ATLANTIC CITY MEETINGS 1970

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Abnormal rheology of oxygenated blood in sickle cell anemia

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The viscosity of oxygenated blood from patients with sickle cell anemia (Hb SS disease) was found to be abnormally increased, a property which contrasts with the well recognized viscous aberration produced by deoxygenation of Hb SS blood. Experiments designed to explain this finding led to considerations of deformation and aggregation, primary determinants of the rheologic behavior of erythrocytes as they traverse the microcirculation. Deformability of erythrocytes is in turn dependent upon internal viscosity (i.e. the state and concentration of hemoglobin in solution) and membrane flexibility. Definition of the contribution made by each of these properties to the abnormal viscosity of oxygenated Hb SS blood was made possible by analysis of viscosity measurements, made over a wide range of shear rates and cell concentrations, on Hb SS erythrocytes and normal erythrocytes suspended in Ringer's solution (where aggregation does not occur) and in plasma. Similar measurements were made on the two cell types separated by ultracentrifugation of Hb SS erythrocytes: high density erythrocytes composed of 50 to 70% irreversibly “sickled” cells (ISC) and low density erythrocytes composed of over 95% non-ISC.

Authors

Shu Chien, Shunichi Usami, John F. Bertles

Mild thalassemia: the result of interactions of alpha and beta thalassemia genes

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Homozygous thalassemia is due to inherited unbalanced synthesis of the α- or β-chains of hemoglobin. Clinical severity may be in part related to the extent of α:β imbalance. Two families are presented that illustrate this concept. Thalassemia in these individuals was evaluated by clinical and genetic criteria. The relative rates of α- and β-chain synthesis in their reticulocytes were estimated by the extent of incorporation of 1-leucine—U-14C into the chains. Unusual combinations of clinical and hematological data and biosynthetic ratios were obtained in certain individuals which indicated the presence of combinations of α- and β-thalassemia genes. The propositus of the first family had mild Cooley's anemia and was believed to have one α- as well as two β-thalassemia genes. Presumably the α-thalassemia gene interfered with α-chain production which lead to less accumulation of α-chains and a reduced rate of intramedullary and peripheral hemolysis. In the second family two individuals were believed to have an α-thalassemia, a “silent carrier,” and a β-thalassemia gene. Despite the fact that they appeared to have the genotype of hemoglobin H disease, their cells contained no hemoglobin H and had a normal lifespan presumably because excess β-chain production was inhibited by the β-thalessemia gene. These family studies suggest that the α:β imbalance observed in thalassemia may be favorably influenced by combinations of α- and β-thalassemia genes.

Authors

Yuet Wai Kan, David G. Nathan

The peripheral metabolism of triiodothyronine in normal subjects and in patients with hyperthyroidism

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In order to assess the contribution of 3.3′,5-triiodo-L-thyronine (T3) to overall thyroid hormone economy, conjoint measurements of the kinetics of peripheral T3 metabolism and the total concentration of T3 in serum were made in a group of normal subjects and in a group of patients with hyperthyroid Graves' disease. As judged from the disappearance of trichloroacetic acid-precipitable 131I from serum after a single intravenous dose of labeled T3, the following mean values were obtained in the normal subjects: volume of distribution, 43 liters or 0.62 liter/kg; fractional turnover rate. 52% per 24 hr: clearance rate, 22.3 liters/24 hr: and absolute disposal rate, 60 μg/24 hr. In the patients with untreated hyperthyroidism, values for all these functions were greatly increased. After treatment, the volume of T3 distribution returned to normal but the fractional turnover rate remained abnormally rapid.

