The intracellular content of K+ in thalassemia minor red blood cells is markedly reduced after incubation in autologous serum for 24 hr at 37°C. There is no compensatory increase in intracellular Na+ concentration of the cell thus reduced. This change is due to an acquired increase in selective permeability of the membrane to K+. This phenomenon follows the depletion of energy sources in the thalassemia minor cells but does not follow comparable depletion in normal cells. The loss of osmotically active intracellular contents probably accounts for the increased resistance of incubated thalassemia minor red blood cells to osmotic lysis.
Robert B. Gunn, David N. Silvers, Wendell F. Rosse
The changes in other plasma lipoproteins which accompany alterations in very low density lipoproteins (VLDL) were studied in 31 normal and hyperlipidemic men and women who underwent weight reduction, carbohydrate induction, or clofibrate treatment. Plasma lipids and individual lipoprotein cholesterol concentrations were measured serially during control and treatment periods. Low density lipoprotein (LDL) protein was determined by radial immunodiffusion. Oppositely directed changes in VLDL and LDL were found with each of the three metabolic perturbations. Changes in high density lipoprotein (HDL) cholesterol generally paralleled those in LDL but were less consistent. Two patients with type III hyperlipoproteinemia failed to demonstrate reciprocal increases in LDL despite more than 40% reduction in plasma glycerides or VLDL with weight reduction or clofibrate therapy. After clofibrate therapy, LDL increased in proportion to the absolute decrease in VLDL cholesterol during treatment. LDL protein changed relatively less than did LDL cholesterol. The mechanism for the interdependency of plasma VLDL and LDL concentrations over the long term is not known and may be the result of altered rates of interconversion of these lipoproteins, or to feedback inhibition by VLDL of LDL production and release.
Dana E. Wilson, Robert S. Lees
This study was designed to answer the question whether human lymphocytes and spleen cells were capable of de novo purine biosynthesis. Experiments were carried out in cell-free extracts prepared from human spleen, and from a cell line established from Burkitt lymphoma. Burkitt lymphoma cells and human spleen cells could synthesize the first and second intermediates of the purine biosynthetic pathway. Cell-free extracts of all cell lines studied contained the enzyme systems which catalyze the synthesis of phosphoribosyl-1-amine, the first intermediate unique to the purine biosynthetic pathway and of phosphoribosyl glycinamide, the second intermediate of this pathway. Phosphoribosyl-1-amine could be synthesized in cell-free extracts from α-5-phosphoribosyl-1-pyrophosphate (PRPP) and glutamine, from PRPP and ammonia, and by an alternative pathway, directly from ribose-5-phosphate and ammonia. These findings suggest that extrahepatic tissues may be an important source for the de novo synthesis of purine ribonucleotide in man. They also indicate that ammonia may play an important role in purine biosynthesis. The alternative pathway for the synthesis of phosphoribosyl-1-amine from ribose-5-phosphate and ammonia was found to be subject to inhibition by the end products of the purine synthetic pathway, particularly by adenylic acid and to a lesser degree by guanylic acid. The alternative pathway for phosphoribosyl-1-amine synthesis from ribose-5-phosphate and ammonia may contribute significantly towards the regulation of the rate of de novo purine biosynthesis in the normal state, in metabolic disorders in which purines are excessively produced and in myeloproliferative diseases.
Gabrielle H. Reem
To study the physical properties of renal tubular basement membranes directly, the epithelial layer of single isolated perfused rabbit proximal convoluted, proximal straight, and cortical collecting tubules was removed with sodium desoxycholate. Tubular segments were perfused using micropipets. The distal end of each segment was occluded in order to simplify the measurement of transmembrane water flow. The relation between outer tubular diameter and applied transmural pressure was identical in intact tubules and their respective isolated tubular basement membranes indicating that the basement membrane determines tubular distensibility. Young's modulus for basement membranes from all tubular segments corresponded to that of tendon collagen. Membrane hydraulic conductivity was measured in two ways: (a) from the rate of transmural flow in response to an applied difference in hydrostatic pressure and, (b) from the rate of transmural flow in response to a difference in colloid osmotic pressure. The hydraulic conductivity of tubular basement membranes was 300-800 times greater than that of the intact epithelial layer. Basement membrane hydraulic conductance was similar to that of peritubular and glomerular capillaries in vivo. The hydrostatic conductance of tubular basement membranes exceeded the osmotic conductance by 3-10-fold owing largely to the fact that the membranes were moderately permeable to the osmotic solute (albumin). In view of these findings we suggest that oncotic and hydrostatic pressure may play an important role in the movement of tubular absorbate from the epithelial compartment into the renal interstitium.
