Previous studies of thyroid function during various infections have yielded conflicting results, but most have suggested an acceleration of peripheral thyroxine (T4) turnover during the acute infectious illness. In the present studies, thyroid function was examined by a method allowing simultaneous analysis of both endogenous thyroidal release and peripheral T4 disposal in normal volunteers after induction of acute falciparum malaria. Subjects received iodide-125I, followed in 5-7 days by 131I-T4 intravenously. 4 days later, infection was induced by the injection of parasitized red blood cells. Bidaily measurements of serum protein-bound 125I and protein-bound 131I, and urinary 125I and 131I, together with frequent estimates of serum 127I-T4 (Murphy-Pattee) and free T4 (FT4), were made during a control period, during acute illness, and during convalescence. Alterations in the peripheral metabolism of 131I-T4 during infection included significant decreases in the fractional disappearance rate for T4 [(k)], and in the clearance and daily disposal of T4, all of which returned to control values during convalescence. Total serum 127I-T4 increased late in the infected period to become greater during convalescence than either before or during infection, while FT4 did not increase significantly until convalescence. An analysis of serum 131I-T4/127I-T4 and 131I-T4/PB125I ratios confirmed these observations. The slope with time of ratios for urinary 125I/131I, a reflection of thyroidal iodine release, was decreased during infection, but rebounded to control values during the convalescent period. The observed increments in serum 127I-T4 concentration in the convalescent phase may reflect in part the slowing of (k), but together with the rising ratios of urine 125I/131I suggests enhanced thyroidal T4 secretion immediately after the acute illness. Thus, with malarial infection, there appears to be an initial depression followed by a rebound in rates of thyroidal iodine release. In contradistinction to other infections, fractional turnover and daily disposal of hormone is decreased in malaria, perhaps due to hepatic dysfunction and the consequent impairment in cellular deiodinative processes.
Leonard Wartofsky, Daniel Martin, Jerry M. Earll
The effect of azathioprine therapy on gammaglobulin synthesis was evaluated in nine patients with rheumatic disorders. The rates of synthesis of IgG and IgM were calculated before and after 4 months of azathioprine treatment using turnover studies of radioiodinated gammaglobulins.
Joshua Levy, Eugene V. Barnett, Norman S. MacDonald, James R. Klinenberg, Carl M. Pearson
The effects of adrenocorticotropin (ACTH), angiotensins I and II, increased potassium, and decreased sodium concentrations upon steroid synthesis were examined by incubation of beef adrenal tissue slices.
Takao Saruta, Robert Cook, Norman M. Kaplan
Prostaglandins E1 and E2 significantly stimulated the synthesis of aldosterone, corticosterone, and to a lesser degree, cortisol in the outer slices of beef adrenal tissue. PGA, PGF1a, and PGF2a were ineffective.
Takao Saruta, Norman M. Kaplan
Lidocaine depresses automaticity in cardiac Purkinje fibers by decreasing the slope of slow diastolic depolarization, but the mechanisms of this effect are poorly understood. To test the proposal that the antiautomatic effect of lidocaine might be mediated by an increase in membrane potassium conductance, transmembrane voltage (Vm) was measured in Purkinje fibers perfused with sodium-deficient Tyrode containing choline as the major cation. Vm was varied by altering the external potassium concentration, [K]o, from 0.5 to 150 mM before and after lidocaine, 2.14 × 10-5 M, a concentration considered equivalent to clinical plasma antiarrhythmic levels. In Purkinje fibers, resting Vm varies linearly with [K]o plotted on a logarithmic scale from 4 to 150 mM, approximately as predicted by the Nernst equation. At [K]o of 0.5-2.7 mM, resting Vm diverges from the predicted potassium equilibrium potential (VK) resulting in an increased driving force for the outward K+ current (Vm — VK). In choline Tyrode at [K]o of 2.7 mM or less, lidocaine caused a significant increase in Vm, the change being a positive linear function of (Vm — VK) with a P < 0.01. This effect was more striking in Purkinje fibers with a Vm reduced by stretch. These findings imply that lidocaine increased membrane chord conductance for the potassium ion (gK).
