Effects of Glucose on Bicarbonate Reabsorption in the Dog Kidney

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Abstract

The effects of glucose on renal bicarbonate reabsorption were investigated in the dog. The infusion of small amounts of glucose calculated to slightly exceed the renal threshold for glucose absorption increased bicarbonate reabsorption in bicarbonate loaded dogs. Galactose in similar doses also increased the reabsorption of filtered bicarbonate. This effect is not due to insulin secretion since insulin alone did not alter bicarbonate reabsorption and the infusion of glucose into alloxan-diabetic dogs given a steady infusion of insulin also enhanced bicarbonate reabsorption. It is more likely that the increased tubular reabsorption of glucose, secondary to an increased filtered load, resulted in the increase in bicarbonate reabsorption since phlorizin reversibly inhibits the effect of glucose.

Authors

Wadi N. Suki, Christy S. Hebert, Bobby J. Stinebaugh, Manuel Martinez-Maldonado, Garabed Eknoyan

Renal Handling of Diamino Acids in Lysinuric Protein Intolerance

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Lysinuric protein intolerance (LPI) is a rare recessively inherited disease in which one of the fundamental physiological defects is in the mechanism by which diamino acids are transported by the kidney. The purpose of the present studies was to examine that mechanism in four controls and seven patients with LPI. Two types of studies were conducted. In the first set, the renal handling of l-arginine and l-ornithine was evaluated by gradually increasing the plasma concentration of each of these amino acids by constant infusion techniques. In the second set of studies, the possible existence of competitive inhibition between l-arginine, l-ornithine, and l-lysine was examined.

Authors

Olli Simell, Jaakko Perheentupa

Effect of Experimental Pneumococcal Meningitis on Respiration and Circulation in the Rabbit

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Pathophysiological studies in bacterial meningitis in man have been limited by clinical variability and the necessity for immediate therapy. After the development of a reliable animal model of pneumococcal meningitis, we studied respiration and circulation in 25 anesthetized New Zealand white rabbits during untreated pneumococcal meningitis and in 33 healthy controls. In meningitis, we found increased lactic acid in cerebrospinal fluid (CSF). Increased ventilation, perhaps due to CSF lactic acid accumulation, resulted in respiratory alkalosis; the concomitant lowering of Pco2 acted as a homeostatic mechanism to restore pH toward normality in the CSF. Hyperventilation increased with the duration of the illness. Cardiac output was also increased with decreased peripheral vascular resistance but with only slight reduction in mean systemic and pulmonary arterial pressures. In the final hour of life, peripheral vascular resistance fell further; ventilation declined and then abruptly ceased while cardiac activity continued. Lactic acid accumulation in the CSF, found in both experimental and human pneumococcal meningitis, may cause the hyperventilation found in this disease and may contribute to death.

Authors

Malcolm R. Sears, J. Morgan O'Donoghue, H. Kenneth Fisher, Harry N. Beaty

High-Affinity Accumulation of Chloroquine by Mouse Erythrocytes Infected with Plasmodium berghei

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Washed erythrocytes infected with chloroquine-susceptible (CS) or with chloroquine-resistant (CR) P. berghei were used in model systems in vitro to study the accumulation of chloroquine with high affinity. The CS model could achieve distribution ratios (chloroquine in cells: chloroquine in medium) of 100 in the absence of substrate. 200—300 in the presence of 10 mM pyruvate or lactate, and over 600 in the presence of 1 mM glucose or glycerol. In comparable studies of the CR model, the distribution ratios were 100 in the absence of substrate and 300 or less in the presence of glucose or glycerol. The presence of lactate stimulated chloroquine accumulation in the CR model, whereas the presence of pyruvate did not. Lactate production from glucose and glycerol was undiminished in the CR model, and ATP concentrations were higher than in the CS model. Cold, iodoacetate, 2,4-dinitrophenol, or decreasing pH inhibited chloroquine accumulation in both models. These findings demonstrate substrate involvement in the accumulation of chloroquine with high affinity.

