Health systems research in the mainstream of academic medicine.

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Paul A. Marks

Abstracts

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Effect of administered mineralocorticoids or ACTH in pregnant women: Attenuation of kaliuretic influence of mineralocorticoids during pregnancy

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The role of augmented aldosterone production in pregnancy is poorly understood. Whereas some consider aldosterone secretion in pregnancy excessive, others suggest that this is a compensatory phenomenon. According to yet another view, mechanisms other than the renin-angiotensin-aldosterone system control sodium homeostasis in pregnancy.

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Edward N. Ehrlich, Marshall D. Lindheimer

Metabolism of plasminogen in healthy subjects: effect of tranexamic acid

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The metabolism of human plasminogen labeled with radioactive iodine was studied in 12 healthy men. The labeled plasminogen had a high specific activity and the same elution on Sephadex G-100 as the plasminogen activity in plasma. Immunoelectrophoresis revealed a single precipitin line. Polyacrylamide gel electrophoresis revealed six main bands, all with plasminogen properties and radioactivity. The purified plasminogen behaved as a homogeneous protein in the turnover experiments. The plasma radioactivity data were adequately approximated by a sum of two exponential terms. The metabolism of plasminogen was therefore represented by a two-compartment mammillary model.

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D. Collen, G. Tytgat, H. Claeys, M. Verstraete, P. Wallén

Impaired lymphocyte transformation in intestinal lymphangiectasia: evidence for at least two functionally distinct lymphocyte populations in man

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Intestinal lymphangiectasia is a disease characterized by hypoproteinemia and edema resulting from protein-losing gastroenteropathy secondary to abnormal intestinal lymphatics. Immunologic abnormalities associated with this disease include hypogammaglobulinemia, lymphocytopenia, skin anergy, and impaired allograft rejection. In the present study, the in vitro blastogenic transformation of lymphocytes from 12 patients with intestinal lymphangiectasia was assessed in order to gain insight into the mechanism of the cellular immune defect in this disease.

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Paul L. Weiden, R. Michael Blaese, Warren Strober, Jerome B. Block, Thomas A. Waldmann

Glucose-induced alkalosis in fasting subjects: Relationship to renal bicarbonate reabsorption during fasting and refeeding

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This study documents the development of alkalosis in patients returning to caloric intake after a period of starvation and investigates the mechanisms responsible for this metabolic alteration. We studied the acid-base status, bicarbonate reabsorption, acid excretion, and sodium metabolism during fasting and glucose refeeding in 19 patients receiving sodium supplements.

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Bobby J. Stinebaugh, Francis X. Schloeder

Biliary excretion of lecithin and cholesterol in the dog

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The biliary excretion rates of bile acid, lecithin, and cholesterol were measured in unanesthetized dogs after interruption of enterohepatic circulation and during infusions of sodium taurocholate, sodium glycocholate, sodium dehydrocholate, SC2644 (a bicyclic organic acid with high choleretic potency), and secretin. Both lecithin output and cholesterol output were directly related to bile acid excretion rate. The curves describing these relationships were concave downward. Molar concentration ratios of lecithin-to-bile acid declined gradually from approximately 0.4 to 0.2 as bile acid output increased from approximately 1 to 70 μmoles/min. Cholesterol-to-lecithin molar ratios were highest (0.05-0.15) at very low rates of bile acid excretion, but descended rapidly to a plateau (0.03-0.04) which was constant over the entire range of bile acid excretion rates from 10 to 70 μmoles/min.

