Renal Adaptation to a High Potassium Intake: THE ROLE OF HYDROGEN ION

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Abstract

The influence on urinary acidification of prolonged ingestion of a high potassium diet was explored in normal men and dogs. In men, the response to acute ingestion of ammonium chloride was assessed in a paired fashion after 5 days of ingesting a formula diet of normal or high potassium content; whereas in animals chronically ingesting a small amount of hydrochloric acid, the response to an increase in daily potassium intake was assessed. Urine pH was lower in the potassium-loaded state with both these models, and the effect persisted in the dog studies as long as a high potassium intake was continued. The decrease in urine pH could not be accounted for by changes in plasma acid-base status, net acid excretion, rate of urine flow, urine ionic strength, or fixed buffer excretion, i.e., phosphate, creatinine, or organic acids. Studies of men with administration of exogenous aldosterone and studies of adrenalectomized dogs with constant, maintenance steroid replacement indicated that the decrease in urine pH does not result from altered aldosterone secretion.

Authors

Richard L. Tannen, Eric Wedell, Ronda Moore

Adrenergic Receptors and the Secretion of Glucagon and Insulin from the Isolated, Perfused Canine Pancreas

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During perfusion with a glucose concentration of 150 mg/100 ml, infusions of l-epinephrine, l-norepinephrine, and d-l-isoproterenol at physiological concentrations of 2 ng/ml for 9 min stimulated secretion of glucagon in a monophasic response pattern, in contrast to the biphasic response normally encountered after glucagon releasing stimuli as previously reported from our laboratory (1971. J. Clin. Invest.50: 2123). Glucagon was stimulated in spite of a glucose concentration which in itself effectively inhibits glucagon release. Release of insulin was strongly inhibited after epinephrine and norepinephrine, and strongly stimulated after isoproterenol.

Authors

Johan Iversen

Contributions of Loss of Lung Recoil and of Enhanced Airways Collapsibility to the Airflow Obstruction of Chronic Bronchitis and Emphysema

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We investigated the contributions of intrinsic disease of the airways, loss of lung recoil and enhanced airway collapsibility to the airflow obstruction of 17 patients with chronic bronchitis and emphysema. Airways conductance at low flow (Gaw), maximum expiratory flow (V̇E, MAX) and static lung recoil pressure [Pst (l)] were measured at different lung volumes, and conductance-static recoil pressure and maximum flow-static recoil pressure curves constructed. Low values of ΔGaw/ΔPst (l) and ΔV̇E, max/ΔPst (l) were attributed to intrinsic airways disease. Airway collapsibility was assessed by comparing Gaw with upstream conductance on forced expiration and by the intercept of the maximum flow-static recoil curve on the static recoil pressure axis (Ptm′).

Authors

D. G. Leaver, A. E. Tattersfield, N. B. Pride

Enhanced Effects of Prostaglandin E₁ and Dibutyryl Cyclic AMP upon Human Lymphocytes in the Presence of Cortisol

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The combined effects of cortisol and agents acting through a cyclic AMP-mediated mechanism have been studied in cultures of highly purified human peripheral lymphocytes. Incubation with prostaglandin E1 (PGE1), dibutyryl cyclic AMP, or cortisol results in a concentration-dependent inhibition of [3H]-thymidine incorporation by both unstimulated and phytohemagglutinin (PHA)-stimulated lymphocytes, and PHA-induced morphologic transformation is prevented. When cortisol and PGE1 (or dibutyryl cyclic AMP) are added together to lymphocyte cultures, enhanced inhibitory effects are observed.

Authors

John Mendelsohn, Michael M. Multer, Robert F. Boone

Intestinal Folate Absorption: II. CONVERSION AND RETENTION OF PTEROYLMONOGLUTAMATE BY JEJUNUM

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Abstract

These studies were designed to determine whether pteroylmonoglutamic acid (PGA) at physiologic concentrations is transported across the small intestine unaltered or is reduced and methylated to the circulating folate form (5-methyltetrahydrofolate [5-MeFH4]) during absorption. [3H]PGA was incubated in vitro on the mucosal side of rat jejunum. Of the folate transferred to the serosal side, the percent identified as 5-MeFH4 by DEAE-Sephadex chromtography was inversely related to the initial mucosa PGA concentration: at 7, 20, and 2,000 nM, 44%, 34%, and 2%, respectively, was converted to 5-MeFH4. In contrast, less than 4% of the folate transferred across ileal mucosa was 5-MeFH4 when the initial mucosa concentration was 20 nM. Specific activity of dihydrofolate (DHF) reductase, the enzyme responsible for converting PGA to tetrahydrofolic acid, was measured in villus homogenates and was significantly greater in the jejunum than in the ileum. 1,000 nM methotrexate (MTX), a DHF reductase inhibitor, markedly inhibited PGA conversion to 5-MeFH4 by the jejunum.

