Proceedings of the Sixty-Fifth Annual Meeting of The American Society for Clinical Investigation, Inc. Atlantic City, New Jersey, 30 April 1973

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Neal S. Bricker

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Studies of the In Vivo Metabolism of Mevalonic Acid in the Normal Rat

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Studies were performed to examine synthesis, tissue localization, and metabolism of mevalonic acid in normal rats. Circulating mevalonate was found to have a rapid turnover phase of 5 min and a slower phase of 40-50 min. Under in vitro conditions the synthesis of mevalonate is carried out most actively by the liver and only to a minor extent by the other tissues studied. The most unexpected finding of this study was that both in vivo and in vitro the kidneys rather than the liver are the primary site of the metabolism of circulating mevalonate. Whereas mevalonate in the liver is rapidly transformed to cholesterol, the major products of mevalonate metabolism in the renal tissues during the same time period are squalene and lanosterol. Exogenous in contrast to circulating mevalonate is metabolized primarily in the intestine.

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Kjell H. Hellstrom, Marvin D. Siperstein, Lee A. Bricker, Lynne J. Luby

Effect of Changes in Hydrostatic Pressure in Peritubular Capillaries on the Permeability of the Proximal Tubule

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The effect of increased hydrostatic pressure in the peritubular vessels on net sodium reabsorption from the proximal tubule was examined in the Necturus. An increase in the pressure gradient of 2.0 cm H2O across the wall of the proximal tubule, produced by ligation of the postcaval vein was associated with a marked reduction in net reabsorption and an increased back flux of water and electrolytes. This change was accompanied by a slight, but significant drop in the transepithelial electrical potential but not by an alteration in the steady-state chemical gradient. These studies highlight the importance of changes in the permeability characteristics of the proximal tubule on net sodium transport.

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John P. Hayslett

Radioimmunoassay for Measurement of Thyroglobulin in Human Serum

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A specific and reproducible double antibody radioimmunoassay for the measurement of thyroglobulin (HTg) in human serum has been developed. Since antithyroglobulin autoantibodies combine with the [131I] HTg tracer, antibody-positive sera were rejected for measurement. Specificity is demonstrated in that thyroid analogous such as thyroxine (T4), triiodothyronine (T2) monoiodotyrosine (MIT) and diiodotyrosine (DIT) did not crossreact. Sera previously reacted with anti-HTg-Sepharose contained no immunoassayable HTg. Finally, sera obtained from patients after total thyroid ablation for thyroid carcinoma did not contain demonstrable HTg. The sensitivity of the assay is 1.6 ng/ml, and HTg was detectable in 74% of 95 normal subjects. The mean concentration was 5.1 ng/ml ±0.49 SEM (range <1.6-20.7 ng/ml). Day to day variation in HTg levels is large in some euthyroid subjects and nearly absent in others. HTg was detectable in 90% of the sera obtained in 23 pregnant women at delivery in whom a mean concentration of 10.1 ng/ml ±1.3 SEM was observed. The mean level for the corresponding newborn infants at birth was 29.3 ng/ml ±4.7 SEM a value significantly higher than the mean maternal HTg concentration (P <0.01). A group of 17 thyrotoxic individuals all had elevated HTg levels; the mean for this group was 344.8 ng/ml ±90.7 SEM. In the acute phase of subacute thyroiditis HTg was also elevated in all of 12 patients, and the mean for this group was 136.8 ng/ml ±74.6 SEM.

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A. J. Van Herle, R. P. Uller, N. L. Matthews, Josiah Brown

Effects of Cortisone Administration on the Metabolism and Localization of 25-Hydroxycholecalciferol in the Rat

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Glucocorticoid administration is known to decrease calcium absorption in vivo and the vitamin D-dependent active transport of calcium by rat duodenum in vitro. The basis for this antivitamin D-like effect of glucocorticoids is unclear.

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Murray J. Favus, Daniel V. Kimberg, Gail N. Millar, Elaine Gershon

Alterations in Cyclic AMP Metabolism in Human Bronchial Asthma. II. LEUKOCYTE AND LYMPHOCYTE RESPONSES TO PROSTAGLANDINS

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In an effort to clarify the basis for the reduced cyclic AMP response to catecholamines in leukocytes and lymphocytes from asthmatic donors the response of these cells to prostaglandins has been examined. Cells with an impaired beta adrenergic response had an essentially unaltered response to prostaglandin E1 (PGE1) indicating the presence of selective beta adrenergic blockade. In contrast to what was observed with cells from asthmatic individuals, in normal control leukocytes with reduced catecholamine responsiveness PGE1 responses were usually reduced as well, suggesting a different mechanism. The excellent cyclic AMP response to PGE1 in cells from asthmatic donors would suggest that the defect in catecholamine responsiveness is at the level of the beta adrenergic receptor although a contributory role of altered substrate concentrations or increased phosphodiesterase activity is not formally excluded.