Morton F. Arnsdorf, J. Thomas Bigger Jr.
The lysozyme content of human cartilage was measured by incubation of lyophilized, powdered cartilage in a variety of buffers and salt solutions, and the factors controlling the binding of lysozyme within cartilage were studied. Lysozyme was extracted from hyaline cartilage by buffers of pH greater than 9.0 by solutions 1 M in monovalent cations, and by solutions 0.12-0.40 M in divalent cations. The ability of cations to extract lysozyme from cartilage agreed with their known affinities for binding to chondroitin sulfate. The total extractable lysozyme content of five samples of human costal cartilage ranged from 1.45 to 3.36 μg lysozyme per mg of cartilage; for five samples of hyaline cartilage from peripheral joints the range was 0.80-3.03 μg lysozyme per mg of cartilage. Cartilage incubated in excess exogenous lysozyme could bind 0.053 equivalents of lysozyme per equivalent of chondroitin sulfate. Fibrocartilage and synovium from knee joints yielded no detectable lysozyme, despite the fact that synovium, a tissue rich in lysosomes, contained measurable quantities of β-glucuronidase. Lysozyme extraction from cartilage was not augmented by incubation with streptolysin S. When incubation was carried out with mild extraction techniques, lysozyme extraction from cartilage tended to parallel uronic acid release, both as a function of time and from one specimen to another. The active material as lysozyme. Lysozyme occurs in human hyaline cartilage as a counterion to polyanionic glycosaminoglycans. Carextracted from cartilage met five criteria for identification tilage lysozyme appears to be extracellular and nonlysosomal. Degradation of cartilage may contribute to the increased serum and synovial fluid lysozyme levels often present in patients with rheumatoid arthritis.
Robert A. Greenwald, Alan S. Josephson, Herbert S. Diamond, Ambrose Tsang
To determine the sites of tubular phosphate reabsorption in the nephron, microinjection studies were undertaken, utilizing isotonic electrolyte solutions, containing either 1.4 or 8.0 mM phosphate and radioactive PO4-33P and inulin-3H, in rats made mildly diuretic by infusion of mannitol. The injected sites were localized by the technique of latex dissection.
Barry B. Staum, Robert J. Hamburger, Martin Goldberg
The behaviour of rat kidney cortex phosphoenolpyruvate carboxykinase has been investigated under conditions of triamcinolone administration and ammonium chloride acidosis. The concentration of phosphoenolpyruvate carboxykinase as measured by enzyme activity and immunotitration was elevated under both conditions. The mechanism of induction is different in the two cases. At doses which produce maximum stimulation, the effects of steroid and ammonium chloride were additive; only the increment in enzyme activity produced by steroid was blocked by actinomycin D.
I. D. Longshaw, C. I. Pogson
The kinetics of the induction of rat kidney phosphoenolpyruvate carboxykinase activity after triamcinolone and ammonium chloride administration have been investigated with a view to the further differentiation of the two processes.
I. D. Longshaw, G. A. O. Alleyne, C. I. Pogson
Brush borders and plasma membranes have been purified from mucosal epithelial cells of rabbit ileum under control conditions and after treatment for 3 hr with cholera toxin in vivo. The activity of several enzymes in these preparations was measured. It was concluded that adenyl cyclase, like NaK-ATPase, seems not to be a normal constituent of brush borders. Both these enzymes are present in plasma membrane preparations derived largely from the basal and lateral margins of the epithelial cells, both may be phospholipid dependent enzymes and both are affected by cholera toxin. Adenyl cyclase activity is increased while NaK-ATPase is decreased. The activities of alkaline phosphatase, leucineaminopeptidase, 5′-nucleotidase, glucose-6-phosphatase, and Mg-ATPase were not found to be affected by the toxin. Cholera toxin, which makes contact with the luminal side of the epithelial cells, in the natural disease and in the experimental model, would appear to exert its pathologic effect on adenyl cyclase at the opposite (basal and lateral) side of the cells.