Authors

Edward J. Olinger, Joseph R. Bertino, Henry J. Binder

Mechanism of the Hypolipemic Effect of Clofibrate in Postabsorptive Man

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Abstract

Splanchnic metabolism of triglycerides and other major substrates was studied in the postabsorptive state in normotriglyceridemic and hypertriglyceridemic human subjects who received ½ g of clofibrate four times daily for 3 wk. Transport in blood plasma of triglycerides produced in the splanchnic region was quantified by three methods: (a) measurement of the transsplanchnic gradient of 14C-labeled triglycerides during constant intravenous infusion of [1- 14C] palmitate (b) chemical measurement of the transplanchnic gradient in concentration of triglycerides of very low density lipoproteins; and (c) determination of clearance of 14C-labeled triglycerides in extrasplanchnic tissues. The first method measures only triglycerides derived from free fatty acids and the last two measure total splanchnic production. In hypertriglyceridemic subjects treated with clofibrate, average rates of total splanchnic production of triglycerides and production from free fatty acids were the same as those of comparable untreated subjects despite a consistent fall in plasma triglyceride levels. The hypotriglyceridemic effect of the drug was therefore accompanied by improved disposal of triglycerides in extrasplanchnic tissues. In treated normotriglyceridemic subjects, unlike their untreated counterparts, total splanchnic production was significantly higher than production from free fatty acids. Failure of clofibrate to reduce triglyceride levels in normotriglyceridemic subjects may have been related to increased total splanchnic production, coupled with improved extrasplanchnic disposal.

Authors

B. M. Wolfe, J. P. Kane, R. J. Havel, H. P. Brewster

Interactions between Intraluminal Bile Acids and Digestive Products on Pancreatic and Gallbladder Function

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Abstract

Interactions between bile acids (taurocholate, TC; taurochenodeoxycholate, TCDC; or taurodeoxycholate, TDC) and digestive products (essential amino acids, EAA or monoolein, MO) in the lumen of the proximal small bowel, affecting pancreatic enzyme secretion and gallbladder contraction, were studied in 77 healthy volunteers by a perfusion method. Perfusion of EAA or MO caused significant increases in pancreatic enzyme output together with gallbladder contraction; MO was more potent and induced enzyme outputs comparable to the maximal response attained with intravenous cholecystokinin-pancreozymin (CCK-PZ). Perfusion of TC alone had no effect, but addition of 10 mM of either TC, TCDC, or TDC to perfusates containing EAA, or 10 mM TC to MO, or both significantly reduced pancreatic enzyme output and prevented gallbladder contraction. A lower concentration of TC (5 mM) added to EAA also produced a significant inhibitory effect. Inhibition of the stimulatory action of digestive products occurred in the jejunum as well as in the duodenum. The inhibitory action of bile acid was considered to be intraluminal since (a) bile acid did not modify the effects of CCK-PZ given intravenously; and (b) the stimulatory effect of digestive products perfused in the duodenum on pancreatic and gallbladder function was not influenced by simultaneous perfusion of bile acid in the jejunum.

Authors

Juan R. Malagelada, Vay L. W. Go, Eugene P. DiMagno, W. H. J. Summerskill

Glucose Metabolism of the Isolated Eccrine Sweat Gland: II. THE RELATION BETWEEN GLUCOSE METABOLISM AND SODIUM TRANSPORT

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Abstract

This paper attempts to further clarify the characteristics of Mecholyl- or epinephrine-stimulated glucose metabolism in the isolated monkey eccrine sweat gland with special emphasis on its relationship to increased sodium transport. The Mecholyl- or epinephrine-stimulated glucose metabolism (as estimated by either lactate or 14CO2 production or both) is seen only in the secretory coil and not in the duct. It is markedly suppressed in the absence of glucose, Na+, or K+. It is inhibited by ouabain (10−3 M) and partially suppressed in a low-sodium (40 mM), high-potassium (100 mM) medium.