Authors

Kenneth A. Woeber, Richard J. Sobel, Sidney H. Ingbar, Kenneth Sterling

The effects of an acute load of thyroxine on the transport and peripheral metabolism of triiodothyronine in man

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In order to examine the question of whether thyroxine-binding globulin (TBG) influences significantly the peripheral metabolism of 3,3′,5-triiodo-L-thyronine (T3) in vivo, paired studies of the effects of a large intravenous load of L-thyroxine (T4) on the kinetics of 131I-labeled T3 metabolism were carried out in five normal subjects. After the T4 load, both the early distributive loss of labeled T3 from serum and the volume of T3 distribution, observed after distribution equilibrium had been attained, were greatly increased. These alterations were consistent with those to be expected from displacement of T3 from its extracellular binding sites. After the T4 load, however, the fractional rate of T3 turnover was decreased. This finding is ascribed either to competition between T3 and T4 for common intracellular pathways of degradation or excretion or to displacement of T3 from sites of more rapid to sites of less rapid metabolism. These effects of alterations in the binding activity of TBG on the peripheral metabolism of T3, together with those previously reported by others, are consistent with the interpretation that T3 is significantly bound by TBG in vivo. However, it is suggested that the effects of alterations in the T3-TBG binding interaction on the metabolism of T3 are obscured by alterations in the extracellular-cellular partitioning of T4 that would result from concurrent alterations in T4-binding by TBG.

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Kenneth A. Woeber, Exequiel Hecker, Sidney H. Ingbar

The measurement of the exchangeable pools of cholesterol in the baboon

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Five male baboons were fed cholesterol-1α-3H until an isotopic steady state was approached in which the ratio of serum to dietary cholesterol specific activity was constant. The animals were then given single intravenous injections of cholesterol-4-14C, and the disappearance curves of the 14C from the circulation were followed for 70-85 days. The total exchangeable cholesterol pools under these conditions were determined by carcass analysis at the end of the experiment and were shown to agree closely with the sums of the two exchangeable cholesterol pools as predicted from analysis of the die-away curve in terms of a two exchangeable pool model, assuming that entry into and exit from the system occur predominantly through the more rapidly exchanging of the two pools. These results have been interpreted as support for the validity of a model consisting of two exchangeable pools and one nonexchangeable or very slowly exchangeable pool as an approximation of over-all cholesterol metabolism in this species. In addition, an anatomical and chemical dissection of these pools was performed. While the three pool model is not applicable to every tissue, it has been possible to show that its general applicability in the intact animal stems from the fact that the major portions of the three cholesterol pools of the body lie within a limited number of tissues.

Authors

Jean D. Wilson

Red cell survival studies in hereditary spherocytosis

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The in vivo survival of hereditary spherocytes has been investigated with the 51Cr red cell survival technique. Spherocytes invariably showed a shorter survival in a normal recipient than in the donor's own circulation. Moreover transfusion of spherocytes from a mother to her son, both with hereditary spherocytosis, showed that “foreign” spherocytes have a shorter survival than the “self” spherocytes of the recipient. These findings are attributed to splenic reticuloendothelial blockade, specific towards hereditary spherocytes in the patient's own circulation. There was no correlation between the Na+ influx and the hemolytic tendency of hereditary spherocytes when the latter was measured by the survival t½ in compatible normal recipients. However osmotic fragility influenced cell survival since cells with high fragility were rapidly sequestered in the normal spleen. It is suggested that both cell shape and a selective reticuloendothelial blockade in the spleen are important factors in determining the severity of hemolysis in the individual patient.

Authors

James S. Wiley

Metabolic properties of IgG subclasses in man

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Metabolic properties of the four subclasses of human IgG were investigated by performing 47 turnover studies in individuals with normal IgG serum concentrations, as well as in patients with an increased level of one of the subclasses. Studies in 12 subjects with normal IgG serum concentration showed that the average biologic half-life of G1, G2, and G4 was 21 days, while that of G3 was only 7.1 days. Fractional catabolic rates of G1, G2, and G4 were 6.9 to 8% of the intravascular pool per day. G3, however, had a higher fractional catabolic rate, amounting to 16.8% of the intravascular pool per day. Distribution of the subclasses was such that the intravascular compartment contained 51-54% of the total body pools of G1, G2, and G4, but 64% of the total body pool of G3.