Authors

Coy D. Fitch, Norman G. Yunis, Rekha Chevli, Yolanda Gonzalez

Reciprocal Influence of Salt Intake on Adrenal Glomerulosa and Renal Vascular Responses to Angiotensin II in Normal Man

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The adrenal glomerulosa cell and the renal vasculature respond to similar arterial angiotensin II (A II) levels. We have assessed the effect of decreased sodium intake on their responses to A II in man. Studies were performed in 42 normal subjects in balance on a daily intake of 100 meq potassium and either 200 or 10 meq sodium/day. Renal blood flow was measured with 133Xe and arterial A II, renin and aldosterone concentrations by radioimmunoassay. A II was infused intravenously (1, 3, or 10 ng/kg/min) for 40—60 min; 14 subjects received graded doses. The A II level increased linearly with dose and plateaued within 3 min; blood pressure and renal vascular resistance showed a similar time-course. Aldosterone rose within 10 and plateaued within 20 min. Dose-response relationships were established between the rate of A II infusion and the adrenal, the renal vascular, and pressor responses. Sodium restriction reduced the pressor (P < 0.01) and the renal vascular response (P < 0.01), but potentiated the adrenal response to A II (P < 0.01). An excellent correlation was found between the plasma A II and aldosterone levels, but the slope of their regression relationship on a high (y = 0.13x + 6) and low salt intake (y = 0.32x + 14) differed significantly (P < 0.0005). Thus, sodium intake reciprocally influences vascular and adrenal responses to A II: salt restriction blunts the vascular response and potentiates the adrenal's, a physiologically important influence in view of aldosterone's role in sodium conservation.

Authors

Norman K. Hollenberg, William R. Chenitz, Douglass F. Adams, Gordon H. Williams

Measurement of Fibrinopeptide A in Human Blood

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Since thrombin cleaves fibrinopeptides A (FPA) and B from the NH2-terminal end of the fibrinogen molecule, measurement of fibrinopeptide levels in plasma may provide a direct index of thrombin action. Recently a radioimmunoassay for FPA has been developed, and in the present paper, we describe the application of this assay to the measurement of FPA levels in clinical blood samples. Since fibrinogen cross-reacts with antibodies to FPA, dialysis was used to extract the peptide from plasma. In vitro generation of FPA was prevented by removing the fibrinogen from the plasma by precipitation with ethanol before dialysis. The processing technique permitted recovery of 75% of FPA added to blood in vitro. Evidence that the immunoreactivity measured in plasma is due to FPA was provided by the results of experiments in which two antisera to FPA with different specificities showed comparable results and addition of thrombin caused no change in immunoreactivity. In contrast, extracts of streptokinasetreated plasma showed a five-fold increase in activity when treated with thrombin and markedly different immunoreactivity with the two antisera.

Authors

H. L. Nossel, I. Yudelman, R. E. Canfield, V. P. Butler Jr., K. Spanondis, G. D. Wilner, G. D. Qureshi

Continuous Distributions of Ventilation-Perfusion Ratios in Normal Subjects Breathing Air and 100% O₂

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A new method has been developed for measuring virtually continuous distributions of ventilation-perfusion ratios (V̇A/Q̇) based on the steadystate elimination of six gases of different solubilities. The method is applied here to 12 normal subjects, aged 21—60. In nine, the distributions were compared breathing air and 100% oxygen, while in the remaining three, effects of changes in posture were examined. In four young semirecumbent subjects (ages 21—24) the distributions of blood flow and ventilation with respect to V̇A/Q̇ were virtually log-normal with little dispersion (mean log standard deviations 0.43 and 0.35, respectively). The 95.5% range of both blood flow and ventilation was from V̇A/Q̇ ratios of 0.3—2.1, and there was no intrapulmonary shunt (V̇A/Q̇ of 0). On breathing oxygen, a shunt developed in three of these subjects, the mean value being 0.5% of the cardiac output. The five older subjects (ages 39—60) had broader distributions (mean log standard deviations, 0.76 and 0.44) containing areas with V̇A/Q ratios in the range 0.01—0.1 in three subjects. As for the young subjects, there was no shunt breathing air, but all five developed a shunt breathing oxygen (mean value 3.2%), and in one the value was 10.7%. Postural changes were generally those expected from the known effects of gravity, with more ventilation to high VA/Q areas when the subjects were erect than supine. Measurements of the shunt while breathing oxygen, the Bohr CO2 dead space, and the alveolar-arterial oxygen difference were all consistent with the observed distributions. Since the method involves only a short infusion of dissolved inert gases, sampling of arterial blood and expired gas, and measurement of cardiac output and minute ventilation, we conclude that it is well suited to the investigation of pulmonary gas exchange in man.

