Abstracts

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Abstract

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The Roles of IgG, IgM Rheumatoid Factor, and their Complexes in the Induction of Polymorphonuclear Leukocyte Chemotactic Factor from Complement

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The induction of chemotactic factor by rheumatoid factor (RF) and by rheumatoid complexes and their constituents was investigated. The presence of chemotactic factor was measured by the number of polymorphonuclear leukocytes (obtained from normal individuals) attracted through a 3 μm Millipore filter and is expressed as a “chemotactic index.” The chemotactic index was used to measure the effect of immunoglobulins and their complexes in stimulating production of complement-derived chemotactic factors from the sera of normal individuals.

Authors

Teresa Wagner, George Abraham, John Baum

Evidence for a Role of the Microtubular System in the Secretion of Newly Synthesized Albumin and Other Proteins by the Liver

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Livers of normal mice were prefused in situ and the secretion of newly synthesized (i.e. labeled) proteins into the perfusate were measured. In control livers, the secretion of newly synthesized proteins was found to be linear with time. In marked contrast, when livers were perfused with vinblastine, vincristine, or colchicine, drugs known to interfere with the hepatic microtubular system, the release of newly synthesized proteins was either strongly inhibited or completely suppressed although total hepatic protein synthesis (estimated by the incorporation of labeled amino acids into hepatic plus perfusate proteins) remained unaltered. Chromatographic separation of the various secreted proteins showed that the release of albumin, globulins, and small polypeptides was decreased to a similar extent by vincristine or colchicine. In the particular case of albumin, it was further observed that total (i.e. liver plus perfusate) labeled amino acid incorporation into albumin was not altered by either vincristine or colchicine, whereas the incorporation of these amino acids into liver albumin was markedly increased but incorporation into perfusate albumin was decreased, suggesting that the translocation of this particular protein from the liver to the perfusate had been affected by the presence of these drugs. It is proposed that the functional integrity of microtubules is necessary for the intracellular movement and eventual release of albumin and other proteins by the liver, and suggested that microtubules might possibly be a site of regulation of hepatic protein secretion.

Authors

Yannick Le Marchand, Christoph Patzelt, Françoise Assimacopoulos-Jeannet, Ernest G. Loten, Bernard Jeanrenaud

Evidence for Different Gestation-Dependent Effects of Cortisol on Cultured Fetal Lung Cells

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The effect of cortisol (5.5 μM) on primary monolayer cultures of trypsin-dispersed lung cells from rabbit fetuses of 20-28 days gestation was monitored with respect to (a) cellular growth as determined by DNA content after 72 h, at which time all cultures were in the exponential phase of growth, and (b) cellular maturation as reflected by the incorporation of [14C]-palmitate into saturated lecithin and its release into the culture medium.

Authors

Barry T. Smith, John S. Torday, C. J. P. Giroud

Storage Iron Kinetics. VII. A BIOLOGIC MODEL FOR RETICULOENDOTHELIAL IRON TRANSPORT

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The processing of erythrocyte iron by the reticuloendothelial cell has been characterized by kinetic measurements of blood radioactivity made after the intravenous injection of heat-damaged erythrocytes labeled with 59Fe and of transferrin-bound 55Fe. The early reticuloendothelial release of iron, a matter of hours, was calculated from the plasma turnover rate of 55Fe and the plasma reappearance of 59Fe. Late release was calculated from the ratio of the cumulative incorporation of both tracers into the circulating red cell mass over a period of 2 wk. There was an initial processing period within the reticuloendothelial cell, after which radioiron either rapidly returned to circulation (t½ 34 min) or was transferred to a slowly exchanging pool of storage iron within the reticuloendothelial cell (t½ release to plasma of 7 days). These pathways were of equal magnitude in the normal dog. Reticuloendothelial release of iron was largely independent of the pre-existing plasma iron level or transferrin saturation. Diurnal fluctuations in the plasma iron level were shown to be the result of a variable partitioning of iron between the early and late release phases. Acute inflammation resulted in a prompt and marked increase in the fraction of iron stored (late phase), whereas depletion of iron stores resulted in a marked increase in early release.