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Henry O. Wheeler, Katherine K. King

Characterization of the kinetics of the passive and active transport mechanisms for bile acid absorption in the small intestine and colon of the rat

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Bile acid uptake occurs via passive diffusion in all regions of the intestine and via active absorption in the ileum. Determination of the passive permeability coefficient for ionized monomers (*P-) demonstrated that permeability decreased by a factor of 3.4, 6.8, and 8.1 for the addition of a hydroxyl, glycine, or taurine group, respectively, to the steroid nucleus. Removal of the negative charge increased permeation by a factor of 4.4; however, permeability coefficients for the protonated monomers showed the same relative decrease with addition of a hydroxyl group. The calculated incremental free energies of solution (δΔFW→1) associated with these additions equaled + 757 (hydroxyl), + 1178 (glycine), and + 1291 (taurine) cal/mole. Passive permeability coefficients for the transverse colon showed the same relative relationships among the various bile acids. After making appropriate corrections for passive permeability across the ileum, apparent values for the maximal transport velocity (*Vmax) and Michaelis constant (*Km) of the active transport system were measured. *Vmax depended upon the number of hydroxyl groups on the steroid nucleus; values for the trihydroxy bile acids were high (1543-1906 pmoles/min per cm) while those for the dihydroxy (114-512 pmoles/min per cm) and monohydroxy (45-57 pmoles/min per cm) acids were lower. In contrast, *Km values were related to whether the bile acid was conjugated; unconjugated bile acids had values ranging from 0.37 to 0.49 mM, while values for the conjugated bile acids were approximately half as high (0.12-0.23 mM).

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Eugene R. Schiff, Neal C. Small, John M. Dietschy

Plasminogen-¹²⁵I responses in dogs to a single injection of urokinase and typhoid vaccine and to vascular injury

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In vivo plasminogen responses to various stimuli were studied. Plasminogen-125I was prepared and used first for metabolic studies of plasminogen in control dogs. The average results were: the plasma plasminogen, 29.3±4.1 (SD) mg/kg; the interstitial plasminogen, 8.79±4.47 (SD) mg/kg; the half-life of plasma plasminogen-125I, 2.81±0.24 (SD) days; the fractional direct catabolic rate of plasminogen (j3), 0.295 day-1; and the catabolic (synthetic) rate of plasminogen, 8.61±1.35 (SD) mg/kg per day. Studies were then made of the plasminogen-125I responses in dogs to a single injection of urokinase (A) and typhoid vaccine (B), and to vascular injury (C), which was produced by the damage of venous endothelium by a phenol injection. Effects of heparin were also studied in dogs given the phenol injection (D). Disc electrophoretic analysis of plasma showed generation of plasmin-125I in all except the control experiments. The duration of plasmin-125I generation was about 6 hr in A, 6 hr in B, and at least 5 days in C. Heparinization (D) shortened the duration of generation to about 6 hr. For further quantitative analysis of the tracer data, a model for coexistent plasminogen-125I and plasmin-125I was proposed and validated, from which some new analytical methods were derived. Using these methods, the average fractional rate of plasmin-125I generation from plasminogen-125I (j4) was 0.41 day-1 in A, 0.30 day-1 in B, 0.324 day-1 in C, and 0.382 day-1 in D. Further mathematical consideration showed that j3 was zero at least in C during plasmin generation. Plasminogen synthesis was unchanged in all experiments. The average fractional breakdown rate of plasmin-125I (j5) in A, B, C, and D was 1.19, 1.13, 1.35, and 1.11 day-1, respectively, and were closely similar. These results indicate that under normal conditions a major portion of plasminogen is directly catabolized without the formation of plasmin, but that significant amounts of plasmin were generated under the conditions described, that the normal process of direct breakdown of plasminogen is abolished during plasmin generation at least in C, and that the potential value of j5 determination should be further explored.

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Y. Takeda

The electrophysiologic effects of low and high digoxin concentrations on isolated mammalian cardiac tissue: reversal by digoxin-specific antibody

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The effects of digoxin on electrophysiologic properties were evaluated in isolated perfused cardiac tissue. In canine Purkinje fiber (PF)-ventricular muscle (VM) preparations, control measurements, using microelectrode technique, were made of: resting potential (RP), action potential (AP) amplitude, rate of rise, overshoot, duration (APD), membrane responsiveness, conduction velocity (CV), and refractory period. The preparation was then exposed to 1 × 10-7 M digoxin and repeat measurements were carried out every 15 min. At slow (30/min) rates of stimulation APD initially prolonged then markedly shortened. With more rapid stimulation (75 and 120/min) no initial APD prolongation was observed. When stimulated at 75/min, RP and AP rate of rise, amplitude, and CV remained near control values for 60-75 min then rapidly decreased until electrical inexcitability (110±15 min). At that time fibers were perfused with serum containing digoxin-specific antibody (DSA) or one of a group of test solutions. In the preparations exposed to DSA, membrane characteristics improved by 15 min, and by 60 min approximated control values. No beneficial effect was seen with the various test solutions. DSA also reversed digoxin-induced enhanced phase 4 depolarization in PF.