Authors

Kenzo Sato, Richard L. Dobson

Degradation of Human Fibrinogen by Plasma α₂-Macroglobulin-Enzyme Complexes

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This study demonstrates that human plasma α2-macroglobulin preparations possess an enzymic activity that degrades fibrinogen, resulting in the formation of products whose structure resembles that of circulating fibrinogen catabolites. The sequence of degradation is similar to that observed in plasmin-catalyzed digests, in that Aα-chain fragmentation precedes that of Bβ-chain. The addition of plasminogen activators to plasma induced an increase in the N-α-tosyl-l-arginine methyl ester HCl esterase and fibrinogenolytic activity associated with α2-macroglobulin purified from this plasma, indicating that the enzymic activity of the complex was preserved and could be increased in the presence of other plasma enzyme inhibitors. Immunochemical studies demonstrated that an α2-macroglobulin-plasmin complex had formed in urokinase-treated plasma. This α2-macroglobulin preparation manifested an esterolytic profile like that of a complex prepared from plasmin and purified α2-macroglobulin. After complex formation with α2-macroglobulin in plasma, plasmin retained less than 0.1% of its fibrinogenolytic activity. That plasmin expressed its activity while bound to α2-macroglobulin was suggested by immunoprecipitation of this activity with α2-macroglobulin antibody and by the demonstration that pancreatic trypsin inhibitor did not effectively inhibit its fibrinogenolytic or esterolytic activity. These results raise the possibility that, in addition to its activity as a major plasma proteolytic enzyme inhibitor, α2-macroglobulin may modulate enzyme-substrate interactions, such as those resulting in the formation of circulating fibrinogen catabolites, by providing a mechanism for the preservation and protection of a portion of the enzymic activity in the presence of other circulating inhibitors.

Authors

Peter C. Harpel, Michael W. Mosesson

Defective Mononuclear Phagocyte Function in Patients with Myelomonocytic Leukemia and in Some Patients with Lymphoma

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Mononuclear phagocytes from 8 of 10 patients with myelomonocytic leukemia and 2 of 9 patients with lymphoma phagocytized several species of bacteria but did not inhibit intracellular bacterial replication normally. Intracellular organisms were protected from the lethal effects of antibiotics in the medium. This defect of microbicidal function of malignant monocytes may explain in part the frequency of infection and the mechanism of antibiotic-resistant infection in some patients with malignant myeloproliferative and lymphoproliferative diseases.

Authors

Martin J. Cline

Studies on the Nature of Antihemophilic Factor (Factor VIII): FURTHER EVIDENCE RELATING THE AHF-LIKE ANTIGENS IN NORMAL AND HEMOPHILIC PLASMAS

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Abstract

Normal human antihemophilic factor (AHF, factor VIII) and the protein antigenically related to it in hemophilic plasma both appeared in the void volume of columns of agarose (Sepharose 4B) during purification of these agents. On ultracentrifugation upon sucrose gradients, both agents had sedimentation characteristics similar to those of an S30 marker. After reduction, the polypeptide chains of purified normal AHF and of the nonfunctional agent from hemophilic patients had an apparent molecular weight of 200,000 as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. These observations suggest that AHF, purified as described, exists as a large molecule with subunits of molecular weight of approximately 200,000.

Authors

Bruce Bennett, Walter B. Forman, Oscar D. Ratnoff

The Subunit Structure of Normal and Hemophilic Factor VIII

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Human factor VIII from normals and hemophiliacs was partially purified by ethanol and polyethylene glycol precipitations. Final purification was achieved by gel filtration on 2 or 4% agarose or ion exchange chromatography on diethylaminoethyl cellulose. Comparable amounts of highly purified protein were obtained from normal and hemophilic plasma following the agarose chromatography step. Highly purified factor VIII was not dissociated by 6 M guanidine hydrochloride or 1% sodium dodecyl sulfate. However, when reduced by β-mercaptoethanol and analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, a single subunit species with an estimated 195,000 molecular weight was found for both normal and hemophilic factor VIII. By sedimentation equilibrium analysis, the normal factor VIII subunit was homogeneous and had an estimated molecular weight of 202,000. The subunit polypeptides from normal or hemophilic factor VIII contained carbohydrate. Each was homogeneous by isoelectric focusing. Immunodiffusion of purified normal and hemophilic factor VIII against rabbit antiserum to purified normal human factor VIII showed a single line of precipitation. Very low concentrations of purified human thrombin initially increased the activity of normal factor VIII about threefold and then progressively destroyed activity by 3 h. Only minimal activation occurred with hemophilic factor VIII. Both the activation and inactivation of normal and hemophilic factor VIII were unaccompanied by detectable changes in subunit molecular weight. These findings may have implications for the definition of the molecular defect in hemophilic factor VIII.

Authors

Gabriel A. Shapiro, Judith C. Andersen, Salvatore V. Pizzo, Patrick A. McKee

Immunology of the Lower Respiratory Tract: FUNCTIONAL PROPERTIES OF BRONCHOALVEOLAR LYMPHOCYTES OBTAINED FROM THE NORMAL CANINE LUNG

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While the alveolar macrophage has been studied extensively, little attention has been directed toward the immune functions of the bronchoalveolar lymphocyte. These cells, obtained by bronchopulmonary lavage of the normal canine lung, are derived from the air side of the alveolar-capillary membrane of the lower respiratory tract. The distribution of lymphocyte types within the bronchoalveolar cell population was determined and compared with that of leukocytes from blood and spleen.