Authors

Georges Fillet, James D. Cook, Clement A. Finch

Effects of Anti-Human Neutrophil Antibodies In Vitro. QUANTITATIVE STUDIES

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Opsonic, antiphagocytic, cytotoxic, and metabolic effects of homologous and heterologous antibodies against human neutrophils were analyzed by means of quantitative assays to facilitate detection of antibody activity, and to probe membrane function of these cells. Normal human neutrophils were purified by gradient centrifugation, sensitized with heat-inactivated antineutrophil antisera, and incubated with rabbit alveolar macrophages in balanced salt solution containing nitroblue tetrazolium. The macrophages engulfed sensitized neutrophils and reduced nitroblue tetrazolium to formazan in phagocytic vacuoles. The initial rate of nitroblue tetrazolium reduction by macrophages ingesting the neutrophils was measured spectrophotometrically. Neutrophils treated with rabbit anti-human leukocyte antiserum or IgG, with sera from mothers of infants with neonatal isoimmune neutropenia, and with 27% of sera from frequently transfused patients promoted rapid rates of nitroblue tetrazolium reduction by alveolar macrophages. This indicates that antineutrophil antibodies without added complement opsonized neutrophils for ingestion by the macrophages. Some sera from frequently transfused patients with opsonic activity for certain donors' neutrophils did not agglutinate these neutrophils (44%), did not lyse them in the presence of fresh plasma (47%), and did not inhibit phagocytosis of particles by the neutrophils (26%). The reverse was not observed. The opsonic activity of antineutrophil antiserum appears to be the most sensitive and a quantitative means of detecting antibody activity in vitro.

Authors

Laurence A. Boxer, Thomas P. Stossel

Studies on the Mechanism of Oliguria in a Model of Unilateral Acute Renal Failure

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To further evaluate the mechanism of the oliguria of acute renal failure, a model was utilized in which intense and prolonged vasoconstriction produced the unilateral cessation of urine flow. The radioactive microsphere method was used to measure total and regional blood flow before and after the intrarenal infusion of norepinephrine, 0.75 μg/kg/min, for 2 h in the dog. In the control kidney, renal blood flow increased 32% 48 h after norepinephrine in association with a fall in the fractional distribution of flow to the outer cortex. In the experimental kidney, total renal blood flow fell from 190 ml/min before norepinephrine to 116 ml/min at 48 h (P < 0.025) with a uniform reduction in cortical blood flow. After the administration of 10% body wt Ringer's solution, there was a marked redistribution of flow to inner cortical nephrons in both the control and experimental kidney. In addition, there was a marked increase in total blood flow in both kidneys. On the experimental side, flow rose to 235 ml/min, a value greater than in either the control period (P < 0.05) or at 48 h after norepinephrine (P < 0.001). However, in spite of this marked increase in blood flow, there was essentially no urine flow from the experimental kidney. In separate studies, the animals were prepared for micropuncture. In all studies, the surface tubules were collapsed, and there was no evidence of tubular obstruction or leakage of filtrate. Over 99% of the 15-μM spheres were extracted in one pass through the experimental kidney. An analysis of the forces affecting filtration suggested that an alteration in the ultrafiltration coefficient may be responsible, at least in part, for the anuria in this model. In this regard, transmission and scanning electron microscopy revealed a marked abnormality in the epithelial structure of the glomerulus. It is suggested that a decrease in glomerular capillary permeability may be present in this model of acute renal failure.

Authors

John W. Cox, Richard W. Baehler, Hari Sharma, Thomas O'Dorisio, Richard W. Osgood, Jay H. Stein, Thomas F. Ferris

The Presence of a Natriuretic Factor in Urine of Patients with Chronic Uremia. THE ABSENCE OF THE FACTOR IN NEPHROTIC UREMIC PATIENTS

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A gel filtration fraction of serum from chronically uremic patients has been shown previously to produce natriuresis in the rat. In the present studies, the same fraction from urine of uremic patients and normal subjects was studied for its natriuretic activity. Urine samples were obtained from 17 chronically uremic patients (mean glomerular filtration rate [GFR], 8.7 ml/min; mean fractional sodium excretion [FENa], 5.7%), and 14 normal subjects. The fraction from the uremic patients produced a significant increase in absolute sodium excretion (UNaV) and FENa; the fraction from normal subjects had no statistically significant effect on either UNaV or FENa; and the difference between the response to the uremic vs. normal fractions was highly significant for both parameters of sodium excretion. When a more concentrated urine fraction from uremic patients was administered, a striking natriuresis was observed with values for FENa rising to levels as high as 12%. Studies also were performed on eight patients with far advanced chronic renal insufficiency and the nephrotic syndrome. The serum fraction was studied in each of these patients and the urine fraction in three. For the group, UNaV in the assay rats decreased by 0.87 μeq/min and FENa decreased by 1.35% after infusion of the serum fraction. These results differ significantly from those of patients with chronic uremia without the nephrotic syndrome. The data are consistent with the view that the increased activity of the natriuretic factor in the serum of chronically uremic patients is not due to failure of excretion; rather it relates either to an increased rate of production and/or a decreased rate of degradation. The data also show that the inhibitor is detectable when FENa is increased, but not when uremia is associated with a sodium-retaining state.