David K. Parkinson, Hans Ebel, Donald R. DiBona, Geoffrey W. G. Sharp
Studies have been performed on a 12-yr-old Chinese girl with compensatory erythrocytosis due to the presence of hemoglobin Bethesda comprising about 45% of the red cell hemoglobin. Her parents and three siblings were normal. The oxygen affinity of her blood was markedly increased: under physiological conditions (pH 7.40, 37°C). P50 was 12.8 mm Hg (normal = 26.5 mm Hg). The red cell 2,3-diphosphoglycerate (2.3-DPG) level was normal. The abnormal hemoglobin could not be separated from hemoglobin A by zone electrophoresis at pH 8.6 or isoelectric focusing on polyacrylamide gel. However, after the hemoglobin was split into free α and β chains by treatment with p-hydroxymercuribenzoate (PMB) or 6 M urea, an abnormal β chain was readily demonstrated having a higher isoelectric point (more positive net charge) than normal βA. Structural analysis of the variant β chain demonstrated the substitution of histidine for tyrosine at position 145: hemoglobin Bethesda (α2β2145His). From earlier chemical and crystallographic studies, it has been postulated that this residue is a critical determinant of hemoglobin function. Hemoglobin Bethesda was separated from hemoglobin A by column chromatography. Oxygen equilibria of purified hemoglobin Bethesda revealed an extremely high oxygen affinity (exceeding that of isolated α and β chains), and markedly reduced cooperativity. The Bohr effect of hemoglobin Bethesda was 1/3 that of hemoglobin A. However, hemoglobin Bethesda showed a significant interaction with 2.3-DPG and inositol hexaphosphate.
H. Franklin Bunn, Thomas B. Bradley, William E. Davis, James W. Drysdale, John F. Burke, William S. Beck, Myron B. Laver
The effects of CCl4 on albumin synthesis were studied employing the isolated perfused liver. Carbonate-14C was used to measure newly synthesized albumin. 2.5 ml of CCl4 was administered by stomach tube 2 hr before perfusion. Albumin synthesis decreased from 36 to 5 mg following the ingestion of CCl4. Preperfusing the livers for 1 hr before measuring albumin synthesis resulted in an increase to 12 mg, and the addition of tryptophan to a final concentration of 10 mM resulted in a further increase to 19 mg. Cortisone did not protect against the toxic effects of CCl4 when administered to the donor rabbits. Fasting resulted in an increased sensitivity to CCl4 and an antioxidant was not effective in protecting against the toxic manifestations of CCl4.
Marcus A. Rothschild, Murray Oratz, Sidney S. Schreiber
In 10 patients with severe, acute respiratory failure we studied the effects of positive end-expiratory pressure when intermittent positive pressure ventilation (IPPV) with inspired oxygen (FIO2) up to 0.5 failed to maintain arterial oxygen tension (PaO2) above 70 torr.
Konrad J. Falke, Henning Pontoppidan, Anil Kumar, David E. Leith, Bennie Geffin, Myron B. Laver
Arterial-venous concentration differences for individual free fatty acids (FFA) were measured across the deep tissues of the forearm, the splanchnic vascular bed, and the kidney in healthy, postabsorptive subjects. In addition, arterial-portal venous FFA differences were determined in five patients undergoing elective cholecystectomy.