Authors

H. B. Kaltreider, S. E. Salmon

Comparative Study of Bone Marrow and Blood B Cells in Infantile and Acquired Agammaglobulinemia: POSSIBLE ROLE OF CIRCULATING ANTI-IgM IN PATHOGENESIS

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Abstract

The status of immunoglobulin (Ig) receptors of the bone marrow dependent (B) cells present in either the bone marrow (BM) or peripheral blood (PB) of three patients with infantile agammaglobulinemia (I-AGG), or seven patients with acquired agammaglobulinemia (A-AGG) is compared with those of 12 controls. Quantitative and qualitative changes of the different classes of Ig receptors on B cells were evaluated by their capacity to bind [125I]anti-Ig, to be stained with fluorescinated anti-Ig and their in vitro proliferative capacity upon incubation with the anti-Ig. Patients with I-AGG lacked B cells in both the BM and PB. Whereas BM cells of patients with A-AGG carried receptors similar to control cells, their blood B cells had fewer IgM, IgG, and IgA cells which failed to proliferate in vitro in the presence of the anti-Ig. An anti-IgM of the IgG class was detected in the sera of patients with A-AGG but not in sera of I-AGG. The isolated anti-IgM agglutinated human red cells coated with IgM. The anti-IgM partially blocked the binding of fluorescinated or radiolabeled anti-IgM to IgM peripheral blood lymphocytes of normal controls. The eluted anti-IgM in presence of complement was partially cytotoxic to normal cells. It is concluded that I-AGG-B cell defect is due to failure of B cell development in the bone marrow compartment whereas the peripheral exclusion of IgM cells by an anti-IgM with the subsequent failure of differentiation of both IgG and IgA cells could be an important mechanism in A-AGG-B cell defect.

Authors

Nabih I. Abdou, Salvatore R. Casella, Nancy L. Abdou, Ises A. Abrahamsohn

Mechanism of Natriuresis after Closure of Chronic Arteriovenous Shunts

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Animals subjected to certain cardiovascular manipulations, such as arteriovenous fistulas, diminish their urinary sodium excretion. It has been shown that closure of such fistulas results in a prompt increase in the rate of sodium excretion. However, the nature of the renal mechanisms increasing the excretion of sodium when the initial cardiovascular abnormality is corrected has remained unclear. Since the elucidation of such mechanisms might provide information pertinent to other sodium-retaining states, the effect of closure of chronic Teflon-Silastic arteriovenous shunts was studied in desoxycorticosterone acetate (DOCA)-treated dogs by utilizing micropuncture techniques.

Authors

Henry Mandin

Hypoxanthine-Guanine Phosphoribosyltransferase Variant Associated with Accelerated Purine Synthesis

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Abstract

We have previously described a 14-yr-old boy with hyperuricemia, renal failure, and accelerated purine production resistant in vivo and in vitro to purine analogs. This patient demonstrated normal red cell hypoxanthine-guanine phosphoribosyltransferase (HPRT) heat stability, electrophoresis at high pH, and activity at standard substrate levels. In the present report an abnormal HPRT enzyme was demonstrated by enzyme kinetic study with phosphoribosylpyrophosphate (PRPP) as the variable substrate and inhibitory studies with sodium fluoride. Apparently normal HPRT activity in a patient with hyperuricemia and gout does not exclude a functionally significant HPRT mutation.

Authors

Paul J. Benke, Norma Herrick, Annette Hebert

Maximal Rates of Excretion and Synthesis of Urea in Normal and Cirrhotic Subjects

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Abstract

When normal individuals eat 0.33 g protein N/kg body weight (BW)¾ per day, they excrete 10-15 mg urea N/h per kg BW¾. If they now ingest (at 0 h) 0.27 (dose A), 0.40 (dose B), 0.53 (dose C), 0.94 (dose D), or 1.33 (dose E) g protein N/kg BW¾ (in the form of casein, ovalbumin, or lactalbumin), the rate of urea N excretion accelerates within 4 h. At dose C a maximal rate of urinary urea N excretion (MRUE) is reached, which averages 55 mg urea N/h per kg BW¾ and which persists for 16 h. Higher doses of protein do not further accelerate urea excretion, but prolong the duration of MRUE to 28 h (after dose E). Blood urea N (BUN) rises by 7-20 mg/100 ml during the first 8 h after dose C to E, and remains stable within ±5 mg/100 ml during the ensuing 8-28 h of MRUE. Each increment of protein above dose C causes a further increment in plasma α-amino N. During infusion of free amino acids at a rate of 110 or 165 mg amino acid N/h per kg BW¾ for 12 h, rate of urea excretion increases to the MRUE value produced by dose C-E of oral protein.

