenesis, and nitrogen metabolism during late gestation in the fed and fasted rat

The effects of late pregnancy on metabolic fuels, liver composition, gluconeogenesis, and nitrogen metabolism have been examined in fed and fasted rats.Plasma free fatty acid (FFA) and immunoreactive insulin (IRI) are greater and glucose and ketones are lower in fed 19-day pregnant than they are in agematched virgin rats. A 48 hr fast elicits greater increases in FFA and ketones and more profound reductions in glucose in the pregnant rats and obliterates the differences in IRI. Fetal weight is not modified by such fasting but maternal weight losses exceed that of the nongravid rats.Livers from rats 19 days pregnant contain more and larger hepatocytes. Per mumole hepatic deoxyribonucleic acid (DNA)-phosphorus, water and protein are more abundant, whereas glycogen is unaffected. Livers from fed pregnant rats contain more lipid phosphorus and less neutral lipid fatty acid. After a 48 hr fast, hepatic steatosis supervenes in gravid animals due to accumulated neutral fat. The contents of hepatic acetyl-coenzyme A (CoA) and citric acid are not different in fed pregnant and virgin rats but are greater in the pregnant rats after fasting.Formation of glucose-(14)C and glycogen-(14)C from administered pyruvate-(14)C are the same in fed pregnant and virgin rats, but greater in the pregnant ones after a 24 or 48 hr fast.Pregnancy does not affect creatinine excretion, and urinary urea is not different in fed pregnant, virgin, and postpartum animals. Contrariwise, more nitrogen, potassium, and phosphorus are excreted by the pregnant animals during a 2 day fast. The increment in urinary nitrogen is due largely to urea on the 1st day, whereas heightened ammonia accounts for half the increase on the 2nd and correlates with the enhanced ketonuria.Muscle catabolism, gluconeogenesis, and diversion to fat are activated more rapidly and to a greater degree when food is withheld during late gestation in the rat. These catabolic propensities are restrained in the fed state. The capacity for "accelerated starvation" may confer survival benefit upon an intermittently eating mother in the presence of a continuously feeding fetus.     

THE INFLUENCE OF DIET UPON THE REGENERATION OF SERUM PROTEIN : II. THE POTENCY RATIOS OF SERUM PROTEIN,LACTALBUMIN AND CASEIN,AND THE EFFECT OF TISSUE PROTEIN CATABOLISM ON THE FORMATION OF SERUM PROTEIN

1. By the technique of quantitative plasmapheresis the effects of single proteins in artificial synthetic diets were studied with respect to their value in promoting the regeneration of serum protein. 2. The ratio of (a) the amount of serum protein per week removed by bleeding above that regenerated by the dog when eating the protein-free diet, to (b) the dietary protein increment (i.e., above that required for nitrogen equilibrium) was termed the potency ratio. The results indicated that serum protein was slightly superior to casein and lactalbumin in promoting the regeneration of serum protein. However, the respective potency ratios, varying from approximately 0.51 to 0.36, were comparable and not widely divergent as those reported by others. It was concluded that, whereas in some individuals dietary proteins may be able to produce a significant increase in the serum protein concentration, the potency ratios are not sufficiently different to warrant the administration of any one protein in preference to another. 3. The inhibitory effect of the basal protein-free diet with respect to serum protein regeneration in the dog was also demonstrated by the inability of the protein concentration to attain the normal level in spite of discontinued plasmapheresis. However, a subsequent fasting period resulted in a progressive rise in the serum protein concentration until the normal value was approximated. These observations are interpreted as indicating that the products of tissue protein catabolism can be utilized in the formation of new serum protein. 4. The experimental production of what seems to be an inhibition of the serum protein regenerating mechanism was described. This observation together with the hypothetical evidence presented by Bloomfield (17) and Weech and his associates (9) suggests that the most profitable line of approach to solution of the problem of hypoproteinemia lies not so much in the evaluation of dietary factors but in finding a way for stimulating internally the serum protein regenerating mechanism, which seems to involve in some manner the capacity of the tissue to furnish protein for the needs of the plasma. 5. A hypothesis explaining the mechanisms responsible for serum protein formation was presented and the experimental support for it discussed. The rôle of tissue protein catabolism in this function was emphasized.     

Renal acid excretion and intracellular pH in salt-sensitive genetic hypertension.

Acid-base status and renal acid excretion were studied in the Dahl/Rapp salt-sensitive (S) rat and its genetically salt-resistant counterpart (R). S rats developed hypertension while on a very high salt diet (8%) and while on a more physiological salt diet (1%) and remained normotensive while on a very low salt diet (0.08%). Under the high salt diet, intracellular pH measured in freshly isolated thymic lymphocytes using 2',7'-bis (carboxyethyl)-5 (6)-carboxyfluorescein acetomethyl ester, a pH-sensitive dye, was lower in S than in R rats both when measured in the presence of HCO3/CO2 (7.32 +/- 0.02 vs. 7.38 +/- 0.02, respectively, P < 0.05) and in its absence (7.18 +/- 0.04 vs. 7.27 +/- 0.02, respectively, P < 0.05). Under the high salt diet, net acid excretion was higher in S than R rats (1,777 +/- 111 vs. 1,017 +/- 73 muEq/24 h per 100 g body wt, respectively, P < 0.001), and this difference was due to higher rates of both titratable acid and ammonium excretion. Directionally similar differences in intracellular pH and net acid excretion between S and R rats were also observed in salt-restricted animals. In S and R rats placed on a normal salt intake (1%) and strictly pair-fed to control food intake as a determinant of dietary acid, net acid excretion was also higher in S than in R rats (562 +/- 27 vs. 329 +/- 21 muEq/24 h per 100 g, respectively, P < 0.01). No significant difference in either blood pH or bicarbonate levels were found between S and R rats on either the 0.08%, 1%, or 8% salt diets. We conclude that renal acid excretion is augmented in the salt-sensitive Dahl/Rapp rat. Enhanced renal acid excretion may be a marker of increased acid production by cells from subjects with salt-sensitive hypertension.