Lars Hagenfeldt, John Wahren, Bengt Pernow, Lars Räf
21 patients with Paget's disease of bone and one with osteoporosis were studied to detect development of antibodies to salmon calcitonin during chronic therapy. Antibody titers ranged from 1:40 to 1:30,000 in plasma obtained after treatment of 11 patients. Radio-immunoelectrophoresis revealed that the antibodies were restricted to the γG class. One patient, W. O., with Paget's disease initially responded to treatment with a decrease in bone turnover, but later became resistant to the hormone in association with the appearance of a very high titer (1:30,000) of antibody against salmon calcitonin. A 1:10 dilution of his plasma was shown to completely inactivate 20 mMRC units/ml of salmon calcitonin as detected by bioassay in rats; slight inactivation was detected at a 1:200 dilution. All other patients continued to respond to salmon calcitonin despite the development of antibody to the hormone in ten cases. No evidence of systemic allergic reactions or other toxicity was found in any patient. The data suggest that although antibody formation may occur in as many as 50% of patients treated with salmon calcitonin, this antibody response is unlikely to be of clinical significance in most patients. However, in an occasional patient, a marked antibody response may occur which interferes with the therapeutic use of the hormone.
Frederick R. Singer, J. Phillip Aldred, Robert M. Neer, Stephen M. Krane, John T. Potts, Kurt J. Bloch
The catabolism of Tay-Sachs ganglioside, N-acetylgalactosaminyl- (N-acetylneuraminosyl) -galactosylglucosylceramide, has been studied in lysosomal preparations from normal human brain and brain obtained at biopsy from Tay-Sachs patients. Utilizing Tay-Sachs ganglioside labeled with 14C in the N-acetylgalactosaminyl portion or 3H in the N-acetylneuraminosyl portion, the catabolism of Tay-Sachs ganglioside may be initiated by either the removal of the molecule of N-acetylgalactosamine or N-acetylneuraminic acid. The activity of the N-acetylgalactosamine-cleaving enzyme (hexosaminidase) is drastically diminished in such preparations from Tay-Sachs brain whereas the activity of the N-acetylneuraminic acid-cleaving enzyme (neuraminidase) is at a normal level. Total hexosaminidase activity as measured with an artificial fluorogenic substrate is increased in tissues obtained from patients with the B variant form of Tay-Sachs disease and it is virtually absent in the O-variant patients. The addition of purified neuraminidase and various purified hexosaminidases exerted only a minimal synergistic effect on the hydrolysis of Tay-Sachs ganglioside in the lysosomal preparations from the control or patient with the O variant of Tay-Sachs disease.
John F. Tallman, William G. Johnson, Roscoe O. Brady
The effect of 20 L-amino acids upon pancreatic glucagon secretion has been studied in conscious dogs. Each amino acid was administered intravenously over a 15 min period in a dose of 1 mmole/kg of body weight to a group of four or five dogs. Pancreatic glucagon and insulin were measured by radioimmunoassay. 17 of the 20 amino acids caused a substantial increase in plasma glucagon. Asparagine had the most glucagon-stimulating activity (GSA), followed by glycine, phenylalanine, serine, aspartate, cysteine, tryptophan, alanine, glutamate, threonine, glutamine, arginine, ornithine, proline, methionine, lysine, and histidine. Only valine, leucine, and isoleucine failed to stimulate glucagon secretion, and isoleucine may have reduced it. No relationship between glucagon-stimulating activity and insulin-stimulating activity was observed. The amino acids which enter the gluconeogenic pathway as pyruvate and, which are believed to provide most of the amino acid-derived glucose, had a significantly greater GSA than the amino acids which enter as succinyl CoA or as α-ketoglutarate. However, pyruvate itself did not stimulate glucagon secretion. The R-chain structure of the amino acid did not appear to be related to its GSA, except that the aliphatic branched chain amino acids, valine, leucine, and isoleucine, were devoid of GSA.
Dalva Marreiro Rocha, Gerald R. Faloona, Roger H. Unger
Parathyroid hormone increased basal adenyl cyclase activity and that increase was inhibited by prostaglandin E1 (PGE1). Tissue cyclic 3′,5′-adenosine monophosphate (cyclic AMP) concentrations were increased by parathyroid hormone and that increase was likewise inhibited by PGE1. Both parathyroid hormone and dibutyryl cyclic AMP increased 32P incorporation into renal cortical phospholipids. PGE1 diminished the effect of parathyroid hormone but not dibutyryl cyclic AMP to influence that parameter. PGE1 likewise modulated the effect of parathyroid hormone but not dibutyryl cyclic AMP to decrease fractional phosphate reabsorption by the renal tubule. It is suggested that PGE1 inhibits the effect of parathyroid hormone by decreasing its effect on adenyl cyclase. Such interaction may be important in modulating the intracellular action of parathyroid hormone on kidney cortex.