Authors

Andreas Morell, William D. Terry, Thomas A. Waldmann

Pharmacologic identification of the lower esophageal sphincter

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The distal 2/3 of the opossum esophagus contains only smooth muscle. Manometry shows that the most distal 1-2 cm is the lower esophageal sphincter. We used a variety of agonists to seek differences between circular muscle from the sphincteric segment and more rostral levels. Isometric contractions of strips from the distal 6 cm were recorded in vitro in response to acetylcholine, carbachol, methacholine, nicotine. DMPP, norepinephrine, norepinephrine with propranolol, barium, atropine, and potassium. Significant differences in threshold concentration occurred for all drugs except barium, atropine, and potassium, the more distal strips being more sensitive. The gradient of threshold was much steeper for norepinephrine than for the other drugs. Maximal responses did not differ among levels for the choline esters or ganglionic stimulants, but showed proximal diminution for norepinephrine. These differences in threshold concentration could represent differences in distribution density of drug receptor sites, differences in affinity of receptors for the agonists, differences in rates of uptake of agonists, or differences in rates of enzymatic hydrolysis; or they may have no common basis. The sphincter is defined, at least in part, in the esophageal wall rather than in the central nervous system. The greater magnitude of the difference in sensitivity to norepinephrine than for the other agents suggests that the adrenergic innervation is important in defining the lower esophageal sphincter.

Authors

James Christensen

Respiration and glucose oxidation in human and guinea pig leukocytes: comparative studies

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A comparison has been made of the metabolic shifts in human and guinea pig leukocytes when they phagocytize. Respiration of guinea pig polymorphonuclear leukocytes (PMN) and the increment during phagocytosis were each about 2½-fold that of human PMN. This was also true of the direct oxidation of glucose-6-P (hexose monophosphate shunt). Enzymes potentially responsible for these phenomena have been compared in each species. Cyanide-insensitive NADH oxidase and NADPH oxidase were measured and only the formed exhibited adequate activity to account for the respiratory stimulus durintg phagocytosis. The hydrogen peroxide formed by this enzyme stimulates the hexose monophosphate shunt by oxidizing glutathione which upon reduction by an NADPH-linked glutathione reductase provides NADP to drive the hexose monophosphate shunt. Other linkages between respiratory stimulation and that of the hexose monophosphate shunt also pertain in the guinea pig.

Authors

Robert L. Baehner, Neal Gilman, Manfred L. Karnovsky

Stimulation of globin synthesis: relative responsiveness of reticulocytes and nucleated erythroid cells

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The effects of iron, cobalt, hemin, and plasma on hemoglobin synthesis by suspensions of rabbit reticulocytes and nucleated bone marrow cells were studied. L-Leucine-14C and sodium pyruvate-3-14C were employed to measure globin and heme synthesis, respectively. Normal plasma (or serum) was found to stimulate the rate of globin synthesis in both systems. The stimulatory effects of iron and hemin were additive to those of plasma or serum only in the reticulocytes.

Authors

Herbert S. Waxman

Altered immunoglobulin metabolism in systemic lupus erythematosus and rheumatoid arthritis

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IgG and IgM metabolism was evaluated in 10 patients with systemic lupus erythematosus (SLE), 10 patients with rheumatoid arthritis (RA), and in seven normal volunteers. The biological half-lives of purified IgG and IgM, labeled with 131I and 125I, respectively, were determined by serial measurements of radioactivity in the blood and urine with a gamma well counter, and by serial counts of total body radioactivity in a total body counting chamber.

Authors

Joshua Levy, Eugene V. Barnett, Norman S. MacDonald, James R. Klinenberg

Urinary polypeptides related to collagen synthesis

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Of the total urinary hydroxyproline in normal subjects and those with skeletal disorders, between 4 and 20% was nondialyzable. In some patients with Paget's disease of bone, hyperparathyroidism with osteitis fibrosa, hyperphosphatasia, and extensive fibrous dysplasia the total urinary hydroxyproline was sufficiently high to permit purification of this polypeptide hydroxyproline by gel filtration and ion exchange chromatography. The partially purified polypeptides had molecular weights between 4500 and 10,000 and amino acid compositions and physical properties resembling those of gelatin. The polypeptide fractions also contained neutral sugar and glucosamine. These fragments had been shown to be susceptible to cleavage by purified bacterial collagenase suggesting the presence of the sequence-Pro-X-Gly-Pro-Y-.