Authors

Jacques J. Bourgoignie, Kuo Hwa Hwang, Ebrahim Ipakchi, Neal S. Bricker

The Effects of the Natriuretic Factor from Uremic Urine on Sodium Transport, Water and Electrolyte Content, and Pyruvate Oxidation by the Isolated Toad Bladder

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The urine of patients with chronic uremia contains a gel filtration fraction that is natriuretic in the rat. The effects of this fraction on the isolated urinary bladder of the toad were examined in the present studies. When added to the serosal surface of the bladder, a significant and substantial fall in short-circuit current and potential difference was observed. The changes began after a lag period of at least 10 min and continued over a period of 60 min. The decrease in short-circuit current at the end of 1 h averaged 44%. The same fraction from the urine of normal subjects produced no significant change in either short-circuit current or potential difference. When the isolated epithelial cells from the toad bladder were incubated in the presence of the inhibitor, intracellular sodium content increased significantly. There was no change in intracellular water content; hence the intracellular concentration of sodium increased by a mean of 7 meq/liter. The changes in intracellular potassium content and concentration were not satistically significant. When the isolated epithelia were incubated with the uremic factor, there was also a significant decrease in pyruvate utilization in relation to cells from paired hemibladders incubated in the absence of the fraction. The fraction from normal subjects produced no change in either intracellular sodium content or pyruvate oxidation.

Authors

Michael A. Kaplan, Jacques J. Bourgoignie, Jeffrey Rosecan, Neal S. Bricker

Metabolic Studies of the Third Component of Complement and the Glycine-Rich Beta Glycoprotein in Patients with Hypocomplementemia

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Metabolic studies using radioiodine-labeled third component of complement (C3) and the glycine-rich β glycoprotein (GBG), a major component of the C3b-feedback pathway, were undertaken in normal subjects, in 22 patients with evidence of complement activation, and in 11 patients with various renal diseases without evidence of complement activation. In seven normal subjects GBG was found to be a rapidly metabolized protein with catabolic rates ranging from 1.7% to 2.2% of the plasma pool/h, synthesis rates from 0.14 to 0.21 mg/kg per h. and extravascular/intravascular distribution ratios from 0.81 to 1.31. In patients with reduced plasma C3, both increased C3 fractional catabolic rates and reduced C3 synthesis rates were observed, and in some patients there was evidence of increased extravascular distribution of the protein. GBG catabolism was usually increased when there was evidence of C3 activation, presumably reflecting activation of the C3b-feedback; but GBG turnover was normal or only slightly accelerated in some patients with accelerated C3 catabolism and profound hypocomplementemia, suggesting that reduced C3 synthesis had limited activation of the C3b-feedback.

Authors

J. A. Charlesworth, D. Gwyn Williams, E. Sherington, P. J. Lachmann, D. K. Peters

Hypothalamic-Pituitary Function in Diverse Hyperprolactinemic States

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Prolactin secretion in normal adults is characterized by periods of episodic secretion which increase in magnitude during sleep. In this study, we report the 24-h mean prolactin concentrations, prolactin secretory patterns, and associated pituitary hormone function in nine patients (seven women and two men) with hyperprolactinemia of diverse etiologies. Four of the women and one of the men had clinically demonstrable pituitary tumors, one boy had a hypothalamic tumor, and the three other women had “functional” hyperprolactinemia. The 24-h mean prolactin concentrations derived from averaging the 20-min interval samples for 24 h ranged from 28.6 to 1,220 ng/ml. The plasma prolactin patterns in these patients showed persistence of episodic secretion in all and loss of the normal sleep-wake difference in plasma prolactin in seven of nine. Three of the patients with galactorrhea and comparable 24-h mean prolactin concentrations (58.3, 59.7, and 64.3 ng/ml) showed similar prolactin secretory patterns despite different etiologic mechanisms. Evaluation of the secretory patterns of luteinizing hormone (LH) in these patients showed loss of normal pulsatile LH release and a low 24-h mean LH concentration in the patient with the pituitary tumor, while the two patients without clinically demonstrable pituitary tumors (“post-pill” galactorrhea and “idiopathic” galactorrhea) showed normal LH secretory patterns and 24-h mean LH concentrations. The 24-h mean cortisol concentrations and secretory patterns were normal in five of the seven patients who had these parameters measured. The patient with the hypothalamic tumor had a low 24-h mean cortisol concentration and production rate and absent response to metyrapone. The patient with “idiopathic” galactorrhea had an elevated 24-h mean cortisol concentration but normal cortisol production rate and urinary 17-hydroxycorticoid excretion. Growth hormone secretion was abnormal in four of the patients (one with the hypothalamic tumor and three with pituitary tumors). Thyrotropin-releasing hormone (TRH) administration in four patients resulted in normal TSH release in two patients (one of whom developed galactorrhea after the test), an absent response in the patient with the hypothalamic tumor, and a blunted response in one of the women with a pituitary tumor. The two men had low 24-h mean plasma testosterone concentrations (69 and 30 ng/100 ml) and symptoms of impotence and loss of libido. Five of the women (four with pituitary tumors and one with Chiari-Frommel syndrome) had either low 24-h mean LH concentrations, abnormal LH secretory patterns, or both. These data indicate that patients with hyperprolactinemia encompassing a varied etiological range frequently show loss of the normal sleep-associated increase in prolactin secretion as well as abnormalities in the regulation of the other hypothalamic pituitary-regulated hormones. The finding that the abnormalities in LH, growth hormone, thyrotropin, and cortisol (adrenocorticotrophic) secretion were almost uniformly confined to the patients with the clinically demonstrable hypothalamic or pituitary tumors suggests that the size of the lesion is the critical factor.