Authors

Peter D. Wagner, Raymond B. Laravuso, Richard R. Uhi, John B. West

Pressure Control of Sodium Reabsorption and Intercellular Backflux across Proximal Kidney Tubule

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The magnitude of changes in luminal hydrostatic pressure (ΔPL), peritubular capillary hydrostatic pressure (ΔPPT), and peritubular capillary colloid osmotic pressure (Δπ) was determined in the Necturus kidney during volume expansion (VE). The specific effects of separate changes of each pressure parameter on proximal net sodium transport (JNa) were studied in isolated perfused kidneys. The combined effect of ΔPL, ΔPPT, and Δπ, of a magnitude similar to that induced by volume expansion, decreases JNa by 26% in the perfused kidney. A major portion of the natriuresis in VE is due to changes in intrarenal pressures. The effect of Δπ on the permeability characteristics of Necturus proximal tubule was studied. With increasing Δπ, the ionic conductance of the paracellular shunt pathway decreased, since transepithelial input and specific resistance rose significantly, whereas cellular membrane resistance remained unchanged. Transepithelial permeability coefficients for sodium chloride and raffinose changed inversely proportional to transepithelial resistance, indicating an alteration of a paracellular permeation route. Net passive sodium backflux and active transport flux components were calculated. Increased net sodium transport with rising Δπ is accompanied by a significant drop in passive back diffusion, without an increment in the active flux component. Change in passive sodium ion back diffusion thus appears to be a key physiological factor in the control of transepithelial sodium transport.

Authors

Alain Grandchamp, Emile L. Boulpaep

Effects of Phorbol Myristate Acetate on the Metabolism and Ultrastructure of Neutrophils in Chronic Granulomatous Disease

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Previous investigations have demonstrated that phorbol myristate acetate (PMA), the active principle of croton oil, stimulates alterations in normal polymorphonuclear leukocytes (PMN) that resemble closely the changes that develop in the cells after phagocytosis of bacteria. The present study has compared the effects of PMA and heat-killed bacteria on the oxygen uptake, glucose oxidation, nitroblue tetrazolium (NBT) reduction, and ultrastructure of normal neutrophils and PMN from six patients with chronic granulomatous disease (CGD). PMA stimulated oxygen consumption, hexose monophosphate shunt activity, and NBT reduction in normal cells but failed to produce similar effects in CGD neutrophils. However, PMA did induce formation of cytoplasmic vacuoles in the CGD cells similar to those observed in normal neutrophils. The results indicate that PMA is a useful nonparticulate agent for distinguishing between normal and CGD neutrophils and for studying basic mechanisms of phagocytosis in normal and abnormal PMN.

Authors

John E. Repine, James G. White, C. Carlyle Clawson, Beulah M. Holmes

Phospholipid Metabolism in the Initiation of Renal Compensatory Growth after Acute Reduction of Renal Mass

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Membrane metabolism was studied during the initiation of compensatory growth after acute reduction in renal mass. The rate of [14C]choline incorporation into phospholipid in renal cortical slices was increased by 37% at 5 min of compensatory growth in mice. The rate increased to the maximal value of 68% by 20 min and remained there for 3 h. The rate then remained increased at 28-34% above normal for 2 days and returned to normal by the 6th day.