Larry W. Welling, Jared J. Grantham
The combination of arterial hypoxemia and low pulmonary vascular resistance in patients with liver cirrhosis is unexplained. Pulmonary microcirculatory dilation, but not gross arterio-venous shunts, has been the usual postmortem finding in patients with liver cirrhosis. When 10 patients with alcoholic liver cirrhosis breathed 10% oxygen in nitrogen, they failed to increase their pulmonary vascular resistance. However, four patients with functional murmurs, three patients with hyperkinetic heart syndrome, six patients with normal pulmonary artery pressures and intracardiac left to right shunts, and five patients with renal failure and anemia all increased their pulmonary vascular resistances when they breathed 10% oxygen in nitrogen. These findings suggested that in liver cirrhosis the normal regulating mechanism (hypoxic vasoconstriction) of the pulmonary circulation may be impaired, resulting in failure of the lung to match perfusion with ventilation.
Fuheid S. Daoud, John T. Reeves, John W. Schaefer
The physiological basis for the polyuria and polydipsia occurring in some manic-depressive patients treated with lithium salts was studied in vivo and in vitro. Three lithium-treated polyuric patients, in whom other causes of a concentrating defect were excluded, had abnormal urinary concentrating abilities after a standard water depreviation test. Two of these patients failed to respond to exogenous vasopressin (ADH) and one had a subnormal response. The abilities of these patients to excrete solute-free water (CH2O) was comparable to normal subjects during steady-state water diuresis, suggesting no gross abnormalities in sodium transport. However, each of these patients demonstrated abnormally low capacities to reabsorb solute-free water (TCH2O) under hydropenic conditions after administration of hypertonic saline and vasopressin. These in vivo findings demonstrate at least a nephrogenic basis for the diabetes insipidus syndrome manifested by these three patients.
Irwin Singer, Donald Rotenberg, Jules B. Puschett
This study was designed to define quantitatively the function of the rat glomerular mesangium in the uptake and processing of intravenously administered protein macromolecules (radiolabeled aggregated human IgG, AHIgG-125I), to relate this function to that of the general reticuloendothelial system, and to examine the effects of increased glomerular permeability to protein on the mesangial cell system.
S. Michael Mauer, Alfred J. Fish, Edward B. Blau, Alfred F. Michael
The studies of sera from two siblings with C1r deficiency are described. The brother (18 yr old) has shown clinical manifestations resembling lupus erythematosus for 5 yr, and the sister (24 yr old) has had arthralgia and recurrent episodes of rhinobronchitis since early childhood. Three siblings have died: one brother died at age 12 with symptoms similar to the disease of the male patient studied here, and two other siblings died in infancy, probably from infection. The low hemolytic C1 activity of the patients could be restored by the addition of purified C1r to their sera. Bactericidal activity and immune adherence were found to be impaired. When alternate pathways of the complement system were studied, both sera permitted activation of terminal components with endotoxin and cobra venom factor. These findings support the view that an alternate pathway for activation of the terminal portion of the complement cascade exists which does not utilize the conventional pathway operating through the usual early components.
N. K. Day, H. Geiger, R. Stroud, M. deBracco, B. Mancado, D. Windhorst, R. A. Good
“Cold” thyroid nodules do not concentrate 131I before or after thyrotropin (TSH) administration. In an attempt to elucidate the reason for this TSH unresponsiveness, the effect of TSH in vitro on several metabolic parameters was studied in 11 “cold” thyroid adenomas, 2 medullary carcinomas, and in the surrounding normal thyroid tissue. Basal adenyl cyclase activity, glucose-1-14C oxidation, and 32P incorporation into phospholipids were significantly greater in the adenomas than in the adjacent normal thyroid; basal cyclic 3′,5′-adenosine monophosphate (cyclic AMP) concentration and adenine-3H incorporation into 3H-labeled cyclic AMP were not different. In adenomas as well as normal thyroid, all parameters responded significantly to in vitro TSH stimulation. The response to TSH of adenyl cyclase activity and 32P incorporation was enhanced in adenomas compared with that of the adjacent normal thyroid. These differences were not explained by an increased cellularity of the adenomas. Medullary carcinomas did not respond to TSH in any of the above parameters.