Authors

R. M. Boyar, S. Kapen, J. W. Finkelstein, M. Perlow, J. F. Sassin, D. K. Fukushima, E. D. Weitzman, Leon Hellman

Coronary Hemodynamics and Regional Myocardial Metabolism in Experimental Aortic Insufficiency

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Acute aortic valvular insufficiency was induced in open chest dogs by employing a special intravascular cannula, or by rupturing an aortic valve leaflet. Phasic and mean coronary flow were assessed in some animals, while in others data were obtained on arterial and coronary sinus blood lactate, pyruvate, PO2, PCO2, and pH, and on myocardial tissue lactate, pyruvate, and water content in the outer and inner halves of the free wall of the left ventricle. Results showed that in acute aortic insufficiency diastolic coronary flow decreased as a function of aortic diastolic pressure, but systolic coronary flow increased in such proportion that mean coronary flow did not decrease. With moderate reductions in aortic diastolic pressure due to aortic insufficiency, myocardial blood flow was judged to be nutritionally adequate in both the outer and inner regions of the left ventricle. With more severe reductions in aortic diastolic pressure, the inner region exihibited biochemical signs of anaerobic metabolism. The presence of these metabolic changes could be correlated with either of two previously described pressure indexes. These findings suggest that the reduced coronary perfusion pressure and the intramyocardial tissue pressure gradient can be compensated for by autoregulation in some cases of aortic insufficiency, but in others such compensation may be incomplete, in which case oxygen delivery to the subendocardium will be inadequate to meet local tissue oxygen needs.

Authors

Douglas M. Griggs Jr., Chin Chi Chen

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

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An examination of the metabolic fate of the R and the S isomers of warfarin revealed that the two isomers were metabolized by different routes. R warfarin was oxidized to 6-hydroxywarfarin and was reduced to the (R,S) warfarin alcohol. In contrast, S warfarin was oxidized to 7-hydroxywarfarin and was reduced to the (S,S) warfarin alcohol. S warfarin was also oxidized to 6-hydroxywarfarin.

Authors

Richard J. Lewis, William F. Trager, Kenneth K. Chan, A. Breckenridge, M. Orme, Malcolm Roland, William Schary

Regional Myocardial Blood Flow in Awake Dogs

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The objectives of this study were to test the hypothesis in awake dogs that during control conditions endocardial vessels are maximally dilated and to determine whether variables introduced by general anesthesia and thoracotomy modify distribution of myocardial blood flow or impair capacity for augmentation of flow in response to a coronary vasodilator stimulus. Myocardial blood flow was measured in relatively small, 2-3 g, left ventricular epicardial and endocardial samples by using 7-10-μm radioisotope-labeled microspheres during control conditions and during infusion of adenosine in dosages which produced maximum increases in coronary blood flow. Measurements were made initially in awake resting animals and were repeated after pentobarbital anesthesia, thoracotomy, and pericardiotomy.

Authors

Frederick R. Cobb, Robert J. Bache, Joseph C. Greenfield Jr.

Incomplete Relaxation between Beats after Myocardial Hypoxia and Ischemia

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Recovery from hypoxia has been shown to prolong cardiac muscle contraction, particularly the relaxation phase. The present studies were designed to examine whether incomplete relaxation between beats can result from this prolongation of contraction and relaxation in isolated muscle after hypoxia and in the canine heart after both hypoxia and acute ischemia. The relationship between heart rate and the extent of incomplete relaxation is emphasized in view of the known enhancement of the velocity of contraction caused by increasing heart rate.

Authors

Myron L. Weisfeldt, Paul Armstrong, Hugh E. Scully, Charles A. Sanders, Willard M. Daggett

Abnormal Secretion of Insulin and Glucagon by the In Vitro Perfused Pancreas of the Genetically Diabetic Chinese Hamster

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Hereditary insulin-deficient diabetes mellitus occurs in certain sublines of nonobese Chinese hamsters. Several characteristics of this syndrome are similar to those seen in insulin-deficient human diabetics. Therefore, to characterize pancreatic islet function, dynamic insulin and glucagon release from normal and nonketotic diabetic hamster pancreases in response to glucose (300 mg/100 ml) and theophylline (10 mM), infused singly and together, was studied in vitro.