Authors

Daniel Rudman, Thomas J. DiFulco, John T. Galambos, Robert B. Smith III, Atef A. Salam, W. Dean Warren

Maturation of Responsiveness to Cardioactive Drugs: DIFFERENTIAL EFFECTS OF ACETYLCHOLINE, NOREPINEPHRINE, THEOPHYLLINE, TYRAMINE, GLUCAGON, AND DIBUTYRYL CYCLIC AMP ON ATRIAL RATE IN HEARTS OF FETAL MICE

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Abstract

Freshly isolated hearts of fetal mice of gestational ages ranging between 12 and 22 days (term) were exposed to several concentrations of a variety of chronotropic agents. Acetylcholine (10−4-10−2 M) caused marked bradycardia in all hearts, even after only 12-14 days' gestation (i.e., even before cardiac innervation had occurred), and the intensity of the response increased steadily with advancing age throughout gestation. Responsiveness to norepinephrine was present but minimal at 12-14 days, so that mean atrial rate rose by < 10% with a maximal concentration of the drug (10−5 M); responsiveness became more marked by 15-16 days (just after the time atrial innervation is thought to begin) and still greater effects appeared just before term. Glucagon had no effect in hearts of < 17 days' gestational age, but caused tachycardia thereafter, indicating that cardiac responsiveness to glucagon differentiates later than does responsiveness to norepinephrine. Responses to theophyl-line in 12-14 day hearts exceeded those to norepinephrine, indicating that the drug can affect heart rate independently of its ability to cause release of endogenous catecholamines. In contrast, tyramine caused no response until 21-22 days, well after the time the beta-receptor has differentiated and after innervation is fairly well developed, suggesting that the drug's primary sympathomimetic effect is indirect rather than direct. Dibutyryl cyclic AMP did not cause tachycardia at any fetal age.

Authors

Kern Wildenthal, Jacquline R. Wakeland

Absence of Detectable HL—A Antigens on Cultured Fibroblasts in Progeria

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Abstract

HL-A phenotypes were determined by a cytotoxicity assay on circulating lymphocytes of two boys with the premature aging syndrome, progeria. The antigenic phenotypes were not unusual inasmuch as they are frequently seen in the normal population. However, none of these antigens could be detected by the same assay on cultured skin fibroblasts from either individual, even when a significant mitotic potential remained before cessation of growth. Fibroblasts from normal donors were concordant with corresponding lymphocytes for HL-A antigens and maintained these antigens until mitotic division had virtually ceased. Absorption studies on fibroblasts with two HL-A2 antisera revealed that HL-A antigens are either absent or have a drastically reduced expression on progeric fibroblasts. The data are in accord with the concept of an immunological role in the pathogenesis of progeria.

Authors

Dharam P. Singal, Samuel Goldstein

The Adrenergic Control of Lower Esophageal Sphincter Function: AN EXPERIMENTAL MODEL OF DENERVATION SUPERSENSITIVITY

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Abstract

To evaluate the adrenergic regulation of lower esophageal sphincter (LES) function, LES pressure, LES relaxation during swallowing, and blood pressure were measured in the anesthetized opossum, Didelphis virginiana, during intravenous administration of alpha and beta adrenergic agonists and antagonists. Studies were done in controls and animals adrenergically denervated with 6-hydroxydopamine. Alpha adrenergic agonists (norepinephrine, phenylephrine) increased LES pressure and blood pressure, whereas a beta adrenergic agonist (isoproterenol) decreased both pressures. Alpha adrenergic antagonism (phentolamine) reduced basal LES pressure by 38.3±3.8% (mean ±SEM) (P < 0.001). Beta adrenergic antagonism (propranolol) had no significant effect on either basal LES pressure or percent of LES relaxation with swallowing. After adrenergic denervation with 6-hydroxydopamine, basal LES pressure was reduced by 22.5±5.3% (P < 0.025) but LES relaxation during swallowing was unaltered. In denervated animals, both LES pressure and blood pressure dose response curves showed characteristics of denervation supersensitivity to alpha but not to beta adrenergic agonists. These studies suggest: (a) a significant portion of basal LES pressure is dependent upon alpha adrenergic stimulation; (b) LES relaxation during swallowing is not an adrenergically mediated response; (c) the LES pressure response to alpha adrenergic agonists after 6-hydroxydopamine may serve as a model of denervation supersensitivity in the gastrointestinal tract.