Authors

F. Gary Toback, Patricia D. Smith, Leah M. Lowenstein

Dermatitis Herpetiformis IMMUNOLOGIC CONCOMITANTS OF SMALL INTESTINAL DISEASE AND RELATIONSHIP TO HISTOCOMPATIBILITY ANTIGEN HL-A8

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In the present study the relation between the gluten-sensitive intestinal lesion observed in dermatitis herpetiformis (DH) and in gluten-sensitive enteropathy (coeliac sprue) (GSE) was analyzed. Jejunal IgA synthesis in DH was estimated from the extent of incorporation of [14C]leucine into IgA in jejunal biopsy specimens during short-term in vitro culture. Patients with DH have significantly elevated incorporation values as compared to normal control individuals (18,880±13,614 vs. 5,830±3,190 cpm/mg tissue protein/ 90 min) (P < 0.02) and the degree of elevation correlates well with the degree of morphologic abnormality. Thus patients with DH are similar to patients with GSE where elevated local mucosal IgA synthesis has also been observed.

Authors

Roger L. Gebhard, Z. Myron Falchuk, Stephen I. Katz, Clementine Sessoms, G. N. Rogentine, Warren Strober

Autonomic Mechanisms in Hemodynamic Responses to Isometric Exercise

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Selective autonomic blockade with intravenous propranolol, practolol, atropine, and combined atropine-propranolol was utilized to elucidate the role of the autonomic nervous system in the hemodynamic responses in young adult male volunteers to handgrip sustained at 30% of maximal voluntary contraction for 3 min. The initial 30 s of the tachycardia response was found to be mediated by withdrawal of vagal dominance, as evidenced by blockade of this response by prior atropinization. The mid and late portion of the heart rate response curve was demonstrated to be sympathetic in origin, since it was unaffected by atropine, but was suppressed by combined atropine-propranolol blockade. Sympathetic stimulation appears to be a secondary mechanism for increasing the heart rate, however, as it becomes operative only after the first mechanism of vagal withdrawal has been utilized. This was confirmed by the finding that beta adrenergic receptor blockade alone had little effect on the heart rate response curve.

Authors

C. Edwin Martin, James A. Shaver, Donald F. Leon, Mark E. Thompson, Pesara S. Reddy, James J. Leonard

Suppression of Human Growth Hormone Secretion by Melatonin and Cyproheptadine

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Pituitary growth hormone (GH) release in the rat is stimulated via serotoninergic pathways and can be inhibited by treatment with compounds that act as serotonin antagonists, such as cyproheptadine or the pineal gland hormone, melatonin. To investigate a possible role for serotonin in the control of human GH release, the effects of cyproheptadine and melatonin administration on the GH responses of normal male subjects were examined.

Authors

G. A. Smythe, L. Lazarus

Antibodies to Human Albumin in Cirrhotic Sera

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In a previous paper we described a monoclonal IgM protein with antibody-like activity towards aggregated and native albumin. The present study was initiated to determine whether sera, other than that from patients with macroglobulinemia, contained similar antibody-like activity. It was demonstrated that approximately 40% of the sera from patients with classical Laennec's cirrhosis contained antibodies which agglutinate sheep red blood cells coated with aggregated albumin. The hemagglutinating activity was present in the void volume on Sephadex G-200 chromatography and was shown to be an immunoglobulin by its removal on passage over an anti-L-chain immunoadsorbent column. The immunoglobulin was isolated from cirrhotic sera by chromatography on an albumin immunoadsorbent column. The acid eluate from the albumin affinity column contained only IgA. After labeling this IgA with 125I and obtaining the Fabα fragment by proteolysis, it was shown that the labeled Fabα complexed noncovalently with aggregated albumin. Complex formation between albumin and the cirrhotic IgA and Fabα could also be demonstrated utilizing facilitation of hemagglutination of sheep red blood cells coated with aggregated albumin. Appropriate controls consisting of normal and myeloma IgA and myeloma Fabα fragments failed to show evidence of complex formation with albumin. We propose that the restriction of the antibody response to the IgA class may result from the formation of antibodies against albumin altered during metabolism in the gastrointestinal tract. A possible role for anti-albumin antibodies in normal albumin catabolism and in the pathogenesis of Laennec's cirhosis is discussed.