Frederick DeRubertis, Kamejiro Yamashita, Andrew Dekker, P. Reed Larsen, James B. Field
Metabolic balance studies were conducted in seven boys with Duchenne-type muscular dystrophy, and in six normal boys of similar age, during a 12 day control period and during a 12 day period of treatment with human growth hormone (HGH) at the following doses: 0.0168, 0.0532, and 0.168 U/kg body weight (BW)¾ per day (doses A, B, and C, respectively). In five of the six normals, dose C caused positive balances in N, P, Na, and K; doses B and A had anabolic effects in two and one normal subjects, respectively. In six of the seven Duchenne cases, dose C caused negative balances of N and K, and sometimes of P. Negative balances were produced in three of the Duchenne subjects by dose B, and in one by dose A. None of the dystrophy cases exhibited an anabolic response to any dosage of HGH tested.
Daniel Rudman, Samuel B. Chyatte, Joseph H. Patterson, Glynda G. Gerron, Irma O'Beirne, Joan Barlow, Ashby Jordan, Joel S. Shavin
Addition of sodium salicylate to human serum at concentrations often obtained during aspirin therapy causes 100-200% increases in free triiodothyronine (T3) and free thyroxine (T4) as estimated by ultrafiltration. The increase in free T3 was unexpected since previous data had suggested that salicylate inhibits binding of T4 only to thyroxine-binding prealbumin (TBPA) and that T3 is not bound to this protein. Using ultrafiltration techniques, we demonstrated binding of T3 to TBPA. The affinity constant for T3-TBPA binding appears to be slightly greater than that for albumin-T3 binding. While salicylate inhibits the binding of T3 (and T4) to TBPA, it can be predicted that little change will be observed in the free T3 (or free T4) without inhibition of thyroid hormone binding to thyroxine-binding globulin (TBG). Using a competitive-binding protein displacement technique, it has been shown that sodium salicylate, like diphenylhydantoin (DPH), inhibits the binding of T3 and T4 to TBG. The magnitude of the increase in free T3 and free T4 induced by salicylates suggests that interference with TBG binding is its major effect.
P. R. Larsen
Rat small intestinal mucosa was examined for ability to produce mucins with human blood group A, B, and H activity. Blood group activity of the mucins was compared to antigenic activity of red blood cells in individual rats and the enzymatic basis for differences was investigated. Red cells in all the rats examined contained human blood group A and B antigens. All rats synthesized intestinal mucins having B and H antigenic activity but 57% failed to produce mucins with blood group A activity (A-); the remaining 43% (A+) produced A substance.
Young S. Kim, Jose Perdomo
Lysozyme turnover studies with 125I-labeled human lysozyme were carried out on 22 patients, viz. nine control patients, seven nephrological patients with varying degrees of renal insufficiency, including three bilaterally nephrectomized patients, and six hematological patients with disturbed turnover of the neutrophilic granulocytes.
Niels Ebbe Hansen, Hans Karle, Vagn Andersen, Klaus Ølgaard
The HL-A phenotypes of 127 patients with Hodgkin's disease have been determined. A very significant association has been found between Hodgkin's disease and two HL-A antigens, HL-A11 (P < 0.009), and W5 (P < < 0.0005). The families of 40 of these patients were genotyped for HL-A antigens. A normal mendelian segregation of the relevant antigen was found in all 12 families of HL-All positive patients and in 6 of 8 families of W5 positive patients. These findings suggest that certain Hodgkin's patients have a genetically determined susceptibility to their disease. It is postulated that this susceptibility could be due to linkage between HL-A genes and genes controlling immune responsiveness. Analysis of subgroups of Hodgkin's patients based on age, sex, and pathology suggests that these HL-A associations are most marked in certain subgroups.