Authors

Stephen M. Krane, Alberto J. Muñoz, Edward D. Harris Jr.

Micropuncture studies of the recovery phase of myohemoglobinuric acute renal failure in the rat

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Micropuncture studies of the recovery phase of glycerol-induced myohemoglobinuric acute renal failure were performed in rats whose blood urea nitrogen (BUN) had fallen at least 20% below its peak value. The glomerular filtration rate (GFR) of individual nephrons in a single kidney in the recovery period generally either was in the normal range or minimal. Each animal's BUN concentration at the time of the study was inversely related to the proportion of functioning surface nephrons, but did not correlate with individual nephron GFR values. Proximal tubule fractional water absorption was significantly depressed as manifested by both depressed inulin (TF/P) values and supernormal volumes of collections, a finding which, in the absence of a urea-induced osmotic diuresis, suggests impaired sodium transport by the damaged nephron. The mean proximal tubule hydrostatic pressure in recovery was normal and there was little variation in pressure among functioning nephrons. It is concluded that recovery from this model of acute renal failure reflects the progressive recruitment of increasing numbers of functioning nephrons. The recovery of individual nephron glomerular filtration, once begun, was rapid and complete. No evidence could be adduced that the gradual return of renal function towards normal reflects a slow release of tubular obstruction or repair of disrupted tubular epithelium. Rather, recovery appeared to be directly attributable to the return of an adequate effective glomerular filtration pressure. Significant limitation in proximal tubule water absorption persisted after individual nephron GFR had returned to normal or supernormal values in this model of experimental acute renal failure in the rat, a finding which readily accounts for the diuresis associated with the recovery phase of this syndrome.

Authors

Donald E. Oken, Gerald F. DiBona, Franklin D. McDonald

The role of inotropic variation in ventricular function during atrial fibrillation

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A series of experiments were performed upon intact anesthetized dogs to determine the relevance of a variety of hemodynamic variables to the irregular ventricular performance associated with atrial fibrillation. During experimentally induced atrial fibrillation central aortic pulse pressure was measured in relation to the duration of the preceding diastolic interval, the relative degree of cycle-length change, the magnitude of the preceding aortic end-diastolic pressure, the rate of ventricular tension development (at a fixed diastolic tension), and to ventricular end-diastolic pressure. While all of the latter variables bore a significant relation to the chosen parameters of ventricular function, the most linear correlation lay with the rate of ventricular tension development. It has been suggested, as a consequence, that the irregular ventricular performance observed during atrial fibrillation under these experimental conditions, may be more directly related to variation in the inotropic state of the ventricular myocardium than to an expression of the Frank-Starling concept, resulting from variable ventricular filling. The lability of the inotropic or contractile state has in turn been attributed to abrupt cycle-length change effecting inotropic alteration analogous to postextrasystolic potentiation of contractility and, at rapid rates, effecting an alternation of the contractile state.

Authors

Robert E. Edmands, Kalman Greenspan, Charles Fisch

Alterations in the mechanical properties of the lung during dyspnea in chronic obstructive pulmonary disease

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The mechanical properties of the lungs in seven patients with chronic obstructive pulmonary disease (COPD) were measured before and during dyspnea on exertion, as well as when relief with added oxygen was obtained. Mean pulmonary dynamic compliance was 0.091 liters/cm of H2O before dyspnea, 0.057 during dyspnea, and 0.101 liters/cm H2O during relief. During dyspnea there was an increase in the total respiratory work (both elastic and nonelastic work) and this fell during relief with oxygen. Nonelastic resistance and respiratory rate were not significantly different during the three periods. In five similar patients a progressive increase in the instantaneous rate of change of transpulmonary pressure (dP/dt) was observed during exercise and this was markedly increased during dyspnea. These changes in dP/dt during exercise could explain the observed fall of pulmonary dynamic compliance.

Authors

Jesus T. Suero, Colin R. Woolf

Kinetics of amino acid transport across bone marrow cell membranes

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Dog bone marrow nucleated cells were incubated in media containing labeled L-amino acids, and the cellular accumulation of radioactivity as a function of time was measured and analyzed according to a three-compartment model.