Authors

S. Hauptman, T. B. Tomasi Jr.

Detection of Anti-Glomercular Basement Membrane Antibodies by a Radioimmunological Technique CLINICAL APPLICATION IN HUMAN NEPHROPATHIES

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Abstract

A radioimmunoassay for detection of anti-glomerular basement membrane (GBM) antibody was set up with a 70,000 mol wt GBM antigen, labeled with Iodine-125I and containing both types of oligosaccharidic chains present in the whole membrane.

Authors

P. Mahieu, P. H. Lambert, P. A. Miescher

Increased Adenosine Triphosphatase in Leukocytes of Asthmatic Children

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Adenosine triphosphatase (ATPase) activities were compared in leukocytes of asthmatic and nonasthmatic children. Both Mg2+- and Ca2+-dependent ATPase activities were significantly elevated in two membrane fractions (59 to 66%) and in a superntant fraction (68 to 72%) prepared from sonicated leukocytes of asthmatic subjects. Intact cell surface or ecto ATPase was also elevated (67 to 76%) in asthmatic leukocytes. Alternate day glucocorticosteroid therapy was associated with leukocyte ATPase activities intermediate between those for asthmatics not receiving steroids and for nonasthmatic control subjects. Incubation of normal leukocytes with 10-8 M hydrocortisone or leukocyte membranes with 10-4-10-3 M hydrocortisone in vitro also resulted in decreased ATPase activities. The elevated leukocyte ATPase activities appear to relate to the adrenergic imbalance in asthma previously characterized by reduced beta adrenergic responsiveness of adenylate cyclase and suggest the possibility of more than one enzymatic abnormality intrinsic to the asthmatic condition.

Authors

Ronald G. Coffey, John W. Hadden, Elliott Middleton Jr.

Orosomucoid Content of Pleural and Peritoneal Effusions

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22 nonneoplastic, noninflammatory effusions (cirrhosis and congestive heart failure), 12 non-neoplastic inflammatory effusions (tuberculosis, lupus erythematosus, rheumatoid arthritis, and idiopathic pleuropericarditis), and 58 neoplastic effusions (cancer of lung, breast, ovary, and pancreas, and lymphoma) were analyzed by radial immunodiffusion for orosomucoid concentration. The average concentration ±SE was 35±4, 65±17, and 130±13 mg/100 ml in the three types of effusion, respectively. By gel filtration and ion exchange chromatography, orosomucoid was isolated from 12 nonmalignant and 14 malignant fluids. The orosomucoid preparations reacted as single components in acrylamide gel electrophoresis at pH 9.0, and in immunodiffusion and immunoelectrophoresis against antisera to human serum and to human plasma orosomucoid. In radial immunodiffusion, the slope of the line relating concentration to the square of the diameter of the precipitate area was identical for orosomucoid isolated from normal human plasma and from nonneoplastic effusions, but was subnormal for orosomucoid isolated from neoplastic fluids. All orosomucoid preparations had normal amino acid composition. Orosomucoid from the nonmalignant effusions had normal carbohydrate content. 11 of 14 samples of orosomucoid isolated from neoplastic fluids had abnormalities in carbohydrate composition, consisting of subnormal content of sialic acid (11 of 14), hexose (10 of 14), and hexosamine (3 of 14), and abnormally high content of hexosamine (4 of 14).