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Charles W. Parker, Mary L. Baumann, Mary G. Huber

Alterations in Cyclic AMP Metabolism in Human Bronchial Asthma. III. LEUKOCYTE AND LYMPHOCYTE RESPONSES TO STEROIDS

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On the basis of serial studies the responsiveness of leukocytes and lymphocytes from asthmatic donors to catecholamines was increased during high dose corticosteroid therapy. Similar changes were observed in the cells of normal control subjects given 200 mg of hydrocortisone intravenously. The increase in responsiveness did not appear to be due to changes in lymphocyte subpopulations although this may be a contributing factor. In an effort to elucidate the basis for the improved response, in vitro effects of glucocorticoids on lymphocyte cyclic AMP concentrations were investigated. Glucocorticoids (prednisolone succinate, hydrocortisone, hydrocortisone phosphate, and hydrocortisone succinate) stimulated cyclic AMP accumulation in asthma and normal control lymphocytes, increases occurring within the first 2 min of incubation. In the absence of theophylline, responses were regularly obtained at 10 μM hydrocortisone and usually at 1 μM hydrocortisone but not at submicromolar steroid concentrations. Theophylline potentiated the cyclic AMP response to glucocorticoids and also increased the percentage of positive responses in the 0.01-1.0 μM corticosteroid range. Combinations of 1 μM hydrocortisone and 1 μM epinephrine were sometimes additive or synergistic but in many instances higher glucocorticoid concentrations were needed to obtain augmentation of the catecholamine response. The in vitro glucocorticoid effects may not fully explain their potentiating action in vivo.

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Charles W. Parker, Mary G. Huber, Mary L. Baumann

Specific Leukocyte Receptors for Small Endogenous Hormones. DETECTION BY CELL BINDING TO INSOLUBILIZED HORMONE PREPARATIONS

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Receptors for small endogenous hormones on human leukocytes were studied by insolubilizing the hormones and incubating them with the cells. Histamine, norepinephrine, and prostaglandin E2 (PGE2) were conjugated to either of two types of carrier: (bovine or rabbit) serum albumin or a random copolymer of DL-alanine and L-tyrosine. The conjugates were linked to agarose beads (Sepharose) and the resultant drug-conjugate-beads were incubated with leukocytes. Norepinephrine (when linked to its carrier via glutaraldehyde) and histamine preparations bound the majority of leukocytes. The binding appeared to be specific for the hormones tested. For example, the binding by histamine-rabbit serum albumin-Sepharose was prevented or reversed by high concentrations of histamine and histamine antagonists, but not by catecholamines or their pharmacologic antagonists. Similarly, binding of cells to the norepinephrine conjugate was inhibited by some catecholamines and propranolol, but not by histamine or histamine antagonists. Conjugates of norepinephrine linked via carbodiimide did not bind cells. The protein or copolymer carriers did not contribute to binding per se. The hormone-protein-conjugates bound more cells than the hormone-polymer conjugates. The former (unlike the free amines) failed to stimulate accumulation of cyclic AMP in leukocytes. The norepinephrine linked to polymer via glutaraldehyde, however, did stimulate leukocyte cyclic AMP accumulation, possibly because of the flexibility of the polymer. Columns of the various Sepharoses were used to determine the distribution of receptors to each hormone in mixed leukocyte populations. The majority of cells appeared to have receptors for both histamine and norepinephrine (bound through glutaraldehyde). Receptors to prostaglandins may have been detected by the column procedure, but their distribution could not be quantitated. The approach described provides a means to separate leukocytes on the basis of what are likely to be preformed receptors to small endogenous hormones, and to study the physiologic importance and function of the receptors.

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Yacob Weinstein, Kenneth L. Melmon, Henry R. Bourne, Michael Sela

Proximal Tubule Potential Difference. DEPENDENCE ON GLUCOSE, HCO₃, AND AMINO ACIDS

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The effect of various intraluminal substrates on the magnitude of the transepithelial potential difference (PD) across the proximal convoluted tubule (PCT) of the mammalian kidney was investigated in two ways. First, the transepithelial PD was measured before and after the removal of glucose, bicarbonate, and alanine from the lumen. Second, the effects of specific transport inhibitors—ouabain, phloridzin, and acetazolamide—was ascertained when placed either on luminal or blood side.