Authors

Max S. Lin, H. Saul Winchell

Partial characterization of antigenic streptococcal plasma membrane components in acute glomerulonephritis

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Fluorescein-labeled immunoglobulin G (IgG) fractions of serum from patients with acute poststreptococcal glomerulonephritis stained parts of the glomerular basement membrane and mesangium of kidney tissue obtained from the same patients during the early phase of the disease. Renal tissue obtained from normal individuals and from patients with other kidney diseases failed to stain with these IgG fractions. Preabsorption of the serum fractions with various freezethawed bacteria demonstrated that only certain group A streptococci abolished the staining capacity. Fractionation of the streptococci into cellular constituents indicated that it was predominantly the plasma membrane fraction which blocked the immune staining. Spectrofluorometry using alkali-solubilized renal tissue confirmed these observations in a quantitative manner. By sucrose density-gradient ultracentrifugation of the plasma membrane two possible antigens were isolated. One was soluble in phosphate-buffered saline and the other was insoluble. The soluble component was a lipoprotein with a molecular weight of approximately 120,000.

Authors

G. Treser, M. Semar, A. Ty, I. Sagel, M. A. Franklin, K. Lange

Effects of chronic ethanol feeding on serum lipoprotein metabolism in the rat

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In rats, chronic ethanol feeding was found to enhance the postprandial hyperlipemia and to increase the incorporation of dietary palmitic acid-3H and intravenously injected L-lysine-14C into serum lipoproteins. The main increases of total amount, labeling, and specific activity of lipid and protein occurred in the d < 1.019 lipoprotein fraction. Fat absorption and the clearance of injected chylomicrons were not affected by ethanol feeding. Blocking of lipoprotein and chylomicron removal with Triton did not prevent the action of ethanol on serum lipids, indicating that the ethanol effect is not likely due to defective removal of lipids from the circulation. Ethanol enhanced the incorporation of chylomicron fatty acids into newly synthetized very low density lipoproteins, as shown by an increased reappearance of the fatty acid label into the lipids of this fraction after injection of palmitate-14C/glycerol-3H doubly labeled chylomicrons. These results indicate that alcoholic hyperlipemia is due, at least in part, to an increase in newly synthetized lipoproteins. The hyperlipemia produced by ethanol was accompanied by hepatic steatosis. The simultaneous production of fatty liver and hyperlipemia makes it unlikely that defective lipoprotein synthesis or secretion is a primary mechanism for the pathogenesis of the alcoholic fatty liver.

Authors

Enrique Baraona, Charles S. Lieber

Acute effects of inhaled isoproterenol on the mechanical characteristics of the lungs in normal man

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We investigated the effects of isoproterenol on the pulmonary mechanics of eight healthy male subjects. We measured the flow-volume, pressure-volume, resistance-volume, and pressure-flow relationships of the lungs of our subjects in addition to the forced expiratory volume (FEV1). The results of this study confirm earlier observations that isoproterenol produces a considerable decrease in airway resistance but only small changes in maximum expiratory flow. Measurements of static pressure-volume curves showed that isoproterenol caused a temporary decrease in the elastic recoil pressure of the lungs. In five men there were mean falls in recoil pressure of 4.1 cm H2O at 85% total lung capacity (TLC), 2.6 cm H2O at 75% TLC, and 1.5 cm H2O at 50% TLC. We postulate that the reason for the relatively small increments in maximum expiratory flow after isoproterenol is primarily that the effects of airway dilatation are in large part negated by the reduction in lung recoil pressure, which results in a fall in the maximum effective driving force for expiratory air flow, and secondly that there is an increase in the compliance of the flow-limiting airways. These studies emphasize that tests of maximum flow and of airway resistance should not be regarded as invariably interchangeable in the assessment of airway reactions or mild disease of the airways.