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William J. Mandel, J. Thomas Bigger Jr., Vincent P. Butler Jr.

Fetal bile salt metabolism: II. Hepatic excretion of endogenous bile salt and of a taurocholate load

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Bile salt metabolism was studied in fetal dogs 1 wk before term. The size and distribution of the fetal bile salt pool were measured, and individual bile salts were identified. The hepatic excretion of endogenous bile salts was studied in bile fistula fetuses, and the capacity of this excretory mechanism was investigated by the i.v. infusion of a load of sodium taurocholate-14C up to 20 times the endogenous pool size.

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R. A. Smallwood, R. Lester, G. J. Piasecki, P. D. Klein, R. Greco, B. T. Jackson

Inosinic acid dehydrogenase activity in the Lesch-Nyhan syndrome

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Inosinic acid dehydrogenase was evaluated in normal subjects and in patients with the Lesch-Nyhan syndrome. A significant difference in activity was found between erythrocytes derived from normal controls (1.21±0.47 pmoles/hr per mg protein) and from 15 patients with the Lesch-Nyhan syndrome (6.72±6.23 pmoles/hr per mg protein). However, no difference in activity was demonstrable in muscle or leukocytes derived from normal and Lesch-Nyhan patients. The increased activity of inosinic acid dehydrogenase in erythrocytes from patients with the Lesch-Nyhan syndrome is due to stabilization of the enzyme in vivo as well as the absence of an inhibitor which is present in erythrocytes from normal subjects.

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D. Michael Pehlke, John A. McDonald, Edward W. Holmes, William N. Kelley

Renal handling of sodium and water in the hypothyroid rat: Clearance and micropuncture studies

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Hypothyroid rats were examined with conventional renal clearance and micropuncture techniques to elicit the mechanism and site within the nephron responsible for the increased salt and water excretion observed in these animals. When compared with age-matched control rats, a decrease in inulin clearance of 30% (P < 0.001) and in Hippuran clearance of 32% (P < 0.005) was observed in the hypothyroid rats. Absolute excretion of sodium and water was increased 3-fold (P < 0.02) and 2-fold (P < 0.025), respectively, while fractional excretion of sodium and water was increased 4.3-fold (P < 0.02) and 2.9-fold (P < 0.05), respectively, in the hypothyroid animals.

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Ulrich F. Michael, Robert L. Barenberg, Rafaelita Chavez, Carlos A. Vaamonde, Solomon Papper

Site of stimulation of aldosterone biosynthesis by angiotensin and potassium

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Studies were undertaken to determine what part of the aldosterone biosynthetic pathway is stimulated by angiotensin and potassium. The availability of a method for isolating the early portion of the aldosterone pathway and a new method for measuring plasma deoxycorticosterone permitted the design of experiments to determine whether angiotensin and potassium stimulate the pathway before deoxycorticosterone. To eliminate ACTH-dependent steroid synthesis, the experiments were performed in subjects receiving constant dosage of dexamethasone. To minimize the intra-adrenal conversion of deoxycorticosterone to corticosterone, all subjects also received constant dosage of metyrapone. Plasma deoxycortisol was measured as an index of the activity of the zona fasciculata. In the absence of changes in plasma deoxycortisol, one may infer that changes in plasma deoxycorticosterone represent changes in function of zona glomerulosa, the site of aldosterone formation. Under these conditions, human subjects responded both to angiotensin and to potassium with significant increases in plasma deoxycorticosterone but without significant increases in plasma deoxycortisol. In contrast, small doses of ACTH given under similar conditions never induced increases in plasma deoxycorticosterone without simultaneously inducing large increases in plasma deoxycortisol. It is concluded that the aldosterone-stimulating effects of angiotensin and potassium are, at least in part, consequences of stimulation of the biosynthetic pathway at some point before the formation of deoxycorticosterone so as to increase the availability of aldosterone precursors.