Nama P. Beck, Frederick R. DeRubertis, Michael F. Michelis, Robert D. Fusco, James B. Field, Bernard B. Davis
Postabsorptive release of alanine from forearm skeletal muscle is large relative to other amino acids, suggesting new synthesis by transamination of pyruvate. This hypothesis was tested and the pathway quantified in six subjects, each given two 30 min intrabrachial arterial pyruvate infusions. The first (12 μmoles/min) supplied approximately that amount of pyruvate produced endogenously by glycolysis in resting muscle. The second (36 μmoles/min) approximated endogenous pyruvate production by glycolysis during moderate exercise. Changes in balance across forearm tissues of pyruvate, glucose, lactate, and amino acids were measured. The time-course of pyruvate equilibration across fore-arm muscles was detailed in three additional subjects.
Thomas Pozefsky, Robert G. Tancredi
Renal hemodynamics and tubular fractional sodium reabsorption (FSR) were evaluated by clearance techniques during acute and chronic extracellular volume expansion in man. (1 − V/GFR) × 100 was used as an index of proximal and (CH2O/V) × 100 as an estimate of distal fractional reabsorption. After acute loading with isotonic saline 37 ml/kg body wt, proximal FSR decreased by 4.8% and distal FSR decreased by 4.4%. After comparable chronic expansion by mineralocorticoids (“escape”), proximal FSR also decreased by 3.9%, but distal reabsorption was not altered.
Edward A. Alexander, David W. Doner Jr., R. Brewer Auld, Norman G. Levinsky
A presumably spontaneous mutation has resulted in the formation of Hemoglobin (Hb) Istanbul in which glutamine is substituted for histidine in the proximal position of the β-chain (F8(92)). The anemia and other physiological effects that occur in the presence of Hb Istanbul were much ameliorated by splenectomy. Hb Istanbul is a relatively unstable molecule which produces a rather moderate case of “unstable hemoglobin hemolytic anemia.”
M. Aksoy, S. Erdem, G. D. Efremov, J. B. Wilson, T. H. J. Huisman, W. A. Schroeder, J. R. Shelton, J. B. Shelton, O. N. Ulitin, A. Müftüoğlu
The influence of plasma free fatty acid (FFA) concentration on the secretion of human growth hormone (HGH) was investigated. (a) FFA depression was produced by means of a nicotinic acid (NA) infusion for either 1 or 5 hr in the presence of glucose-induced hyperglycemia. Controls received only saline. (b) FFA depression was also produced by a 90 min NA infusion and then rapid FFA elevation by a lipid-plus-heparin (lipid) infusion. This procedure was compared with a similar NA infusion not followed by lipid. (c) FFA elevation was produced either by a lipid or by a norepinephrine (NE) infusion and then HGH secretion was stimulated by insulin-induced hypoglycemia. Each subject in this group received both the lipid and the NE infusion on seperate days as well as two control tests (insulin alone and NE alone).
Hans-Jürgen Quabbe, Hans-Jürgen Bratzke, Ulrike Siegers, Kadip Elban
Phagocytic vesicles were isolated from rabbit alveolar macrophages and guinea pig polymorphonuclear leukocytes that had ingested emulsified paraffin oil. Phospholipids and their fatty acids were determined in whole cells and in the phagocytic vesicle and pellet fractions separated from them. The cholesterol-to-phospholipid ratios in the vesicle fractions were distinctly higher than those of the respective whole cells or pellet fractions. The vesicle fractions also had higher phospholipid-to-protein ratios than did the whole cells. The phospholipids of the phagocytic vesicle fraction from macrophages contained relatively more sphingomyelin, lyso-(bis)phosphatidic acid, and phosphatidylserine and less lecithin, phosphatidylethanolamine, and phosphatidylinositol than did the whole cells or pellet fractions. The phospholipids of phagocytic vesicles from polymorphonuclear leukocytes contained significantly more phosphatidylinositol than did the pellet fractions. Lyso(bis)phosphatidic acid, which constituted 15% of the phospholipid in rabbit alveolar macrophages and 25% of that in their phagocytic vesicles, contained almost 60% oleic acid and 20% linoleic acid. This lipid was not detected in rabbit peritoneal macrophages or in rat alveolar macrophages.