Authors

Anthony J. DiMarino, Sidney Cohen

Circadian Rhythm of Plasma Aldosterone Concentration in Patients with Primary Aldosteronism

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Abstract

Plasma aldosterone, cortisol, and renin activity were measured in nine recumbent patients with hyperaldosteronism, including seven with adenomas, one with idiopathic hyperplasia, and one with glucocorticoid suppressible hyperplasia. All had peak values of plasma aldosterone concentration from 3 a.m. to noon and lowest values at 6 p.m. or midnight. This rhythm was similar to the circadian pattern of plasma cortisol in the same patients. When these data were normalized to eliminate the wide variation in ranges of plasma aldosterone and cortisol between individuals, there was an excellent correlation (r = + 0.87, P < 0.005) between the two hormones. In contrast, plasma aldosterone concentrations did not correlate with plasma renin activity before or after normalization of data.

Authors

David C. Kem, Myron H. Weinberger, Celso Gomez-Sanchez, Norman J. Kramer, Robert Lerman, Shunsuke Furuyama, Charles A. Nugent

Effective Erythropoiesis Induced by 5β-Pregnane-3β-Hydroxy-20-One in Squirrel Monkeys

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The erythropoietic effect of 5β-pregnane-3β-hydroxy-20-one, a naturally occurring steroid metabolite of progesterone, was evaluated in the squirrel monkey by ferrokinetic studies. red cell survival, and blood volume measurements. The intramuscular administration of this steroid in pharmacologic doses shortened the 59Fe plasma clearance and increased the plasma iron turnover, thereby indicating an increase in erythropoiesis. A normal 59Fe red cell uptake was observed, and the bone marrow maturation time was not altered. Red cell survival was the same in the treated and control groups. After five weekly injections of the steroid, the monkeys increased their red cell mass by 57%. A significant increase in white blood cells and a slight elevation of platelet counts in the treated monkeys also suggest a possible direct stimulation of hemopoietic stem cells by the steroid metabolite.

Authors

Emmanuel C. Besa, Dov Gorshein, William A. Hait, Frank H. Gardner

Comparison of Cardiac Output Responses to 2,4-Dinitrophenol-Induced Hypermetabolism and Muscular Work

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Both electrically induced exercise and infusion of 2,4-dinitrophenol (DNP) increased oxygen consumption and tissue metabolism in chloralose-anesthetized dogs. Cardiac output increased with oxygen consumption at the same rate in both experimental conditions. The increase in cardiac output induced by exercise was, as expected, accompanied by increases in both lactate-to-pyruvate ratio and “excess lactate” in arterial blood. However, these parameters did not increase after DNP infusion until the rate of oxygen consumption had increased four- to fivefold, perhaps due to facilitation of mitochondrial electron transport by DNP. Anaerobic tissue metabolism therefore probably did not contribute significantly to increased cardiac output during the mild-to-moderate tissue hypermetabolism induced by DNP. The increased cardiac output may have been the result of metabolic changes common to both exercise and DNP infusion; muscular activity alone may not have been the primary determinant of the cardiac output response during exercise.

Authors

Chang-Seng Liang, William B. Hood Jr.

Differential Effects of Immunosuppressants on Lymphocyte Function

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Abstract

In vitro and in vivo parameters of T lymphocyte function were evaluated in guinea pigs following treatment with the “cycle-active” drugs, 6-mercaptopurine (6MP) and methotrexate, and the “non-cycle-active” alkylating agent, cyclophosphamide. Commencing at the time of sensitization to tuberculin protein, animals were treated with an 8 day course of one of the cytotoxic drugs. This regimen either reduced or abolished the cutaneous response to PPD. The two cycle-active drugs inhibited the in vitro lymphoproliferative response to PPD and suppressed the elaboration of migration inhibition factor (MIF) by lymph node cells. However, these agents did not reduce blood lymphocytes, deplete the cellularity of the thymic dependent areas of peripheral tissues, or alter the in vitro response of lymph node cells to the nonspecific mitogen PHA. In contrast, treatment with cyclophosphamide was associated with a reduction in peripheral blood and tissue lymphocytes and impaired responses to PHA by residual lymph node cells. In vitro proliferative responses to PPD were inhibited but the capacity of lymph node cells to elaborate MIF was not suppressed. In addition to their effects on antigen-reactive lymphocytes, all three drugs significantly reduced the number of macrophages in induced peritoneal exudates. With respect to immunosuppressive activities, results of these investigations suggest that the noncycle-active agents affect both intermitotic and dividing T lymphocytes without impairing certain intermitotic functions of residual cells. The cycle-active drugs have a more restricted toxicity limited to those T lymphocytes which have been stimulated to undergo active DNA synthesis by antigenic challenge.