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Ronald D. Brown, Charles A. Strott, Grant W. Liddle

Peptide hydrolases in the brush border and soluble fractions of small intestinal mucosa of rat and man

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Peptide hydrolases, catalyzing the hydrolysis of 13 dipeptides and 5 tripeptides into their respective amino acids, were studied in small intestinal mucosa and other tissues, in man and in the rat.

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Y. S. Kim, W. Birtwhistle, Y. W. Kim

Impaired utilization of serum folate in pernicious anemia: A study with radiolabeled 5-methyltetrahydrofolate

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The possible role of cobalamins in the utilization of serum methyltetrahydrofolate has been investigated by means of radiolabeled methyltetrahydrofolate in subjects suffering from pernicious anemia. After intravenous administration, methyltetrahydrofolate-3H (SA 11,500 Ci/mole; dose 0.05 μg/kg) was cleared from the serum to tissues of B12-deficient subjects half as fast as after the same subjects had received vitamin B12 therapy. B12 deficiency was also associated with an increased rate of renal excretion of methyltetrahydrofolate or its derivatives, and a decreased rate of renal metabolism of methyltetrahydrofolate to other urinary folate derivatives.

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Peter F. Nixon, Joseph R. Bertino

Hypoalaninemia: a concomitant of ketotic hypoglycemia

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The cause of of ketotic hypoglycemia, the commonest form of hypoglycemia in childhood, is not known. The present study was undertaken to determine whether the primary defect in this condition is a deficiency of gluconeogenic precursor(s) or an abnormality in the hepatic gluconeogenic enzyme system. Plasma glucose, alanine, and insulin and blood β-hydroxybutyrate (β-OHB), pyruvate, and lactate levels were determined in eight ketotic hypoglycemic children and seven agematched controls maintained on a normal diet and after being fed a provocative hypocaloric low-carbohydrate diet (1200 kcal/1.73 m2, 15% carbohydrate, 17% protein, and 68% fat). On a normal diet, overnight fasting plasma alanine (211±10 μM) and glucose (68±4 mg/100 ml) were significantly lower and blood β-OHB (1.22±0.37 mM) significantly higher in ketotic hypoglycemic children than in controls (alanine, 315±15 μM; glucose, 81±3 mg/100 ml; β-OHB, 0.18±0.08 mM).

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Anthony S. Pagliara, Irene E. Karl, Darryl C. De Vivo, Ralph D. Feigin, David M. Kipnis

The relation between cholesterol absorption and cholesterol synthesis in the baboon

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To determine the relation between cholesterol absorption, total endogenous cholesterol synthesis, and hepatic cholesterol synthesis in a primate, cholesterol synthesis has been studied in biopsies of liver and ileum from normal baboons fed varying amounts of cholesterol and in biopsies of liver from baboons that had been subjected to ileal diversion. In addition, total cholesterol production rates, cholesterol absorption, and total endogenous cholesterol synthesis have been measured in these animals by a double isotope technique in which the animals were given a single injection of cholesterol-4-14C and fed constant amounts of cholesterol-1,2-3H for 4 months. From these studies, it has been concluded that on a low cholesterol intake cholesterol synthesis in the liver accounts for about three-fourths of total endogenous cholesterol production. The feeding of cholesterol produces complete inhibition of hepatic synthesis in the normal animal only when absorption approximates the amount synthesized by the liver when no cholesterol is fed, e.g., 400-500 mg/day. Finally, the intestine, which does not possess complete negative feedback control of cholesterol synthesis when cholesterol is fed, may be a significant site of nonhepatic cholesterol synthesis in these animals.