Authors

Daniel Rudman, Rajender K. Chawla, Alejandro E. Del Rio, Bettye M. Hollins, Elmer C. Hall, Judy M. Conn

Relative Rates of Transcapillary Movement of Free Thyroxine, Protein-Bound Thyroxine, Thyroxine-Binding Proteins, and Albumin

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The rate of appearance of labeled thyroxine (T4) and albumin in lymph from various areas after simultaneous i.v. injection of the labeled substances in conscious ambulatory sheep has been used to estimate the relative rates of transcapillary movement of stable T4 and albumin. Labeled T4 appeared in hepatic lymph at the same rate as albumin. In intestinal and leg lymph, labeled T4 appeared eight and four times as rapidly as albumin indicating that T4 crosses capillaries in these areas independently of and much more rapidly than albumin and other proteins having similar distribution kinetics. The lymph:plasma ratios for all the T4-binding proteins including albumin were very similar in any one area showing that the relative fractional rates of transcapillary movement of these proteins were very similar.

Authors

Clifford H. G. Irvine, M. W. Simpson-Morgan

Glutamine Transport in Rat Kidney Mitochondria in Metabolic Acidosis

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In order to study factors regulating renal ammoniagenesis, the transport and metabolism of L-glutamine were studied in mitochondria from kidneys of control and acidotic rats. On incubation in 1 mM [14C]glutamine, there was production and accumulation of [14C]glutamate within the matrix space. However no [14C]glutamine was detected in the matrix space, even with 10 mM [14C]glutamine as substrate or with inhibition of glutamine deamidation (low temperature, p-chloromercuribenzoate, mersalyl). These results suggest that glutamine crosses the inner membrane by a carrier-mediated step and that this step is rate-limiting in glutamine deamidation.

Authors

William Adam, David P. Simpson

Immunoreactive Forms of Circulating Parathyroid Hormone in Primary and Ectopic Hyperparathyroidism

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The immunoreactive forms of parathyroid hormone (iPTH) in the plasma of six patients with primary, adenomatous hyperparathyroidism and six patients with ectopic hyperparathyroidism due to non-parathyroid cancer were compared by using gel filtration on columns of Bio-Gel P-150 and radioimmunoassay of iPTH in eluted fractions after concentration. We found much less (p<0.001) small (mol wt<9,500) COOH-terminal fragments of iPTH in plasma samples from ectopic hyperparathyroid patients (0.52±0.13 ng eq/ml) than in samples from primary hyperparathyroid patients (3.70±1.15 ng eq/ml). The quantity of iPTH eluting with or before native bovine PTH [1-84] was the same in both syndromes (ectopic hyperparathyroidism, 0.82±0.22 ng eq/ml; primary hyperparathyroidism, 0.73±0.09 ng eq/ml), and these values correlated positively with plasma calcium concentration (ectopic hyperparathyroidism, r=0.908; primary hyperparathyroidism, r=0.919). In both syndromes, plasma samples had an iPTH component that eluted well before PTH [1-84] (mol wt 9,500), but this component was present in much larger quantities in three patients with ectopic hyperparathyroidism. We conclude that (a) the decreased quantity of biologically inactive COOH-terminal fragments of iPTH circulating in ectopic hyperparathyroidism accounts for the previously reported relatively lower total serum iPTH values in this syndrome as compared with primary hyperparathyroidism (Riggs et al. 1971. J. Clin. Invest. 50: 2079); (b) there appears to be sufficient iPTH with presumed biologic activity to account for the hypercalcemia in both syndromes; (c) a large PTH component, not previously recognized in plasma, is present in both ectopic and primary hyperparathyroidism and may exist as the predominant immunoreactive form of the hormone in some patients with ectopic hyperparathyroidism.