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Juha P. Kokko

Origins of the Uricosuric Response

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The acute effects of intravenous (i.v.) probenecid and chlorothiazide on renal urate handling were investigated in paired studies in normal men. Uricosuric responses to these agents were compared in the same subjects, both without and with pyrazinamide (PZA) pretreatment. Assuming that PZA selectively inhibits the tubular secretion of urate and that uricosuric agents act by increasing the excretion of filtered urate, then the uricosuric responses (the increment in urate excretion or clearance) should have been unaffected by PZA. Defined in this manner, however, uricosuric responses to probenecid and chlorothiazide were significantly decreased after PZA pretreatment. In order to determine whether PZA diminished other renal actions of chlorothiazide, changes in sodium and inorganic phosphorus excretion were examined. Chlorothiazide produced equivalent natriuretic and phosphaturic responses after PZA pretreatment, indicating that PZA does not interfere with at least some of the renal actions of chlorothiazide. In separate studies, PZA depressed urate excretion by at least 68% during the maintenance of chlorothiazide-induced natriuresis and phosphaturia, suggesting that chlorothiazide does not diminish the anti-secretory action of PZA.

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Thomas H. Steele, Geoffrey Boner

Effects of Cycloheximide on the Response of Intestinal Mucosa to Cholera Enterotoxin

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Prior studies have indicated that effects of cholera enterotoxin (CT) on the small intestine are delayed in onset and involve an interaction with adenyl cyclase in the mucosa. It has also been shown that the administration of cycloheximide to rabbits in doses which inhibit crypt cell mitoses (20 mg/kg), diminishes CT-induced fluid production in jejunal loops. These latter studies have been interpreted as indications that CT-related intestinal secretion is a crypt cell function and that it is mediated by a CT-induced protein.

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Daniel V. Kimberg, Michael Field, Elaine Gershon, Robert T. Schooley, Antonia Henderson

The Different Effects on the Serum Lipids and Fecal Steroids of High Carbohydrate Diets Given Orally or Intravenously

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The hypothesis that diets high in carbohydrate produce hyperlipidemia in man was tested in new experiments which provided all calories either by the intravenous route or orally. After a base-line general diet, eight healthy men were fed fat-free diets consisting of 80% of the calories from glucose and 20% from an amino acid hydrolysate. The calories were adequate to maintain body weight. The solutions (1 cal/ml) were infused by constant drip over a 24 h period through either a superior vena cava catheter or a nasogastric tube. Each feeding was for 12 days in sequence but assigned in random order.

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Lawrence DenBesten, Roberto H. Reyna, William E. Connor, Lewis D. Stegink

Plasma Inhibitors of the Components of the Fibrinolytic Pathway in Man

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The effect of highly purified inhibitor of the first component of complement (CāINH), α2 macroglobulin (α2M), and α1 antitrypsin on the components of the fibrinolytic pathway in human plasma has been examined. CāINH was the only factor active upon the Hageman factor fragments functioning at the initial step of the fibrinolytic pathway, α2M was the only factor active against the plasminogen activator and the most active inhibitor of plasmin. The inhibition of plasmin by α2M appeared stoichiometric with one molecule of α2M inhibiting two molecules of plasmin. All three plasma inhibitors were active against plasmin.

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Alan D. Schreiber, Allen P. Kaplan, K. Frank Austen

Inhibition by CāINH of Hageman Factor Fragment Activation of Coagulation, Fibrinolysis, and Kinin Generation

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Highly purified inhibitor of the first component of complement (CāINH) was shown to inhibit the capacity of active Hageman factor fragments to initiate kinin generation, fibrinolysis, and coagulation. The inhibition of prealbumin Hageman factor fragments observed was dependent upon the time of interaction of the fragments with CāINH and not to an effect upon kallikrein or plasmin generated. The inhibition of the coagulant activity of the intermediate sized Hageman factor fragment by CāINH was not due to an effect on PTA or other clotting factors. The inhibition by CāINH of both the prealbumin and intermediate sized Hageman factor fragments occurred in a dose response fashion. The CāINH did not appear to be consumed when the activity of the Hageman factor fragments was blocked, although the fragments themselves could no longer be recovered functionally or as a protein on alkaline disc gel electrophoretic analysis. These results suggest that the CāINH may have an enzymatic effect on the fragments or that an additional site on CāINH is involved in Cā inactivation.