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Jean D. Wilson

Metabolism of testosterone-¹⁴C by cultured human cells

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The metabolism of 14C-labeled testosterone by cultured human fibroblasts and amniotic fluid cells was investigated. Radiolabeled testosterone was incubated with the cultured cells for 48 hr, and the labeled metabolites present in the medium were subsequently identified. The major metabolic products of testosterone formed by cultured fibroblasts were Δ4-androstenedione, dihydrotestosterone, androsterone, and androstanediol. The amount of testosterone metabolized through each of two pathways was calculated and used to form a ratio designated the 17β-hydroxyl/17-ketonic ratio. Fibroblasts from normal male and female children and adult females had high 17β-hydroxyl/17-ketonic ratios indicating testosterone metabolism occurred primarily through the 17β-hydroxyl pathway. There was change in the pattern of testosterone metabolism with age in males, i.e., adult males had much lower 17β-hydroxyl/17-ketonic ratios than did male children.

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Donna D. Shanies, Kurt Hirschhorn, Maria I. New

Effects of adrenergic stimulation on ventilation in man

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The mechanism by which catecholamines affect ventilation in man is not known. Ventilatory responses to catecholamines were observed in normal subjects before and after adrenergic receptor blockade. Intravenous infusions of norepinephrine and isoproterenol caused significant increases in minute volume and decreases in end-tidal PCo2 which were blocked by the administration of propranolol, a beta adrenergic receptor blocker. The hyperventilatory response to hypoxia was not altered by propranolol.

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Donald D. Heistad, Robert C. Wheeler, Allyn L. Mark, Phillip G. Schmid, Francois M. Abboud

Studies on the secretion of newly synthesized proinsulin and insulin from isolated rat islets of langerhans

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Islets of Langerhans isolated from rat pancreas were incubated at 37°C(95% O2/5% CO2) in buffered medium containing 1.0 mg/ml glucose and leucine 3H for 1 hr (1st hr), washed, and incubated for an additional hr (2nd hr) in low glucose medium (0.5-1.0 mg/ml) containing unlabeled leucine. A portion of the islets was then extracted with acid-ethanol and the remainder were transferred to medium containing 3.0 mg/ml glucose and incubated for 2 hr (3rd and 4th hr) at 37°C. The medium was exchanged at 30-min intervals and portions of the islets were extracted at the 3rd and 4th hr. The total amounts and specific activities of the proinsulin and insulin in the islet extracts and medium samples were determined after fractionation on Biogel P-30 columns in 3 M acetic acid.

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Hiroyuki Sando, Jo Borg, Donald F. Steiner

Evidence for the identity of the major apoprotein in low density and very low density lipoproteins in normal subjects and patients with familial hyperlipoproteinemia

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The major apoprotein(s) from human plasma low density lipoproteins was isolated and compared with a major protein fraction (fraction I) from very low density lipoproteins (VLDL). Fraction I had been previously found to comprise approximately 40% of the total protein of VLDL. Fraction I from VLDL and apoLDL from normal subjects were indistinguishable in amino acid compositions and circular dichroic spectra. They yielded indistinguishable displacement curves of LDL-125I by radioimmunoassay and formed immunoprecipitin lines of complete identity. Fraction I from VLDL of normal subjects was compared with the fraction isolated from patients with familial types II, III, IV, and V hyperlipoproteinemia. There were no detectable differences between any of these fractions in amino acid compositions, circular dichroic spectra, and immunochemical properties. It was, therefore, concluded that short of peptide mapping or determination of amino acid sequence, fraction I from VLDL of each subject with familial hyperlipoproteinemia appears to be identical with fraction I and apoLDL from normal individuals.

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A. M. Gotto, W. V. Brown, R. I. Levy, Maria E. Birnbaumer, D. S. Fredrickson

The formation of abnormal bile and cholesterol gallstones from dietary cholesterol in the prairie dog

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To study the pathogenesis of cholesterol gallstones, we fed 24 adult male prairie dogs a high cholesterol, egg yolk diet. 13 control animals received a cholesterol-free diet. All animals fed the egg yolk diet formed multiple gallstones in 2-6 months' time. These stones contained cholesterol, 77±14% by dry weight. No stones ocurred in the control group.