Authors

Barbara J. Frankel, John E. Gerich, Ryoko Hagura, Rudy E. Fanska, George C. Gerritsen, Gerold M. Grodsky

Human Platelet Collagenase

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The presence of proteolytic enzymes such as cathepsin and elastase in platelets and the important role of collagen in platelet aggregation suggested that collagenase might be present in platelets. Epinephrine, ADP, and collagen liberate collagenase from platelets in plasma as measured by the hydrolysis of [14C]glycine-labeled collagen fibrils. The collagenase activity appeared in an early phase of platelet aggregation and was not a part of the release reaction. However, only 50% of the total collagenase could be liberated by the aggregating agents used. Sucrose density gradient analysis of platelet homogenates using appropriate sub-cellular markers indicated that collagenase appeared in both the granule and membrane fractions. Gel-filtered platelets failed to show collagenase activity before exposure to aggregating agents but released more collagenolytic activity than was found in platelet-rich plasma. This observation was explained by the finding that collagenolytic activity was inhibited by normal human plasma. One of the inhibitors is α1-antitrypsin as demonstrated by decreased inhibition in plasma from a patient with homozygous α1-antitrypsin deficiency. Platelet collagenase activity could also be demonstrated by its ability to decrease the viscosity of collagen solutions and to produce collagen fragments similar to those produced by other mammalian collagenases on disk gel electrophoresis. The observation that partially purified platelet collagenase could destroy the platelet-aggregating activity of collagen suggests that the enzyme might function in a negative feedback mechanism limiting thrombus formation.

Authors

Carolyn McI. Chesney, Elvin Harper, Robert W. Colman

Reversal of Ouabain and Acetyl Strophanthidin Effects in Normal and Failing Cardiac Muscle by Specific Antibody

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Isolated cat right ventricular papillary muscles were used to study the effects of antibodies with high affinity for ouabain and acetyl strophanthidin on myocardium exposed to these cardioactive steroids. Antibodies with average intrinsic affinity constants for ouabain and acetyl strophanthidin of the order of 108 M-1 were raised in rabbits challenged by repeated injection of a conjugate of ouabain covalently linked to a poly D,L-alanyl derivative of human serum albumin. Effects were assessed in terms of time-course and extent of inotropy reversal, influence of experimentally induced ventricular failure, digitalis-antibody concentration relations, influence of digitalis-antibody complex on response to additionally added digitalis, and relation of antibody effects on digitalis-induced automaticity and contracture to reversal of inotropy. Specific antibody (but not control antibody) in 1.1-1.5-fold molar excess over cardioactive steroid concentrations blocked positive inotropic effects of ouabain and acetyl strophanthidin, and gradually reversed established contractile effects of these agents with a mean time for half-reversal of ouabain-induced inotropy of 124±6 (SEM) min and 37±3 min for half-reversal of acetyl strophanthidin-induced inotropy. Papillary muscles from cats with right ventricular failure induced by chronic pulmonary artery constriction responded similarly. Both normal and failing muscles returned to but not below levels of contractility existing before cardioactive steroid exposure, and time for half-reversal of inotropy by antibody was significantly shorter than time for half-reversal after removal of ouabain or acetyl strophanthidin by muscle bath washout alone. Presence of ouabain- or acetyl strophanthidin-antibody complex did not alter the myocardial contractile response to subsequently added cardioactive steroids.

Authors

Herman K. Gold, Thomas W. Smith

Biological Defense Mechanisms THE EFFECT OF BACTERIA AND SERUM ON SUPEROXIDE PRODUCTION BY GRANULOCYTES

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We previously reported that granulocytes are able to produce superoxide (O2-), a highly reactive compound formed by the one-electron reduction of oxygen. The demonstration of O2- production was based on the observation that the reduction of extra-cellular cytochrome c by granulocytes was greatly diminished by superoxide dismutase, an enzyme catalyzing the conversion of O2- to hydrogen peroxide and oxygen. In the present report, studies concerning the effect of bacteria and serum on O2--dependent cytochrome c reduction by granulocytes are described.