Authors

Ralph C. Benson Jr., B. Lawrence Riggs, Barbara M. Pickard, Claude D. Arnaud

Cysteine Activation in Cultured Cystinotic Cells THE SPECIFIC ACTIVITY OF CYSTEINYL-tRNA SYNTHETASE AND tRNA_Cys AND THE DETERMINATION OF THE MICHAELISMENTEN CONSTANTS FOR CYSTEINYL-tRNA SYNTHETASE

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This study explored the possibility whether an altered cysteinyl-tRNA synthetase might lead to the faulty regulation of cyst(e)ine levels in cystinotic cells. This hypotheses is attractive, since amino acid activation is important in the regulation of amino acid metabolism in microorganisms. By using cultured fibroblasts from patients with cystinosis, those cell components responsible for cysteine activation were examined: cyst(e)ine, the cysteinyl-tRNA levels, cysteinyl-tRNA synthetase activity, and the Km of cysteine, ATP, and tRNACys for cysteinyl-tRNA synthetase, Fibroblasts from two patients with the infantile form of cystinosis were labeled for three days with [35S]-cystine. In comparison with normal cells, these cells contained high levels of free cysteine and cystine. Labeled fibroblasts from a patient with the adolescent form of the disease contained elevated levels of cystine, although elevated cysteine levels were not detected. The ratio of acceptor activity of tRNACys to tRNALeu in cystinotic cells was 0.46 in cystinotic cells and 0.54 in normal cells. The specific activity of cysteinyl-tRNA synthetase measured in fibroblasts of two infantile and one adolescent form was: 6.1, 2.2, and 2.1 pmol of [14C]aminoacyl-tRNA formed/μg protein/10 min, respectively. In addition, the cysteine Km's for the same cells, respectively, were: 3.1 μM, 1.5 μM, and 1.2 μM. The corresponding data for specific activities of two normal cell lines were 2.0 and 5.1 pmol [14C]aminoacyl tRNA formed/μg protein/10 min, with Km's of 3.0 μM and 1.7 μM. These data indicate that cystinotic cells contain levels of tRNACys and Cys-tRNA synthetase comparable to normal cells. In addition, within the cystinotic cells, the relative level of the Cys-tRNA synthetase and tRNACys to those of leucine and alanine are comparable to normal cells. Finally, the Km of Cys-tRNA synthetase for ATP and tRNA is similar in normal and cystinotic cells.

Authors

John R. Waterson, William P. Winter, Roy D. Schmickel

Hepatic Autophagy in Uncontrolled Experimental Diabetes and Its Relationships to Insulin and Glucagon

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Exogenous glucagon is known to increase hepatic lysosomes, but the relationships between endogenous glucagon and insulin levels and hepatic lysosomes have not been examined. To determine if the hormones of the pancreatic islets influence the development of these organelles glycogenosomes, dense bodies, and autophagosomes were morphometrically quantitated in normal rats, in rats with mild streptozotocin diabetes with normal hormone levels, and in rats with severe streptozotocin diabetes with hyperglucagonemia, hypo-insulinemia, and clinical evidence of uncontrolled diabetes and ketoacidosis. In the latter volume density of lysosomes averaged 222.8×10-4 (SEM ±19.8×10-4), significantly above the control value of 75×10-4 (SEM ±7.0×10-4) (P<0.0005); glycogenosomes were absent in the diabetics, the increase being largely the result of increased autophagosomes. Insulin treatment corrected the hyperglucagonemia, hypoinsulinemia, and other manifestations of uncontrolled diabetes and reduced the volume density of lysosomes to 37.4×10-4 (SEM ±2.0×10-4), significantly below both the untreated diabetic rats and the nondiabetic controls (P<0.0025). In mild streptozotocin diabetes, in which hyperglucagonemia, hypoinsulinemia, and other evidence of uncontrolled diabetes were absent, lysosomes averaged 77.6×10-4 (SEM ±5.5×10-4), not different from the controls. A statistically significant correlation between all measurements of lysosomal volume density and plasma glucagon was observed (r=0.79; P<0.001). It is concluded that uncontrolled streptozotocin diabetes in rats is accompanied by hepatic autophagy which may be related to the increased plasma glucagon level and/or the decreased insulin and which is corrected by insulin therapy.