John F. Forbes, Peter J. Morris
Effects of diphenylhydantoins on (Na+ + K+)-ATPase activity in rat and cat brain microsomes were studied. 5,5-diphenylhydantoin (DPH) in concentrations of 5-20 μg ml-1 produces an apparent stimulation of the rat brain (Na+ + K+)-activated ATPase of 55-65% in media containing 50 mM Na+, 0.15 mM K+, 3 mM Mg++, and 3 mM ATP. No effects are found on the Mg-ATPase. At constant K+ levels of 0.05 mmole/liter and 0.15 mmole/liter, increasing the Na+ concentration activates the enzyme similarly with and without DPH. However, Na+ concentrations greater than 5 mmoles/liter and 10 mmoles/liter, respectively, which are inhibitory in these low K+ media, produce less inhibition in the presence of DPH. In media containing 10 mM Na+, the K+ activation, on the other hand, is potentiated by DPH. In preparations from cat brain qualitatively similar results are obtained. No effect of DPH is seen on the inhibition produced by high K+ in low Na+ media. DPH produces an approximately constant apparent stimulation of 45% in the (Na+ + K+) increments when these ions are varied simultaneously at a fixed ratio of 150 Na+:1 K+ with cat brain extracts. 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH) has the same potency as DPH in reducing the Na+ inhibition at high Na:K ratios. The hydantoins appear to act by decreasing the Na+ inhibition that occurs at high Na:K ratios.
George J. Siegel, Beverly B. Goodwin
The influence of several factors on the course of herpes zoster was studied in 151 patients. Dissemination of zoster was associated with the presence of a concurrent disease, especially Hodgkin's disease, and/or the use of immunosuppressive therapy. Several host-immune parameters, including quantitative immunoglobulins, circulating lymphocyte counts, delayed hypersensitivity to multiple skin test antigens, and lymphocyte transformation to phytohemagglutinin did not correlate with dissemination of disease. Development of virus-specific complement-fixing antibody (CFA) was delayed in some patients with disseminated disease.
David A. Stevens, Thomas C. Merigan
The composite response of the erythron to exogenous erythropoietin has been studied in normal, splenectomized, and polycythemic mice. After stimulation the normal animal doubled its marrow nucleated red cells by the 3rd day with little further change by the 5th. Nucleated red cells within the spleen began to increase sharply on the 2nd day and, by the 5th, exceeded those in the marrow. The total nucleated erythroid response represented a fourfold increase. Reticulocytes lagged behind the expansion of the nucleated red cell mass, but by the 5th day the original ratio was re-established. Hemoglobin synthesis was increased, but the ratio of hemoglobin synthesized in nucleated red cells and reticulocytes was basically unchanged. Early displacement of marrow reticulocytes into circulation and the production of a larger red cell also occurred. No evidence of a change in the number of erythroid mitoses was found; only a slight decrease in the average cell cycle time was demonstrated. Thus, whereas erythropoietin stimulation induced several changes in erythropoiesis, the increased number of cells entering into the maturing pool appeared to be of greatest quantitative significance.
Thalia Papayannopoulou, Clement A. Finch
The effects of bacterial products on selected synovial fibroblast functions were studied. Extracts of commonly encountered microorganisms were prepared by sonic or mechanical disruption. “Purified” endotoxins were prepared from selected organisms, and in some cases were purchased commercially. Normal fibroblasts were derived from synovial connective tissue obtained from amputations or arthrotomy. The cells were grown as a monolayer on glass and were nourished by a semisynthetic nutrient medium.
Robert B. Buckingham, C. William Castor
To evaluate the factors regulating gluconeogenesis in pregnancy, plasma amino acid levels were determined during the course of an 84-90 hr fast in physically healthy women studied during wk 16-22 of gestation (before undergoing therapeutic abortion), and in nonpregnant controls. The effect of pregnancy on the glycemic response to exogenous alanine administration during starvation was also investigated.
Philip Felig, Young Jin Kim, Vincent Lynch, Rosa Hendler
The mechanical properties of the lungs were studied in two groups of coal miners. The first group consisted of miners with either simple or no pneumoconiosis and was divided into two subgroups (1A and 1B). The former (1A) consisted of 62 miners most of whom had simple pneumoconiosis but a few of whom had clear films. Although their spirometry was normal, all claimed to have respiratory symptoms. The other subgroup (1B) consisted of 25 working miners with definite radiographic evidence of simple pneumoconiosis but normal spirometric findings. The second major group consisted of 25 men with complicated pneumoconiosis.