Robert J. Mason, Thomas P. Stossel, Martha Vaughan
In the present studies, the effect of ampicillin (40 mg intramuscularly twice a day) in combination with water diuresis, produced by the ingestion of 5% dextrose in water, was determined on renal titers of enterococci after intravenous inoculation of 4 × 108-2 × 109 enterococci into rats.
Sandra P. Levison, Donald Kaye
The permeability of the proximal and distal rabbit intestine for two to six carbon polyhydric alcohols was compared. Intestinal segments were mounted in chambers that permitted the measurement of the unidirectional flux across the brush border membrane. For both proximal and distal intestine, the permeability for a series of polyhydric alcohols decreased with increasing size. The proximal intestine was more permeable for four, five, and six carbon polyhydric alcohols than distal intestine. This regional permeability difference can be attributed to variations in the permeability characteristics of the brush border specifically. The uptake of alcohols was nonsaturable and was not inhibited by phlorizine or n-ethylmaleimide. The results are compatible with the concept that the brush border membrane has properties similar to artificial porous membranes and that the equivalent radius of the pores of the proximal intestine exceeds that of the distal gut.
Allan Ross, Allen W. Rubin, Julius J. Deren
50 Caucasian children with acute lymphocytic leukemia (ALL) and 219 members of their families have been genotyped for 15 antigens of the HL-A system. The antigen and gene frequencies for HL-A2 were significantly higher in the patient population than in a 200 member normal Caucasian panel. No other antigen frequencies were significantly elevated. All antigens typed for were found in the patients. No antigen gain or loss was detected in the leukemic cells.
G. Nicholas Rogentine Jr., R. A. Yankee, J. J. Gart, J. Nam, R. J. Trapani
Long-term clinical studies have associated tolbutamide therapy with an increased incidence of cardiovascular deaths. The effects of this and other sulfonylurea drugs on contractility and rate of isolated rabbit atria, automaticity of isolated dog Purkinje fibers, and adenyl cyclase activity in particulate preparations of rabbit and human hearts were studied. At concentrations that are attained clinically, tolbutamide (10 mg/100 ml) increased contractility of driven rabbit atria to 124±5% of control, acetohexamide (3.9 mg/100 ml) to 140±5%, chlorpropamide (8.3 mg/100 ml) to 139±6%, and tolazamide (3.1 mg/100 ml) to 119±6%. These effects were accentuated in the presence of 2.5 × 10-4 M theophylline and were not blocked by 1 × 10-5 M propranolol. Adenyl cyclase was activated by each of these drugs at concentrations below those which increase contractility. The drugs also increased the rate and slope of phase 4 depolarization in spontaneously beating Purkinje fibers, but did not alter the spontaneous rate of isolated rabbit atria. Since inotropic and chronotropic stimulation can be deleterious in some clinical settings, these findings may be of significance in interpretation of cardiovascular mortality data.
Kenneth C. Lasseter, Gerald S. Levey, Roger F. Palmer, Jeane S. McCarthy
Muscle pieces from 11 patients with dermatomyositis or polymyositis were incubated with autologous peripheral blood lymphocytes and the supernates examined for the production of lymphotoxin, a mediator of delayed hypersensitivity, using human fetal muscle monolayers as the target cell. In the case of all 10 active patients, production of lymphotoxin was demonstrated. This mediator was also demonstrated when muscle alone was incubated from two patients with extensive cellular infiltration. Lymphotoxic activity was not found in supernates obtained by incubation of muscle from nine control subjects with their autologous peripheral blood lymphocytes.