Authors

John T. Curnutte, Bernard M. Babior

Role of Sweat in Accumulation of Orally Administered Griseofulvin in Skin

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Griseofulvin, an orally effective antimicrobial agent, appears in the stratum corneum within 4-8 h after oral administration. Griseofulvin distribution was found to be highest in the outermost layers of the stratum corneum (level I, 20.8±1.5 ng/mg) and lowest inside (level II, 10.0±1.5; level III, 7.5±2.2 ng/mg). In order to study the precise mechanism of griseofulvin transfer to stratum corneum, the role of sweat in the accumulation of griseofulvin was considered. Heat-induced total body sweating decreased the mean stratum corneum concentration of griseofulvin by 55%, and 200-300 ng of griseofulvin accumulated per ml of sweat. A silicone hydrophobic resin was used to differentiate between “wash-off” and carrier properties of sweat for griseofulvin. Prevention of transepidermal water and sweat loss by (a) topical application of formaldehyde-releasing cream to one palm, (b) occlusion by a 2 × 2-cm patch on one arm, and (c) wearing a rubber glove for 24 h, showed a lower griseofulvin concentration when compared to control areas in the same subjects. The results of the gloved hand experiment show that a complete equilibrium is established at all three levels of stratum corneum, thereby removing the reversed gradient. These results support the hypothesis that a “wick effect” is responsible for the observed reversed drug gradient within the stratum corneum. The results of the experiments suggest that sweat and transepidermal fluid loss play an important role in griseofulvin transfer in stratum corneum.

Authors

Vinod P. Shah, William L. Epstein, Sidney Riegelman

Effects of Intravenous Administration of Slow-Reacting Substance of Anaphylaxis, Histamine, Bradykinin, and Prostaglandin F_2α on Pulmonary Mechanics in the Guinea Pig

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The effects of intravenous administration of a purified preparation of slow-reacting substance of anaphylaxis (SRS-A), histamine, bradykinin, and prostaglandin F2α (PGF2α) on the mechanics of respiration were assessed in the unanesthetized guinea pig. Geometrically increasing doses of SRS-A resulted in graded decreases in average pulmonary compliance, with only modest increases in average pulmonary resistance. A dose with apparent maximal effects. 3,000 U/kg, resulted in a decrease of 49±7% of compliance below control values, with an increase in resistance of 24±8% above control. Intravenous administration of geometrically increasing amounts of histamine, bradykinin, and prostaglandin F2α also resulted in decreased compliance; but in each case this was accompanied by a marked increase in respiratory resistance. A decrease of compliance of approximately 50%, induced by intravenous histamine, bradykinin, or PGF2α, was accompanied by an increase of 60-140% in resistance. Thus, intravenously administered SRS-A alters pulmonary mechanics with a more peripheral effect than any of the other agents tested.

Authors

Jeffrey M. Drazen, K. Frank Austen

Active and Passive Bile Acid Absorption in Man. PERFUSION STUDIES OF THE ILEUM AND JEJUNUM

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Absorption of the major human bile acids was studied in 12 healthy volunteers by steady state perfusion of the ileum in 112 experiments and of the jejunum in 48 experiments. Use of a randomized order of four perfusions on 1 day of study and use of up to 4 consecutive days of study in a subject allowed important comparisons of data from the same individuals. That there is active ileal absorption of chenodeoxycholic, glycochenodeoxycholic, and taurocholic acids in man was supported by the finding of saturation kinetics and of competition for absorption among conjugated bile acids. Values for apparent kinetic constants (apparent maximal transport velocity [*Vmax] and apparent Michaelis constant) in man are similar to those in other species. The ileum absorbed chenodeoxycholic acid more rapidly than its glycine conjugate, due mainly to a ninefold greater permeability for the free acid. Taurocholate had the highest *Vmax and was absorbed more rapidly than glycochenodeoxycholate. Passive permeability of the jejunum to bile acids was twice that of the ileum, and the permeabilities to free and glycine-conjugated chenodeoxycholate were in the same ratio as in the ileum (9: 1). Jejunal permeability to chenodeoxycholic acid was three times that to cholic acid. Variation of intraluminal pH by up to 1.4 units did not influence jejunal uptake of free bile acids. These results, which are comparable with those from animal experiments, provide a basis for estimation of intestinal reabsorption of bile acids in intact man.

Authors

Einar Krag, Sidney F. Phillips

Interference with Feedback Control of Glomerular Filtration Rate by Furosemide, Triflocin, and Cyanide