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D. E. Brenneman, William E. Connor, E. L. Forker, Larry DenBesten

Simultaneous study of the metabolic turnover and renal excretion of salivary amylase-¹²⁵I and pancreatic amylase-¹³¹I in the baboon

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The metabolic turnover of salivary and pancreatic amylase was studied in the baboon, an animal with a serum amylase level and renal clearance of amylase similar to man. Purified amylase was electrolytically iodinated. Although iodinated and uniodinated amylase had similar gel filtration, electrophoretic, enzymatic, glycogen precipitation characteristics, the labeled enzyme was cleared less rapidly by the kidney than was the unlabeled material. However, urinary iodinated amylase which had been biologically screened by the kidney had a renal clearance and serum disappearance rate indistinguishable from unlabeled amylase and thus can serve as a tracer in metabolic turnover studies. Administration of a mixture of salivary amylase-125I and pancreatic amylase-131I made it possible to simultaneously measure the serum disappearance and renal clearance of these two isoenzymes. The metabolic clearance of both isoenzymes was extremely rapid with half-times of about 130 min. This rapid turnover of serum amylase probably accounts for the transient nature of serum amylase elevation which frequently occurs in pancreatitis. Pancreatic amylase-131I was consistently cleared more rapidly (mean clearance ratio: 1.8) by the kidney than was salivary amylase-125I. This more rapid renal clearance of pancreatic amylase may help to explain the disproportionate elevation of urinary amylase relative to serum amylase observed in pancreatitis.

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William C. Duane, Roger Frerichs, Michael D. Levitt

A natriuretic factor in the serum of patients with chronic uremia

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Sera from chronically uremic and normal individuals were subjected to gel filtration with Sephadex G-25 and the same fraction of both was infused into rats with a decreased nephron population to determine the effects on sodium excretion. Sodium excretion rate and fractional sodium excretion increased slightly with the normal fractions; but the increase in both functional parameters produced by the uremic fractions was substantially and significantly greater. The natriuresis could not be explained by associated changes in glomerular filtration rate (GFR), para-aminohippurate (PAH) clearance, filtration fraction, hematocrit, or blood pressure. The possibility thus exists that the inhibitor affected some component part of the transepithelial sodium transport system. The elution characteristics of the fraction plus certain of its physicochemical properties suggest that the inhibitor of sodium reabsorption by the rat nephron may be identical with the inhibitor of PAH uptake by kidney slices and the inhibitor of transepithelial sodium transport by the frog skin and toad bladder previously found in the serum of chronically uremic patients.

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Jacques J. Bourgoignie, Kuo Hwa Hwang, Carlos Espinel, Saulo Klahr, Neal S. Bricker

The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia

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The metabolism of low density lipoprotein (LDL, beta lipoprotein) was studied in 10 normal individuals and 10 patients with familial type II hyperlipoproteinemia using purified radioiodinated LDL. Over 97% of the label was bound to the protein moiety of LDL and therefore the turnover data reflect the fate and distribution of LDL-apoprotein. Comparison of the metabolic behavior of biologically screened and unscreened labeled LDL preparations in dogs as well as the analysis of the urinary excretion of radioiodide derived from labeled LDL degradation in humans indicated that no significant denaturation resulted from the isolation, purification, and labeling techniques.

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Terry Langer, Warren Strober, Robert I. Levy

Glycerol turnover and oxidation in man

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The oxidation and turnover of plasma glycerol has been studied in lean and obese, fed and starving man by means of a long-term infusion of glycerol-14C, and the participation of glycerol in gluconeogenesis has been determined.

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Walter M. Bortz, Pavle Paul, Agnes C. Haff, William L. Holmes

Energy metabolism in human erythrocytes: II. Effects of glucose depletion

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Normal red cells were incubated in the absence of glucose to develop a system in which total adenosine triphosphate (ATP) turnover could be assessed. After 1 hr, the triose pool had been completely consumed. Thereafter, the metabolism of 2,3-diphosphoglycerate (DPG) to pyruvate and lactate was the sole significant source of ATP synthesis.