Anthony Seaton, N. LeRoy Lapp, Wm. Keith C. Morgan
A strain of Shigella dysenteriae 1, freshly isolated from a patient with dysentery in Guatemala in August 1969, was found to elaborate an enterotoxin into the liquid of broth cultures. Partial purification of the enterotoxin by ultrafiltration on graded polymeric membranes and Sephadex gel filtration (Pharmacia Fine Chemicals, Inc., Piscataway, N. J.) suggested an approximate molecular weight of 55,000-60,000. The partially purified toxin was heat-labile, pronase sensitive, and activated by alkaline pH, and it elicited fluid production in ligated rabbit ileal segments; it failed, however, to cause increased vascular permeability in skin. When the activities of equal weights of identically prepared Vibrio cholerae and S. dysenteriae enterotoxins were compared in the rabbit ileum the latter caused a significantly smaller volume response with increased concentrations of potassium, chloride, and protein.
Gerald T. Keusch, George F. Grady, Leonardo J. Mata, James McIver
A technique was developed to quantitate the absorption of ingested carbohydrate by means of continuous measurements of pulmonary H2 excretion. This technique is based on the observation that H2 is produced in the colon when carbohydrate is fermented by colonic bacteria, and this H2 is then excreted by the lungs. The quantitative relationship of pulmonary H2 excretion to unabsorbed carbohydrate was studied in nine subjects. After ingestion of 6.5, 13, and 26 g of lactulose (a nonabsorbable disaccharide), H2 excretion increased linearly, averaging (±1 SEM) 13±3.5, 23±7.2, and 49±7 ml per 2 hr. Because of consistent individual differences in H2 excretion per gram of lactulose, the variability of this linear response was less in a given subject, with the H2 excretion after 6.5 g and 26 g lactulose dosages averaging 55±4.2% and 214±16% of that observed after the 13 g dose. It was further demonstrated with fecal homogenates, as well as in rats after direct intracecal instillation of carbohydrate, that there was no significant difference in the rate of H2 formation from lactulose as compared with the normally ingested sugars. Thus, a subject's H2 excretion after a 13 g dose of lactulose can be used as a standard to convert H2 excretion after ingestion of other carbohydrates into grams of carbohydrate not absorbed. Application of this technique to seven partially gastrectomized patients indicated all subjects malabsorbed a portion of a 100 g dose of glucose whereas six of seven completely absorbed a 25 g dose. Malabsorption of physiologic quantities of various carbohydrates was clearly demonstrated in one subject. This technique appears to provide quantitative information on carbohydrate malabsorption not readily obtained by presently available techniques.
John H. Bond Jr., Michael D. Levitt
The metabolic clearance rate (MCR) and blood production rate (BP) of testosterone (T) and dihydrotestosterone (DHT), the conversion of plasma testosterone to plasma dihydrotestosterone, and the renal clearance of androstenedione, testosterone, and dihydrotestosterone have been studied in man. In eight normal men, the MCRT (516±108 [SD] liters/m2/day) was significantly greater than the MCRDHT (391±71 [SD] liters/m2/day). In seven females, the MCRT (304±53 [SD] liters/m2/day) was also greater than the MCRDHT (209±45 [SD] liters/m2/day) and both values were less than their respective values in men (P < 0.001). In men the conversion of testosterone into dihydrotestosterone at 2.8±0.3% (SD) was greater than that found in females, 1.56±0.5% (SD) (P < 0.001). In five pregnant females the MCRT (192±36 [SD] liters/m2/day), the MCRDHT (89±30 [SD] liters/m2/day) and the conversion of testosterone into dihydrotestosterone (0.72±0.15%) (SD) were significantly less than the values found in nonpregnant women. In five females with hyperthyroidism, the MCR for testosterone and dihydrotestosterone were similar to those observed in pregnant females, but the conversion of testosterone into dihydrotestosterone (2.78±1.7%) (SD) was greater, and similar to that found in men. In men the production of dihydrotestosterone was 0.39±0.1 (SD) mg/day, 50% being derived from the transformation of plasma testosterone. In women the production of DHT was 0.05±0.028 (SD) mg/day, only 10% coming from testosterone. During pregnancy, the production of testosterone and dihydrotestosterone are similar to that in normal women. In three patients with testicular feminization syndrome (an adult with hyperthyroidism and two children) these two MCRs were greatly reduced compared to the normal females, but the conversion of testosterone into dihydrotestosterone was in the limits of normal male range
J. M. Saez, M. G. Forest, A. M. Morera, J. Bertrand
Human platelets were separated by desity-centrifugation into heavy and light populations. Heavy platelets have an average volume approximately twofold greater than light platelets, and have previously been shown to be young platelets.