Authors

M. Amherdt, V. Harris, A. E. Renold, L. Orci, R. H. Unger

Effects of Dietary Sodium and of Acute Saline Infusion on the Interrelationship between Dopamine Excretion and Adrenergic Activity in Man

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The effects of dietary sodium and of saline infusion on urinary dopamine and norepinephrine and on the relationship of these catecholamines to adrenergic activity were determined. In seven normal subjects on a 9-meq sodium intake, urinary dopamine and norepinephrine were 136±18 (SE) and 37.4±5.3 μg/day, respectively. When sodium intake was increased to 209 or 259 meq/day, urinary dopamine increased to 195±20 μg/day (P<0.01) whereas urinary norepinephrine decreased to 21.1±3.0 μg/day (P<0.01). Infusion of saline in seven subjects increased sodium excretion and urinary dopamine (from 2.18±0.22 to 2.79±0.19 μg/20 min, P<0.01), but decreased plasma dopamine-β-hydroxylase by 33% and urinary norepinephrine insignificantly. The clearance of inulin and p-aminohippurate did not change significantly and filtration fraction was the same. The data indicate that an increase in dietary sodium or infusion of saline results in an apparent decrease in adrenergic activity and an increase in urinary dopamine. Dopamine excretion would thus appear to relate inversely to adrenergic activity and to parallel sodium excretion. These findings suggest a possible role for dopamine and norepinephrine in the regulation of renal sodium excretion.

Authors

R. Wayne Alexander, John R. Gill Jr., Hirohiko Yamabe, Walter Lovenberg, Harry R. Keiser

Triiodothyronine and Thyroxine in Hyperthyroidism COMPARISON OF THE ACUTE CHANGES DURING THERAPY WITH ANTITHYROID AGENTS

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In 66 untreated patients with hyperthyroidism, serum triiodothyronine (T3) and thyroxine (T4) concentrations were measured by immunoassay. The mean T3 level was 478±28 ng/100 ml (all values mean±SEM) and the T4 was 20.6±0.6 μg/100 ml. The serum T4/T3 ratio by weight was 48±2 as opposed to a value of 71±3 in euthyroid adults. There was a significant inverse correlation of the T4/T3 ratios with serum T3 (r=0.77; P<0.01) but not with serum T4(r=0.21). These results suggested that relative overproduction of T3 is consistently present in patients with hyperthyroidism.

Authors

J. Abuid, P. R. Larsen

Elevation of Plasma Neurophysin in Women on Oral Contraceptives

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The effect of oral contraceptives on the neurohypophysis was demonstrated by changes in the plasma level of a posterior pituitary protein. neurophysin. Neurophysins are intraneuronal proteins associated with oxytocin and vasopressin. They have been shown to be released into the bloodstream. The resting plasma level of neurophysin in normal nonpregnant women is 0.69 ng/ml±0.7 SD. In women on oral contraceptives, the plasma level is 6.4 ng/ml±4.2 SD (P<0.001). Estrogen rather than progesterone causes the elevated neurophysin. The effect is observed within 12-24 h of estrogen administration and disappears 3-11 days after estrogen is discontinued.

Authors

Alan G. Robinson

Lung Tissue Elastin Composition in Newborn Infants with the Respiratory Distress Syndrome and Other Diseases

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Amino acid analysis of human fetal lung elastin was undertaken in 49 instances of live-born neonates, ranging from 380 g to full term, and in 3 abortuses of 12-14 wk gestation. The data suggest that formation of the cross-linking agents, desmosine and isodesmosine, occurs early, between 14 and 22 wk. The ratio of neutral to charged amino acids remains low until the 36th wk when it attains adult levels. The composition of elastin was independent of sex and duration of survival. In three neonatal pulmonary diseases (respiratory distress syndrome, atelectasis, and hemorrhage) ratios were significantly lower than those found in nondiseased lungs. This may be a reflection of immaturity or may be a predisposing factor in neonatal lung disease. The latter hypothesis is attractive and receives indirect support from the association of a more polar elastin with other diseases, including adult emphysema and atheromatous aortic change.

Authors

Hugh E. Evans, Stephen Keller, Ines Mandl

ERRATUM

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Abstract

Authors