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Microperfusion experiments have shown that increases in flow rate of tubule fluid through the loop of Henle are followed by reductions in single nephron glomerular filtration rate (SNGFR) and stop-flow pressure (SFP) measured in the proximal tubule of the same nephron. Because changes in luminal sodium concentration are not consistently related to changes in SNGFR and SFP, we explored the possibility that a transport step at a flow-dependent distal-sensing site might be involved in feedback control of SNGFR. Because the macula densa cells of the distal tubule are adjacent to the glomerular vessels of the same nephrons, they could be the distal-sensing mechanism. We perfused superficial loops of Henle from late proximal to early distal segments in three groups of rats while measuring SFP in the proximal tubule of the same nephron, SNGFR in the proximal tubule of the same nephron, or flow rates of fluid, Na, K, and Cl emerging from the perfused loops. Perfusion solutions used were 0.15 NaCl, Ringer or Ringer with one of several inhibitors of electrolyte transport. Perfusion rates were 10 or 40 nl/min (also, zero during measurements of SFP and SNGFR). With Ringer alone the loop-flow rate increased from 10 to 40 nl/min, caused a decrease in SFP from 37.6 to 32.1 mm Hg, and a decrease in SNGFR from 29.9 to 18.7 nl/min. Concentrations of Na, K, and Cl in early distal fluid and absorption of Na and Cl along the loop segment were also increased when loop perfusion rate was increased. Decreasing the perfusion rate to zero had little effect on SFP or SNGFR. The SFP response to increased flow rate did not occur when the perfusion solution contained furosemide (10-4 M). No reduction of the SFP response was seen with other diuretics tested (amiloride, acetazolamide, ethacrynic acid, mercaptomerin) or with 0.15 M NaCl alone. The SNGFR response to increased perfusion rate was reduced by furosemide, triflocin, and cyanide but not by amiloride. Na and Cl absorption by the perfused segment were inhibited by furosemide, triflocin, cyanide, and amiloride. Amiloride and acetazolamide, probably do not act in the ascending limb. Ethacrynic acid and mercaptomerin are known to be ineffective in rat nephrons. Thus, agents that could have inhibited NaCl absorption by macula densa cells interfered with the feedback mechanism.

Authors

Fred S. Wright, Jürgen Schnermann

Effect of Maternal Intrahepatic Cholestasis on Fetal Steroid Metabolism

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Abstract

Estriol, estriol sulfate, progesterone, and 17 neutral steroid sulfates, including estriol precursors and progesterone metabolites, were determined in 27 cord plasma samples collected after pregnancies complicated by intrahepatic cholestasis of the mother. The levels of these steroids were compared with those in the cord plasma of 42 healthy controls.

Authors

Timo J. Laatikainen, Jari I. Peltonen, Pekka L. Nylander

Digitalis-Induced Increase in Aortic Regurgitation and the Contrasting Effects of Glucagon in the Sedated Dog

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The hemodynamic and phasic ascending aortic flow changes induced by acetylstrophanthidin and glucagon were studied in closed-chest sedated dogs with aortic regurgitation. While the positive inotropic effect of both agents was reflected in an increase in peak rate of rise of left ventricular pressure, acetylstrophanthidin increased aortic regurgitation, while glucagon decreased it. With the former, left ventricular end-diastolic pressure rose from 20±6 to 27±6 mm Hg (P < 0.005), but fell from 18±4 to 11±3 mm Hg (P < 0.001) with glucagon. Acetylstrophanthidin increased systemic vascular resistance, aortic diastolic pressure, and diastolic regurgitant flow rate, and, heart rate and the duration of regurgitation per beat and per minute being unchanged, regurgitant flow per beat increased 32±15% (P < 0.001). Glucagon decreased regurgitant flow per beat 27±14% (P < 0.001) because of abbreviation of diastole associated with tachycardia, and because of reduction in regurgitant flow rate. Despite tachycardia, the duration of regurgitation per minute was unchanged, and the small fall in regurgitant blood flow per minute was not significant, but this pertained in the face of 47% increase in effective cardiac output (P < 0.001). In contrast, acetylstrophanthidin increased regurgitant flow per minute 28±14% (P < 0.001) without change in effective cardiac output. The increase in cardiac contractility, tachycardia, and systemic vasodilatation induced by glucagon preferentially enhanced forward blood flow, which led to reduction in left ventricular volume overload, while it increased cardiac output. Contrarily, acetylstrophanthidin increased aortic regurgitation and, despite its inotropic effect, increased left ventricular volume overload without an increase in cardiac output.

Authors

Barry E. Hopkins, Roger R. Taylor

Immunochemical Localization of Parathyroid Hormone in Cancer Tissue from Patients with Ectopic Hyperparathyroidism

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Abstract

Immunoreactive parathyroid hormone (PTH) in nonparathyroid malignant tumors associated with hypercalcemia and hypophosphatemia in the absence of demonstrable bone metastases was determined by radioimmunoassay and immunofluorescent techniques. Six of seven tumors contained material with immunological cross-reactivity to bovine PTH by radioimmunoassay and immunofluorescence. The intensity of the immunofluorescent stain varied considerably in the different tumors. From 15 to 90% of neoplastic cells were stained specifically with fluorescein-labeled anti-PTH. In contrast, normal parathyroid glands and parathyroid adenomas showed uniform distribution of immunofluorescence in all parenchymal cells. In one malignant tumor, PTH was localized also by immunoautoradiography. In every case PTH was detected only in the cytoplasm of parenchymal cells. One patient lacked detectable PTH in his tumor, yet showed regression of the hypercalcemia to normal values after removal of large masses of neoplastic tissue and recurrence of hypercalcemia when new growth occurred.