Robert L. Johnson, Chester W. Fink, Morris Ziff
After the simultaneous intravenous administration of unconjugated bilirubin-3H and δ-aminolevulinic acid-4-14C, the plasma disappearance curves of unconjugated bilirubin-3H and the plasma appearance curves of biosynthesized unconjugated bilirubin-14C have been defined in seven patients, three of whom had acute intermittent porphyria (AIP). The incorporation of 14C into plasma unconjugated bilirubin, derived by an analysis which involves deconvolution of the two plasma curves, varied between 13.1 and 23.5% (mean 19.3%) of the injected dose in the nonporphyric patients and between 5.4 and 13.6% (mean 8.3%) of the injected dose in the porphyric patients. In five of the patients, the stercobilin-14C specific activity in a pooled specimen of feces was measured, enabling the following further values to be calculated: (a) the total 14C radioactivity incorporated into bilirubin (21.0 and 25.3% [mean 23.2%] of the injected dose in two of the nonporphyric patients and between 8.5 and 25.3% [mean 14.2%] of the injected dose in the porphyric patients), and (b) the proportion of hepatic synthesized bilirubin delivered directly to plasma in the unconjugated form (between 0.520 and 0.904; mean for nonporphyric patients 0.712; mean for porphyric patients 0.614). The results demonstrate that a large proportion of bilirubin derived from hepatic hemes passes through the plasma in the unconjugated form before conjugation and secretion into bile.
E. A. Jones, R. Shrager, J. R. Bloomer, P. D. Berk, R. B. Howe, N. I. Berlin
Hypoxia has been found to depress the concentration response curve of norepinephrine (NE) in isoalted cat papillary muscles. To investigate the effects of hypoxia in intact hearts, a heart-lung preparation was developed and maximum left ventricular dp/dt (max dp/dt) was measured at constant heart rate, preload, and after load. Left main coronary arterial flow (Qe) was measured with an electromagnetic flow probe. As arterial PO2 decreased from 90 mm Hg (96% saturation) to 20-25 mm Hg (40% saturation) at constant PCO2 and pH, no change in max dp/dt occurred and Qe increased 298%. In contrast to cat papillary muscles, the contractile responses to NE were augmented in hypoxia. The NE dose-response curves shifted to the left. No deterioration of contractility occurred after exposure to NE. In contrast, the chronotropic response was unaltered in hypoxia. Dose-response curves to isoproterenol also were shifted to the left in hypoxia, but responses to paired pacing were unchanged. The responses to NE under oxygenated conditions were unaltered by mechanically increased coronary flow or by increased coronary flow with nitroglycerin. Although the mechanisms responsible for these effects are unknown, the results suggest that hypoxia may open previously nonfunctioning vascular channels and thereby allow more extensive exposure of beta adrenergic receptors to circulating catecholamines.
Kenneth M. Kent, Stephen E. Epstein, Theodore Cooper
Calcium, but not other divalent cations, is required for optimal uptake of intrinsic factor-bound 57Co-labeled cyanocobalamin (IFB12) by microvillous membranes isolated from hamster ileal-absorptive cells. Chelation of divalent cations by disodium ethylenediaminetetraacetate (EDTA) promptly removes IFB12 previously attached to microvillous membranes. High concentrations of CaCl2 or MgCl2 also markedly inhibit membrane uptake of IFB12 and rapidly remove previously attached IFB12. Similarly, reduction of pH to below 5.4 prevents membrane attachment of IFB12 and removes virtually all IFB12 already bound to microvillous membranes. The effects of calcium depletion, increased salt concentrations, and acidification on membrane uptake of IFB12 were completely reversible. These findings are consistent with the concept that the formation of calcium salt bridges is essential for attachment of IFB12 to the ileal-absorptive surface.
Iain L. Mackenzie, Robert M. Donaldson Jr.