Authors

E. R. McFadden Jr., Jan Newton-Howes, N. B. Pride

Hemodynamic effects of pneumonia: I. Normal and hypodynamic responses

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Since an excessive mortality from pneumonia persists in spite of antimicrobial therapy, the hemodynamics during and after the acute phase of pneumonia were studied in 17 patients. None of the patients had clinical heart disease and all had normal venous pressures. The arteriovenous oxygen difference was used to assess the adequacy of the circulation to meet peripheral tissue perfusion, and a spectrum of arteriovenous oxygen differences was noted. In 11 patients, tissue perfusion was considered adequate because the arteriovenous oxygen difference did not exceed 5.5 vol%. In six patients, the arteriovenous oxygen difference was greater than 5.5 vol% and these six patients differed hemodynamically from the others. In these six patients during the acute phase of pneumonia, cardiac output was decreased, and total peripheral resistance and hematocrit were increased. When five patients with varying arteriovenous oxygen difference were studied during exercise in the acute phase, cardiac output increased while venous pressure remained unchanged. Arteriovenous oxygen difference in these five exercising patients increased in all, but most markedly in those with an initially widened arteriovenous oxygen difference. The inadequate response to pneumonia is most consistent with depressed myocardial function, but the possibility of decreased intravascular volume as a contributory factor could not be excluded.

Authors

Herbert Benson, Mohammed Akbarian, Lawrence N. Adler, Walter H. Abelmann

Hemodynamic effects of pneumonia: II. Expansion of plasma volume

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Previous work has demonstrated that approximately one-third of patients with pneumonia have a hypodynamic circulatory response. This response is characterized by an abnormally wide arteriovenous oxygen difference, a low cardiac output, increased peripheral resistance, and an increased hematocrit. This state was found to abate in convalescence. In an attempt to elucidate the pathogenesis of this hypodynamic state, nine additional patients were studied hemodynamically during the acute phase of pneumonia before and during acute expansion of blood volume by low molecular weight dextran (seven patients) or normal saline (two patients). Five patients were restudied before and during acute blood volume expansion in convalescence.

Authors

Raj Kumar, Wayne A. Wallace, Alberto Ramirez, Herbert Benson, Walter H. Abelmann

Effect of 2,3-diphosphoglycerate on oxygen affinity of blood in sickle cell anemia

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Blood of patients with sickle cell anemia (SS) exhibits decreased affinity for oxygen, although the oxygen affinity of hemoglobin S is the same as that of hemoglobin A. SS red cells contain more 2,3-diphosphoglycerate (DPG) than normal erythrocytes. The oxygen affinity of hemolyzed red cells is decreased by added DPG, and hemolysates prepared from SS red cells do not differ from normal hemolysates in this regard. Reduction of oxygen affinity to the levels found in intact SS red cells required DPG concentrations in excess of those found in most SS patients. The same was true of oxygen affinity of patients with pyruvate kinase deficiency. Other organic phosphates, as well as inorganic ions, are known to alter the oxygen affinity of dilute solutions of hemoglobin. These substances, the state of aggregation of hemoglobin molecules, and cytoarchitectural factors probably play roles in determining oxygen affinity of both normal and SS red cells.

Authors

Samuel Charache, Santiago Grisolia, Adam J. Fiedler, Andre E. Hellegers

The effect of uncomplicated potassium depletion on urine acidification

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Studies were performed on normal human subjects to determine the effects of potassium depletion on urine acidification. Depletion was induced by ingestion of a low potassium diet either alone or in combination with a potassium-binding resin, and the response of each subject to an acute ammonium chloride load in the potassium-depleted state was compared to his normal response. Urine pH was significantly higher during potassium deficiency if sufficient potassium depletion had been induced. No differences in blood acid-base parameters, urinary flow rate, or urinary fixed buffer excretion rate were found to account for this change; however, the increase in urine pH was accompanied by a concomitant increase in net acid and ammonium excretion. It is proposed that these changes during potassium depletion reflect an increase in ammonia diffusion into the urine, presumably as a result of increased renal ammonia production. In addition, it is speculated that changes in ammonia metabolism may be a physiologic control mechanism for potassium conservation.