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Alan D. Schreiber, Allen P. Kaplan, K. Frank Austen

In Vitro Myelosuppression and Immunosuppression by Ethanol

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Concentrations of ethanol similar to those in the blood of intoxicated patients suppressed phytohemagglutinin- or streptolysin O-induced lymphocyte transformation, and inhibited bone marrow granulocyte colony growth in soft agar. Inhibition of lymphocyte transformation and granulocyte colony growth occurred despite the presence of large concentrations of folate and other vitamins. These in vitro findings may relate to in vivo effects of ethanol on myeloid and lymphoid tissue.

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Glenn Tisman, Victor Herbert

The Effect of Gastrin on Basal- and Glucose-Stimulated Insulin Secretion in Man

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The effect of gastrin on basal- and glucose-stimulated insulin secretion was studied in 32 normal, young subjects. The concentration of gastrin and insulin in serum was measured radioimmunochemically.

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Jens F. Rehfeld, Flemming Stadil

Tissue Factor Activity in Lymphocyte Cultures from Normal Individuals and Patients with Hemophilia A

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The procoagulant material of lymphocytes has been characterized as tissue factor. Lymphocytes stimulated with phytohemagglutinin or the purified protein derivative of the tubercle bacillus developed procoagulant activity with incubation in tissue culture. While this material corrected the prolonged clotting time of factor VIII (AHF) deficient plasma, we have shown, utilizing a sensitive radioimmunoassay, that no AHF antigen was present in the cell cultures. Further, we have demonstrated this material to be tissue factor by coagulation techniques and immunological cross-reactivity. The published data regarding factor VIII synthesis is reviewed in light of these observations and comments are made regarding the role of the lymphocyte procoagulant.

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Frederick R. Rickles, John A. Hardin, Frances A. Pitlick, Leon W. Hoyer, Marcel E. Conrad

Effect of Phloretin on Water and Solute Movement in the Toad Bladder

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It is generally believed that urea crosses the cell membrane through aqueous channels, and that its movement across the membrane is accelerated in the direction of net water flow (solvent drag effect). The present report presents evidence for a vasopressin-sensitive pathway for the movement of urea, other amides, and certain non-amides, which is independent of water flow. Phloretin, when present at 10-4 M concentration in the medium bathing the luminal surface of the toad bladder, strongly inhibits the movement of urea, acetamide, and propionamide across the toad bladder, both in the absence and presence of vasopressin. The vasopressin-stimulated movement of formaldehyde and thiourea is also reduced. Osmotic water flow, on the other hand, is not affected; nor is the movement of ethanol and ethylene glycol, or the net transport of sodium. On the basis of these studies we would conclude that the movement of many, if not all, solutes across the cell membrane is independent of water flow, and that a vasopressin-sensitive carrier may be involved in the transport of certain solutes across the cell membrane.

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Sherman Levine, Nicholas Franki, Richard M. Hays

In Vitro Antibody-Enzyme Conjugates with Specific Bactericidal Activity

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IgG with antibacterial antibody opsonic activity was isolated from rabbit antisera produced by intravenous hyperimmunization with several test strains of pneumococci, Group A β-hemolytic streptococci, Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, and Escherichia coli. Antibody-enzyme conjugates were prepared, using diethylmalonimidate to couple glucose oxidase to IgG antibacterial antibody preparations. Opsonic human IgG obtained from serum of patients with subacute bacterial endocarditis was also conjugated to glucose oxidase. Antibody-enzyme conjugates retained combining specificity for test bacteria as demonstrated by indirect immunofluorescence. In vitro test for bactericidal activity of antibody-enzyme conjugates utilized potassium iodide, lactoperoxidase, and glucose as cofactors. Under these conditions glucose oxidase conjugated to antibody generates hydrogen peroxide, and lactoperoxidase enzyme catalyzes the reduction of hydrogen peroxide with simultaneous oxidation of I- and halogenation and killing of test bacteria. Potent in vitro bactericidal activity of this system was repeatedly demonstrated for antibody-enzyme conjugates against pneumococci, streptococci, S. aureus, P. mirabilis, and E. coli. However, no bactericidal effect was demonstrable with antibody-enzyme conjugates and two test strains of P. aeruginosa. Bactericidal activity of antibody-enzyme conjugates appeared to parallel original opsonic potency of unconjugated IgG preparations. Antibody-enzyme conjugates at concentrations as low as 0.01 mg/ml were capable of intense bactericidal activity producing substantial drops in surviving bacterial counts within 30-60 min after initiation of assay. These in vitro bactericidal systems indicate that the concept of antibacterial antibody-enzyme conjugates may possibly be adaptable as a mechanism for treatment of patients with leukocyte dysfunction or fulminant bacteremia.