Simon Karpatkin, Nathan Strick
The activities of intestinal sucrase and isomaltase are not detectable in rats before 15-16 days of age, but administration of corticosteroids precociously induces the activities of these two α-glucosidases. 9-day old rats were removed from their mothers, warmed in an incubator, and fed by constant infusion through gastrostomies. The basic diet was a soya preparation to which various sugars were added. When the diet contained 2% sucrose, diarrhea ensued for 48 hr, but subsided when intestinal sucrase and isomaltase appeared precociously. In animals fed sucrose, the activities of sucrase and isomaltase were markedly increased as compared to animals on carbohydrate-free diets (sucrase 2.41±0.23 vs. 0.63±0.13 U, isomaltase 3.43±0.42 vs. 0.78±0.18 U). Maltase activity was doubled, while lactase was not altered significantly. The mitotic index of crypt cells, the depth of crypts, and incorporation of thymidine-3H into DNA were increased. In adrenalectomized rats, activities of sucrase and isomaltase were not detected nor induced by sucrose. Steroids given to adrenalectomized rats caused appearance of the enzymes; but if cortisone and sucrose were given together, there was synergism evidenced by a marked increase in activities (sucrase 7.2±1.1 vs. 0.68±0.12 U). In contrast to observations in adult animals, the effect of sucrose on α-glucosidases in developing animals demands the participation of the adrenal gland.
Emanuel Lebenthal, Philip Sunshine, Norman Kretchmer
Studies of the metabolism of glutamine and glutamate by renal cortex slices from acidotic, alkalotic, and control rats were performed. 88-95% of the glutamine and 104-115% of the glutamate taken up from the medium could be accounted for by the products found. Acidosis increased glutamine uptake and conversion to ammonia, CO2, glucose, lactate, pyruvate, lipid, and protein. The increase in glutamine conversion to ammonia after acidosis could be completely accounted for by the associated increase in its conversion to glucose, glutamate, lactate, and pyruvate. When glutamate metabolism was examined, acidosis did not affect substrate uptake but did increase its conversion to ammonia, glucose, lactate, CO2, and lipid. The increase in 14CO2 from U-14C-glutamine and U-14C-glutamate found with cortex slices from acidotic animals could be explained by the CO2 production calculated to be associated with the enhanced conversion of these substrates to other products during acidosis. 14CO2 production from 1.2-14C-acetate was found to be significantly increased in alkalosis rather than acidosis. These studies suggest that in the rat, the rate at which glutamine is completely oxidized in the Krebs cycle is not a factor regulating renal ammonia production. A comparison of the effects of acidbase status on glutamine and glutamate metabolism suggests that either glutamine transport or glutamine transaminase activity are significantly increased by acidosis.
Donald E. Kamm, Gerald L. Strope
These experiments were intended to evaluate the effects of antidiuretic hormone (ADH) on dissipative water transport in cortical collecting tubules isolated from rabbit kidney. In the absence of ADH, the osmotic (Pf, cm sec-1) and diffusional (PDW cm sec-1) water permeability coefficients were, respectively, 6±6 and 4.7±1.3 (SD). When ADH was added to the bathing solutions, Pf and PDW rose to, respectively, 186±38 and 14.2±1.6 (SD). In the absence of ADH, the tubular cells were flat and the lateral intercellular spaces were closed when the perfusing and bathing solutions were, respectively, hypotonic and isotonic; in the presence of ADH, the cells swelled and the intercellular spaces dilated. These data suggest that ADH increased the water permeability of the luminal membranes of the tubules.