Authors

Richard L. Tannen

Identification of neurohypophysial hormones with their antisera

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Identifying posterior pituitary hormones in body fluids or neurohypophysial extracts was heretofore partially achieved by using pharmacologic potency ratios or semispecific inactivation by thioglycolate or enzymes. Production of antisera against oxytocin and lysine-vasopressin has prompted us to test their specificity against lysine-vasopressin, arginine-vasopressin, arginine-vasotocin, and oxytocin. In ethanol anesthetized rats, antidiuretic and milk-ejection activities were assayed for each peptide-antiserum combination after 0, 30, 60, and 90 min of incubation. Results indicate that (a) oxytocin antiserum inactivates oxytocin, but not arginine-vasopressin, lysine-vasopressin, or arginine-vasotocin; vasopressin antiserum inactivates arginine-vasopressin and lysine-vasopressin, but neither oxytocin nor arginine-vasotocin; (b) an identifiable antigenic site exists for each hormone; (c) relatively specific identifications of natural neurohypophysial peptides are possible using antisera and bioassays; (d) this method is promising for identifying neurohypophysial peptides in body fluids and pituitary extracts; and (e) active and passive immunization against oxytocin and vasopressin may increase our understanding of their physiologic functions.

Authors

Helmuth Vorherr, Robert A. Munsick

Studies of pancreatic alpha cell function in normal and diabetic subjects

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The development of a glucagon radioimmunoassay with a relatively high degree of specificity for pancreatic glucagon made possible studies of alpha cell function in healthy nondiabetic subjects and in patients with diabetes mellitus. In the former group mean fasting plasma glucagon averaged 108 μμg/ml (SEM ±10). In 12 juvenile-type diabetics fasting glucagon averaged 110 (±9) and in 33 adult-type diabetics the average was 114 (±8). The diabetic averages did not differ significantly from the nondiabetic subjects; however, when hyperglycemia was induced by glucose infusion in the nondiabetic subjects so as to simulate the fasting hyperglycemia of the diabetics, mean glucagon fell to 57 μμg (±8), which was significantly below the diabetic mean.

Authors

Roger H. Unger, E. Aguilar-Parada, Walter A. Müller, Anna M. Eisentraut

Effect of alterations in the thyroid state on the intrinsic contractile properties of isolated rat skeletal muscle

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Contractile properties of soleus muscles isolated from 31 euthyroid (EU), 20 hyperthyroid (HT), and 18 myxedematous (MY) rats were studied in a myograph. At 100 stimuli/sec maximum isometric tension was essentially identical in EU (17.2 ±0.5 g/mm2) and HT (17.7 ±0.5 g/mm2) muscles, but was significantly depressed in MY muscles (11.5 ±0.7 g/mm2). The rate of tension development was increased in HT (103 ±4.5 g/sec per mm2) as compared to both EU (86.2 ±4.6 g/sec per mm2) and MY (38.4 ±2.2 g/sec per mm2) muscles, while the duration of the active state was shortened in HT (77.1 ±2.3 msec) as compared to EU (105.1 ±1.1 msec) muscles and was prolonged in MY muscles (153.3 ±6.0 msec). The mean rate of isometric relaxation was 26.5 ±4.9 g/mm2 per sec in EU muscles, more rapid in HT muscles (33.1 ±1.3 g/sec per mm2), and slower in MY muscles (16.0 ± g/mm2 per sec). The fusion frequency was greater in HT muscles, averaging 68.5 ±3.6 stimuli/sec compared to EU muscles (38.1 ±1.2 stimuli/sec) and to MY muscles (33.3 ±4.0 stimuli/sec). At 40 stimuli/sec tension averaged 16.4 ±0.8 g/mm2 in EU muscles while at the same frequency tension was reduced in HT muscle, averaging 14.2 ±0.5 g/mm2. All differences were significant (P < 0.01). In conclusion, HT and MY result in profound alterations in the intrinsic contractile properties of skeletal muscle. While tension in HT muscles is maintained in vitro at a stimulus frequency of 100 stimuli/sec, the reduction in duration of active state may lower tension in vivo by preventing complete fusion of contractile events. In MY tension is reduced as a consequence of the lowered intensity of the active state. These changes explain, at least in part, the weakness of muscle activity in both HT and MY.

Authors

Herman K. Gold, James F. Spann Jr., Eugene Braunwald