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Daniel M. Knowles II, Timothy J. Sullivan III, Charles W. Parker, Ralph C. Williams Jr.

β-Thalassemia in the American Negro

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In Italian patients with high hemoglobin A2 β-thalassemia trait, the synthesis of β-chains of adult hemoglobin in the peripheral blood is approximately one-half that of α-chains. In this study the relative rates of β- and α-chain synthesis were determined in 26 Negro heterozygotes and five homozygotes for β-thalassemia in six families. The β/α ratio of globin synthesis was decreased in only 15 heterozygotes, whereas in the other 11, β/α globin synthesis was in the normal range or was slightly increased. These unusual findings did not appear to be due to the presence of α-thalassemia or a hyperactive “normal” β-allele. This study demonstrates that the β/α ratio of globin synthesis in the peripheral blood is normal in some patients with β-thalassemia trait. In five Negro homozygotes with relatively mild clinical disease the β/α ratios were similar to those of Caucasians with Cooley's anemia. Further studies are needed to explore the relationship between normal synthesis ratios in many Negro heterozygotes and milder clinical disease in homozygotes in the same families.

Authors

Shlomo Friedman, Robert W. Hamilton, Elias Schwartz

Effect of Conjugated Dihydroxy Bile Salts on Electrolyte Transport in Rat Colon

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The mechanism by which excess quantities of bile salts in the colon produce diarrhea is not known. Therefore, experiments were performed in which the effect of conjugated dihydroxy bile salts on ion transport was evaluated in the in vitro short-circuited rat colon. 2 mM glycochenodeoxycholic acid (GCDC), taurochenodeoxycholic acid (TCDC), or taurodeoxycholic acid caused a prompt increase in short-circuit current (Isc) and electrical potential difference (PD). Similar results were obtained when theophylline was added. Removal of HCO2 and C1 prevented the effects of both bile salts and theophylline. Pretreatment with theophylline blocked the increase in Isc and PD produced by TCDC and pretreatment with either TCDC or GCDC inhibited the expected theophylline response. Na fluxes in the presence of both TCDC and theophylline demonstrated a decrease in net absorption; and TCDC decreased net C1 absorption and theophylline caused a reversal of net C1 absorption to net C1 secretion. It is proposed that the diarrhea associated with cholerheic enteropathy is produced by active anion secretion possibly mediated by cyclic AMP.

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Henry J. Binder, Claudia L. Rawlins

Cholesterol Solubility in Bile. EVIDENCE THAT SUPERSATURATED BILE IS FREQUENT IN HEALTHY MAN

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The development and validation of a direct method for measuring maximum cholesterol solubility in bile is described. Application of this method to five large mammalian species, including man, produced a micellar zone significantly smaller than that previously reported. Further studies on in vitro model solutions patterned after bile confirmed this new micellar zone. Thus, direct evidence demonstrates that the micellar zone boundary derived in vitro from model solutions is applicable to human gallbladder bile. Using the present criteria, normal human bile, in contrast to bile from other mammalian species, is commonly supersaturated with cholesterol. A male-female difference in bile composition is not demonstrable despite the well-established female preponderance of cholelithiasis. Bile from patients with cholesterol cholelithiasis has a micellar zone similar to normals but differs compositionally in that there is a greater excess of cholesterol above saturation. We conclude that cholesterol supersaturation may be a necessary but not solely sufficient cause for gallstone formation.

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R. Thomas Holzbach, Mitsuko Marsh, Monica Olszewski, Keith Holan

A Micropuncture Study of Potassium Excretion by the Remnant Kidney

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In order to study the mechanism of enhanced potassium excretion by the remaining nephrons of the remnant kidney, micropuncture and clearance experiments were carried out in rats after surgical ablation of 3/4 of the total renal mass. The potassium intake in all animals was approximately 5 meq/day. Animals were studied 24 h and 10-14 days after 3/4 nephrectomy. Balance measurements in the chronic animals before micropuncture study indicated that 24 h K+ excretion by the remnant kidney was equal to that of the two kidneys before ablation of renal mass. Measurements of distal tubular inulin and potassium concentrations revealed progressive reabsorption of potassium in this segment of the nephron in both the 24-h and chronic 3/4-nephrectomized rats, as well as in normal control rats. A large increase in tubular fluid potassium content occurred between the end of the distal tubule and the final urine in the 3/4-nephrectomized rats, but not in the normal controls. These observations suggest that the segment of the nephron responsible for enhanced potassium excretion by remaining nephrons was the collecting duct.