Authors

Alan Winkelstein

Hormonal Control of Pancreatic Growth

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Abstract

Investigations have outlined pancreatic secretory and synthetic responses to gastrointestinal hormones. However, there is little information concerning hormonal influences on pancreatic growth.

Authors

David L. Mainz, Owen Black, Paul D. Webster

Repetitive Administration of Thyrotropin-Releasing Hormone Results in Small Elevations of Serum Thyroid Hormones and in Marked Inhibition of Thyrotropin Response

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Abstract

Repetitive administration of thyrotropin-releasing hormone (TRH) to human subjects was used to produce small elevations of endogenous serum triiodothyronine (T3) and thyroxine (T4) levels and thereby to determine the effect of these small elevations on the serum thyrotropin (TSH) response to subsequent doses of TRH. Each subject received 13 consecutive doses of 25 μg TRH at 4-h intervals. Serum T3, T4, and TSH levels were measured before the 1st, 7th, and 13th doses (“basal levels”) and for the 4 h after each of these doses.

Authors

Peter J. Snyder, Robert D. Utiger

A Comparison of the Segmental Analysis of Sodium Reabsorption during Ringer's and Hyperoncotic Albumin Infusion in the Rat

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Abstract

Studies were designed to compare the segmental analysis of sodium reabsorption along the nephron during volume expansion with either 10% body weight Ringer's or 0.6% body weight hyperoncotic albumin. Total kidney and nephron glomerular filtration rate increased similarly with both, but urinary sodium excretion (12.7 vs. 4.0 μeq/min, P < 0.001) and fractional sodium excretion (5.0 vs. 1.6%, P < 0.001) increased to a greater extent with Ringer's. Fractional reabsorption of sodium in the proximal tubule was diminished in both groups but to a significantly greater extent during Ringer's (P < 0.005). Absolute reabsorption was inhibited only in the Ringer's group. Delivery of filtrate out of the proximal tubule was greater in the Ringer's studies, 45 vs. 37 nl/min (P < 0.001). However, both fractional and absolute sodium delivery to the early and late distal tubule were not significantly different in the two groups. Fractional reabsorption in the collecting duct decreased from 96% in hydropenia to 31% during Ringer's but fell only slightly to 80% in the albumin studies. Absolute collecting duct reabsorption was also greater in the albumin studies, 0.55 vs. 0.21 neq/min (P < 0.001), which could totally account for the difference in urinary sodium excretion between the two groups. 22Na recovery in the final urine after end distal microinjections was 71% during Ringer's infusion and 34% during albumin (P < 0.001). From these data we conclude that: (a) Ringer's solution has a greater inhibitory effect on proximal tubular sodium reabsorption, and (b) in spite of this effect, differences in mucosal to serosal collecting duct sodium transport are primarily responsible for the greater natriuresis during Ringer's infusion.

Authors

Jay H. Stein, Richard W. Osgood, Sampanta Boonjarern, Thomas F. Ferris

Thyroid Hormone Inhibition of the Prolactin Response to Thyrotropin-Releasing Hormone

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The influence of serum triiodothyronine (T3) and thyroxine (T4) concentrations on the release of prolactin in man was studied by determining the prolactin response to synthetic thyrotropin-releasing hormone (TRH) in hypothyroid and hyperthyroid patients before and after correction of their serum thyroid hormone abnormalities. The maximum increment in serum prolactin above the basal level (maximum Δ prolactin) was used as the index of response to TRH.

Authors

Peter J. Snyder, Laurence S. Jacobs, Robert D. Utiger, William H. Daughaday

A Definition of Proximal and Distal Tubular Compliance: PRACTICAL AND THEORETICAL IMPLICATIONS

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Abstract

Micropuncture studies were carried out in the rat to evaluate the in situ distensibility characteristics of the proximal and distal tubules under a variety of experimental conditions. In the first phase, we determined the response of tubular diameter (D) to changes in tubular pressure (P) induced by partially obstructing single tubules. The response observed under these conditions (i.e., when interstitial pressure is presumed to be constant) has been defined as the compliance of the tubule. Over the range of tubular pressures studied (10-35 mm Hg for the proximal tubule, 5-25 mm Hg for the distal tubule) the compliance characteristics of the proximal and distal tubule were found to be markedly different; the proximal tubular pressure-diameter relationship was linear, ΔD/ΔP = 0.45 μm/mm Hg, whereas the distal pressure-diameter relationship was curvilinear, ΔD/ΔP = c−0.1×P+2.2.