James A. Schafer, Thomas E. Andreoli
These experiments were intended to evaluate the antidiuretic hormone (ADH)-dependent reflection coefficients of urea, sucrose, and NaCl in cortical and outer medullary collecting tubules isolated from mammalian kidney. In one group of experiments, the ADH-dependent osmotic water flows, when the perfusing solutions contained hypotonic NaCl solutions, were indistinguishable from control observations when either urea or sucrose replaced, in part, NaCl in isotonic bathing solutions (cortical collecting tubules). Similarly, both in cortical and outer medullary collecting tubules exposed to ADH, there was zero net osmotic volume flow when a portion of the NaCl in the bathing and/or perfusing solutions was replaced by either sucrose or urea, so long as the perfusing and bathing solutions were isosmolal. Taken together, these observations suggest that the ADH-dependent reflection coefficients of NaCl, urea, and sucrose, in these tubules, were identical. Since the effective hydrodynamic radii of urea and sucrose are, respectively, 1.8 and 5.2 A, it is likely that σi, for urea, sucrose, and NaCl, was unity. In support of this, the diffusion permeability coefficient (PDi cm sec-1) of urea was indistinguishable from zero. Since the limiting sites for urea penetration were the luminal interfaces of the tubules, these data are consistent with the view that ADH increases diffusional water flow across such interfaces.
James A. Schafer, Thomas E. Andreoli
The development of a vitamin D-resistant state in the course of renal failure may be responsible for reduced intestinal absorption of calcium and an impaired response of skeletal tissue. Moreover, the kidney has been shown to carry out the conversion of 25-hydroxycholecalciferol (25-OH-CC) to a highly biologically active metabolite, 1,25-dihydroxycholecalciferol (1,25-diOH-CC). In the present studies, vitamin D-deficient rats, made acutely uremic by either bilateral nephrectomy or urethral ligation, received physiological doses of cholecalciferol (vitamin D3) (CC), 25-OH-CC or 1,25-diOH-CC; 24 hr later intestinal calcium transport, in vitro, and bone calcium mobilization, in vivo, were assessed. Whereas CC and 25-OH-CC stimulated calcium transport in sham-operated controls, they were without effect in the uremic animals. In contrast, administration of 1,25-diOH-CC stimulated calcium transport in both groups of uremic animals. Administration of 1,25-diOH-CC also stimulated calcium mobilization from bone in each group of animals. However, CC and 25-OH-CC were only effective in the sham controls and the uremic group produced by urethral ligation and had little or no effect in animals without kidneys. These results indicate that renal conversion of calciferol to a more biologically active form is necessary for the stimulation of intestinal calcium absorption and calcium mobilization from bone, and that 1,25-diOH-CC may bypass a possible defect in vitamin D metabolism in uremia. From these studies it is likely that uremia, per se, may also impair intestinal calcium transport.
Richard G. Wong, Anthony W. Norman, Chilumula R. Reddy, Jack W. Coburn
Lacking reliable data on cholesterol concentrations in muscle, adipose tissue, skin, and connective tissues (i.e., the “bulk tissues”) in “normal” man, we have completed these analyses in 21 men and 8 women who died suddenly and unexpectedly; their ages ranged from 23 to 78 yr.
J. R. Crouse, S. M. Grundy, E. H. Ahrens Jr.
Previous studies reported from this laboratory provided support for the hypothesis that the natriuresis of volume expansion is mediated in part by a humoral mechanism. In the present study we examined whether suppression of this factor participates in the antinatriuresis of acute constriction of the thoracic inferior vena cava. An isolated kidney was perfused by a second dog pretreated with deoxycorticosterone acetate. Expansion of the perfusion dog with equilibrated blood from a reservoir resulted in an increase in sodium excretion from 102±30 to 259±65 μEq/min, P < 0.001. Fractional sodium excretion increased from 2.3±0.6 to 6.2±1.2%, P < 0.01. Inulin clearance, plasma protein concentration, and packed cell volume remained constant; renal perfusion pressure and renal blood flow decreased. After the natriuresis was established, the thoracic inferior vena cava was constricted to decrease systemic arterial pressure in the perfusion dog 50 mm Hg. This maneuver suppressed urine output in the dog but did not significantly alter sodium excretion in the isolated kidney. During the period of caval constriction absolute sodium excretion in the isolated kidney measured 198±42 μEq/min and fractional sodium excretion measured 5.7±1.1%. Neither value is significantly different from that measured during volume expansion alone. The data suggest that the antinatriuresis of acute caval constriction probably does not require suppression of a humoral natriuretic factor and that other more rapidly acting mechanisms, presumably hemodynamic and neural, may be involved.
George J. Kaloyanides, Maher Azer