Authors

Genaro M. A. Palmieri, Robert E. Nordquist, Gilbert S. Omenn

On the Adaptation in Sodium Excretion in Chronic Uremia. THE EFFECTS OF “PROPORTIONAL REDUCTION” OF SODIUM INTAKE

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Abstract

Renal mass and glomerular filtration rate (GFR) were reduced from normal to approximately 15% of normal in two groups of dogs. One group received a constant salt intake (CSI) throughout the study. The second group was subjected to “proportional reduction” of sodium intake (PRS), a dietary regimen which involved the reduction of sodium intake in exact proportion to the decrement in GFR. In the CSI group, absolute sodium excretion rate (UNaV) remained essentially unchanged as GFR fell, while fractional sodium excretion (FENa) increased progressively from a mean control value of 0.3% to a final value of 4.4%. In the PRS group, UNaV decreased with each reduction in GFR and salt intake, and FENa remained constant throughout. In a second study, the fraction of serum that previously has been shown to possess natriuretic activity in studies of uremic patients was obtained from a group of uremic dogs on the CSI and from another group on the PRS regimen, and the effects of the fraction was measured on sodium excretion in rats. The serum fractions from the dogs on the CSI regimen produced a significant increase in both UNaV and FENa in the assay rats. The same serum fraction from the dogs on the PRS regimen failed to produce a significant increase in either UNaV or FENa.

Authors

R. William Schmidt, Jacques J. Bourgoignie, Neal S. Bricker

The Effect of Bacillus Calmette-Guerin-Induced Macrophage Activation on the In Vivo Clearance of Sensitized Erythrocytes

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Abstract

The clearance of 51Cr-labeled guinea pig erythrocytes, sensitized with a known amount of IgM or IgG antibody, was examined in normal and BCG-infected guinea pigs. In normal animals, IgM-coated cells were rapidly sequestered in the liver. Most of these cells were then slowly released into the circulation where they survived normally as Coombs-positive erythrocytes. Neither the site nor extent of initial clearance showed major alterations in BCG-infected animals; however, there was no return of the sequestered erythrocytes into the circulation. This pattern of clearance was only seen in normals at very high levels of sensitization. In contrast to the IgM studies, the pattern of clearance of IgG-sensitized erythrocytes was not altered, but the rate and magnitude was markedly increased at all levels of sensitization. In addition, complement-independent clearance of IgG-sensitized erythrocytes was augmented in BCG-infected guinea pigs lacking classical complement pathway function. The spleen remained the organ primarily responsible for this increased clearance of IgG-sensitized erythrocytes. Sensitized cells in BCG-infected animals were removed from the circulation as if they were coated with several times the amount of antibody. Serum factors were shown not to be responsible for the increased clearance. These data suggest that increased macrophage activation in BCG-infected animals plays a critical role in determining the consequences of cell sensitization in vivo. These studies may help to explain exacerbations of hemolytic anemias and related states after intercurrent infections.

Authors

John P. Atkinson, Michael M. Frank

Effects of Exogenous Estrogen and Progestin on Pituitary Responsiveness to Synthetic Luteinizing Hormone-Releasing Factor

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Abstract

The effect of estrogen and progestin on pituitary responsiveness to 150 μg synthetic luteinizing hormone-releasing factor (LRF) was assessed in premenopausal women receiving sequential (n=12) and combination (n=7) contraceptive steroids. A marked contrast in the time-course and maximal response to LRF was found; a prompt but quantitatively smaller luteinizing hormone (LH) response was seen during cyclic combination therapy, while a delayed (five times) but enhanced (fivefold) LH response was observed during estrogen segments of cyclic sequential therapy. For follicle-stimulating hormone (FSH), the maximum rise was also higher, and the peak response was similarly delayed in the latter group. The quantitative secretion in response to LRF for LH (area under the curve), but not for FSH, was significantly greater (P < 0.01) in subjects receiving sequential, as compared to subjects receiving combination treatment. In both groups, characteristic gonadotropin responses to LRF were reproducible and were independent of the duration of treatment. Since LRF studies were performed during the estrogen segment of treatment cycle in subjects receiving sequential steroids, our data suggest that estrogen exerts a direct feedback action at the pituitary level and that pituitary responsiveness to LRF is augmented by estrogen.

Authors

G. Vandenberg, G. DeVane, S. S. C. Yen

Proceedings of the Sixty-Sixth Annual Meeting of The American Society for Clinical Investigation, Inc. Atlantic City, New Jersey, 6 May 1974. PRESIDENTIAL ADDRESS. The Individual, Science, and Society

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Abstract

Authors

Edward C. Franklin

Abstracts

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Abstract

Authors