Authors

Stanley Cortell, F. John Gennari, Michael Davidman, William H. Bossert, William B. Schwartz, Melvin L. Ponte

Development and Clinical Application of a New Method for the Radioimmunoassay of Arginine Vasopressin in Human Plasma

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Abstract

A radioimmunoassay has been developed that permits reliable measurements of plasma arginine vasopressin (AVP) at concentrations as low as 0.5 pg/ml in sample volumes of 1 ml or less. Nonhormonal immunoreactivity associated with the plasma proteins is eliminated by acetone precipitation before assay, leaving unaltered a component that is immunologically and chromatographically indistinguishable from standard AVP. Storage of plasma results in a decline in AVP concentration and, thus, must be carefully regulated. The plasma AVP values obtained by our method approximate the anticipated levels and vary in accordance with physiologic expections. In recumbent normal subjects, plasma AVP ranged from (mean ±SD) 5.4±3.4 pg/ml after fluid deprivation to 1.4±0.8 pg/ml after water loading, and correlated significantly with both plasma osmolality (r=0.52; P<0.001) and urine osmolality (r=0.77; P<0.001). After fluid restriction, plasma AVP was uniformly normal relative to plasma osmolality in patients with nephrogenic diabetes insipidus and primary polydipsia but was distinctly subnormal in all patients with pituitary diabetes insipidus. The infusion of physiologic amounts of posterior pituitary extract caused a dose-related rise in plasma vasopressin that afterwards declined at the expected rate (t½=22.5±4 min). We conclude that, when used appropriately, our radioimmunoassay method provides a useful way of assessing AVP function in man.

Authors

Gary L. Robertson, Ermelinda A. Mahr, Shahid Athar, Tushar Sinha

Regulation of Cholesterol Metabolism in the Dog: I. EFFECTS OF COMPLETE BILE DIVERSION AND OF CHOLESTEROL FEEDING ON ABSORPTION, SYNTHESIS, ACCUMULATION, AND EXCRETION RATES MEASURED DURING LIFE

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Abstract

Six adult pedigreed dogs were studied as long as 3 yr in order to determine the effects of cholesterol feeding and of bile diversion on absorption, synthesis, and storage of cholesterol. These measurements were based on cholesterol balance and isotope kinetic studies.

Authors

Demetrius Pertsemlidis, Ernest H. Kirchman, E. H. Ahrens Jr.

Regulation of Cholesterol Metabolism in the Dog: II. EFFECTS OF COMPLETE BILE DIVERSION AND OF CHOLESTEROL FEEDING ON POOL SIZES OF TISSUE CHOLESTEROL MEASURED AT AUTOPSY

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Abstract

In six adult pedigreed dogs the effects of high-cholesterol diets or bile diversion on the sizes of body cholesterol pools were studied at autopsy. Total body cholesterol was determined by measuring the cholesterol content of discrete organs and of the eviscerated carcass: neither cholesterol feeding nor bile diversion had altered total body cholesterol or the cholesterol content of individual organs and tissues. These results validated the conclusion based on sterol balance data obtained during life, that high-cholesterol feeding did not lead to substantial expansion of tissue cholesterol pools.

Authors

Demetrius Pertsemlidis, Ernest H. Kirchman, E. H. Ahrens Jr.

Cyclic AMP and Sodium Transport: QUANTITATIVE AND TEMPORAL RELATIONSHIPS IN TOAD URINARY BLADDER

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Abstract

The effects of oxytocin upon tissue cAMP content and short-circuit current (SCC) were measured in the urinary bladder of the toad, Bufo marinus. Tissue cAMP levels doubled before any increment in SCC was observed, the two hormone responses were quantitatively related, and a threshold level for an effect of cAMP upon sodium transport was demonstrated. The period of time over which cAMP levels continued to rise after the threshold level had been attained seemed invariant with hormone concentration. The rate at which cAMP levels rose increased with hormone concentration yielding hormone concentration-dependent maximal levels. The decay of cAMP levels was delayed when sodium influx was curtailed, suggesting a sodium-regulatory effect upon tissue cAMP levels.

Authors

Victor S. Sapirstein, Walter N. Scott

Uric Acid: CHARACTERIZATION OF ITS INTERACTION WITH HUMAN SERUM ALBUMIN

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Abstract

Binding of sodium urate to human serum albumin (HSA) was measured by continuous ultrafiltration at pH 7.4 and ionic strength 0.16 over the concentration range 1-13 mg/100 ml. The percent sodium urate bound to 5 g/100 ml HSA was constant over this concentration range: 30.3 (SE±0.6)% being bound at 4°C, 22.6±0.3% at 22.5°C, and 19.6±0.3% at 37°C. Derived association constants, assuming one binding site were 6.0 × 102 M−1 (4°C), 4.47 × 102 M−1 (22.5°C), and 3.88 × 102 M−1 (37°C).

Authors

David S. Campion, Rodney Bluestone, James R. Klinenberg