To investigate the interaction of lipoproteins with semipermeable membranes, solutions of low density lipoproteins (LDL), very low density lipoproteins (VLDL), mixtures of the two, and diluted, normal, and hyperlipidemic serum were ultrafiltered through a synthetic membrane (500 A nominal pore diameter) using a stirred laboratory ultrafiltration cell. The pressure dependence of ultrafiltrate flux showed that a concentrated layer of lipoproteins was built up at the membrane surface (concentration polarization) and that VLDL was more subject to polarization than LDL. This phenomenon controlled the observed lipoprotein transport behavior. Whereas true membrane rejection (the fraction of the solute on the membrane surface which does not pass through the membrane) was greater than 0.95 for both LDL and VLDL, observed solute rejection varied from nearly 0 to 1.0, depending upon experimental conditions.
Clark K. Colton, Sigmund Friedman, Dana E. Wilson, Robert S. Lees
Conjugates of bilirubin were studied in normal bile of man and rat, and in bile of liver patients. In general human bile was obtained by duodenal intubation. In addition T-tube bile was examined in patients operated on for mechanical obstruction. The bile pigment compositions of duodenal and T-tube bile were similar in two patients where comparison was possible. Obstruction of the bile duct in rats was used as an animal model for obstructive jaundice.
J. Fevery, B. Van Damme, R. Michiels, J. De Groote, K. P. M. Heirwegh
6-n-propylthiouracil (PTU) administered to male Sprague-Dawley rats maintained on 2 and 5 μg L-thyroxine (T4)/100 g body weight resulted in a marked reduction in the rate of conversion of L-thyroxine to L-triiodothyronine (T3). These effects could not be ascribed to induced hypothyroidism since the group maintained on 5 μg T4/day had normal levels of liver mitochondrial alpha glycerophosphate dehydrogenase. In confirmation of previous studies, PTU also reduced the fractional rate of deiodination of T3. These observations provide a possible explanation of the many published observations indicating that PTU antagonizes the tissue effects of T4 but not of T3. The data suggest that monodeiodination of T4 but not of T3 is essential before hormonal effects can be manifested at the cellular level.
Jack H. Oppenheimer, Harold L. Schwartz, Martin I. Surks
Thyroidectomized and euthyroid rats were injected with three doses of triiodothyronine (T3) or of the diluent over a 6 day period, and liver homogenates were assayed for basal, epinephrine-stimulated, and NaF-stimulated adenyl cyclase activity. Based on NaF-stimulated levels, total adenyl cyclase activity, expressed per milligram of liver protein, was increased after thyroidectomy. Administration of T3 to either hypothyroid or euthyroid rats, however, had no effect on the NaF-stimulated levels. Basal and epinephrine-stimulated enzyme activities were the same in hypothyroid, euthyroid, and hyperthyroid (euthyroid + T3) liver homogenates. In contrast, injections of T3 in hypothyroid rats increased the activities of basal and epinephrine-stimulated adenyl cyclase. In view of the findings in euthyroid and hyperthyroid liver, it is possible that this effect is transient. In general, no correlation was found between the effects of thyroid hormone on respiration and on adenyl cyclase activity of the rat liver. These results imply that the hepatic thermogenic response to thyroid hormone is not mediated by stimulation of adenyl cyclase activity with the possible exception of the early effects of T3 in the athyroid rat.
Judith K. Jones, Faramarz Ismail-Beigi, Isidore S. Edelman
Isolated renal tubules from vitamin D-deficient chicks catalyse the in vitro conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol. This conversion is stimulated by 5 × 10-10 M bovine parathyroid hormone, or by 10-6 M cyclic AMP. It is inhibited by 10-9 M porcine calcitonin. It is concluded that these hormonal controls of the synthesis of the renal hormone 1,25-dihydroxycholecalciferol are of particular physiological significance in coordinating the activities of the various organs involved in extracellular calcium homeostasis.
Howard Rasmussen, Mitzi Wong, Daniel Bikle, David B. P. Goodman