Authors

Norman Bank, Hagop S. Aynedjian

Evidence for a Postsecretory Reabsorptive Site for Uric Acid in Man

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The effects of administration of drug combinations on uric acid excretion were studied in order to test the hypothesis that a portion of renal tubular reabsorption of uric acid occurs distal to the uric acid secretory site.

Authors

Herbert S. Diamond, James S. Paolino

Dynamics of Glomerular Ultrafiltration in the Rat. IV. DETERMINATION OF THE ULTRAFILTRATION COEFFICIENT

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Pressures and flow rates were measured in accessible surface glomeruli of mutant Wistar rats under conditions deliberately designed to prevent achievement of filtration pressure equilibrium, that is, the equalization of transcapillary hydrostatic and oncotic pressures by the efferent end of the glomerulus as typically observed in the normal hydropenic rat. Disequilibrium was obtained at elevated levels of glomerular plasma flow (GPF) brought about by acute expansion of plasma volume with a volume of rat plasma equal to 5% of body weight. Glomerular hydrostatic and oncotic pressures measured at high GPF were used to calculate the ultrafiltration coefficient, Kf, the product of effective hydraulic permeability and surface area. GPF was then either lowered (by aortic constriction) or raised (by carotid occlusion) in order to examine the dependence of Kf on GPF. The value of Kf per glomerulus, 0.08 nl/(s·mm Hg), was found not to vary over an approximately twofold range of GPF. This finding, taken together with data from previous studies from this laboratory, leads us to conclude that plasma-flow dependence of glomerular filtration rate (GFR) results primarily from flow-induced changes in mean ultrafiltration pressure, rather than large changes in Kf.

Authors

William M. Deen, Julia L. Troy, Channing R. Robertson, Barry M. Brenner

Effects of Corticosteroids and Splenectomy on the Immune Clearance and Destruction of Erythrocytes

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Corticosteroids and splenectomy constitute two important therapeutic modalities in the treatment of autoimmune hemolytic anemia. Each of these may affect both the rate of synthesis of autoantibody and the clearance of antibody sensitized cells. The latter possibility has been examined in an experimental model which allows evaluation of the role of antibody and complement in the immune clearance of erythrocytes in molecular terms. The in vivo clearance of 51Cr-labeled guinea pig erythrocytes sensitized with purified rabbit IgG or IgM antibody to produce a known number of complement-fixing sites per cell was studied.

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John P. Atkinson, Alan D. Schreiber, Michael M. Frank

Specificity and Sensitivity of Cortisol-Induced Changes in Alpha Aminoisobutyric Acid Transport in Human Leukemic Small Lymphocytes and Leukemic Myeloblasts

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We have examined the in vitro effect of glucocorticoid and nonglucocorticoid steroids on the transport of [3-14C]alpha aminoisobutyric acid (AIB) in lymphocytes from patients with chronic lymphocytic leukemia (CLL), and myeloblasts from patients with acute granulocytic leukemia (AGL). AIB uptake by CLL lymphocytes was markedly inhibited at 1.0 μM (52±2.1%) and slightly inhibited at 0.1 μM (17±3.0%) cortisol. A similar degree of inhibition developed at 50-fold lower concentrations of dexamethasone, indicating that the effect of these steroids on AIB accumulation parallels their glucocorticoid activity in vivo. In contrast, minimal or no inhibition was observed with steroids devoid of glucocorticoid activity (progesterone, testosterone, cortisone). 11-deoxycortisol, a nonglucocorticoid known to impede the binding of cortisol to cellular receptors in animal lymphocytes, failed to inhibit AIB uptake by CLL lymphocytes appreciably, but reduced the effect of cortisol to a statistically significant degree. Hence, cortisol-induced inhibition of AIB transport in CLL lymphocytes is related to its glucocorticoid activity and appears to require initial interaction with glucocorticoid-specific cellular receptors.

Authors

Patrick A. Frengley, Marshall A. Lichtman, William A. Peck