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Stephen A. Feig, George B. Segel, Stephen B. Shohet, David G. Nathan

Restoration and maintenance of glomerular filtration by mannitol during hypoperfusion of the kidney

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Glomerular filtration (GF) during progressive reduction of renal perfusion pressure by aortic clamping was studied in hydropenic rats and in rats infused with isotonic saline, hypertonic saline, or mannitol. As judged by visual observation of Lissamine green movements in superficial nephrons. GF was absent in hydropenic or saline-loaded rats at 40 mm Hg aortic pressure, but continued in some nephrons of all rats infused with mannitol and of some rats infused with hypertonic saline. Urine flow persisted only in rats infused with mannitol. By use of the qualitative Hanssen technique, it was found that all glomeruli in superficial and deep portions of the cortex were perfused at 40 mm Hg in all groups of rats. By the same method. GF continued in 1% of nephrons in hydropenic rats, 12% of nephrons in isotonic saline-loaded rats, and 78% of nephrons in rats infused with mannitol. By means of a quantitative Hanssen technique, GF was 5.8 nl/min per nephron in mannitol-infused rats and not measurable (< 0.5 nl) in hydropenic rats. Superficial and deep nephrons were similar in both qualitative and quantitative studies. Although urine flow did not persist in rats infused with hypertonic saline, GF was detected in four of seven studies by the Hanssen method (mean, 9.1 nl/min per nephron). In additional experiments, mannitol infused after perfusion pressure had already been lowered to 40 mm Hg in hydropenic rats reestablished urine flow and GF (mean, 9.8 nl/min). Furosemide, isotonic and hypertonic saline did not restart urine flow; however, GF (Lissamine green) was restarted by hypertonic saline. We conclude that mannitol can maintain or reestablish by an extratubular mechanism GF which otherwise would not occur during renal hypoperfusion. Hypertonic saline has a similar effect on GF in some cases, but urine flow is not maintained, implying complete reabsorption of filtrate.

Authors

C. Richard Morris, Edward A. Alexander, Frank J. Bruns, Norman G. Levinsky

Altered membrane sodium transport in Bartter's syndrome

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To explore the possibility that Bartter's syndrome is the manifestation of an inherited abnormality of sodium transport, we have measured various parameters of sodium transport in erythrocytes from patients with Bartter's syndrome, their siblings, and their parents. Sodium transport in six of the eight patients with Bartter's syndrome differed significantly from that in the other two patients. On the basis of this difference, the patients were divided into two groups (type I and type II). In the six type I patients, fractional sodium outflux (0.38±0.05/hr [SD]) was significantly less than normal (0.50±0.07) and erythrocyte sodium concentration (9.48±0.84 mmoles/liter cells per hr) was significantly greater than normal (5.24±0.66). In the two type II patients, none of the measured parameters of sodium transport differed significantly from normal. Erythrocyte sodium transport in the relatives of three type I patients was altered in a way similar to that in the type I patients and was significantly different from that in the relatives of a type II patient. These findings indicate the presence of inherited alterations of erythrocyte sodium transport in certain patients with Bartter's syndrome.

Authors

Jerry D. Gardner, Artemis P. Simopoulos, Allen Lapey, Shlomo Shibolet

Thyroxine-induced stimulation of hepatic cell transport of calcium and magnesium

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The effect of L-thyroxine on the bidirectional transport of calcium and magnesium in rat liver was assessed in vitro. An increase of 34% in the fractional coefficient for calcium influx was observed 24 hr after the administration of 500 μg of thyroxine. Chronic treatment with thyroxine for 1 and 3 wk at a dose of 750 μg/wk resulted in increases in calcium influx of 57 and 51%, respectively. Calcium efflux was increased irregularly, by 14-26%. Magnesium transport measured in a similar system was not altered by 24 or 48 hr of treatment with thyroxine, but continuation of treatment for 1-3 wk resulted in increases in magnesium influx of 47-49%. Magnesium efflux was not significantly affected. Neither increased cellular binding of divalent cations nor enhanced protein synthesis could be incriminated in the stimulatory effect of thyroxine on divalent cation transport. Actinomycin-D and D,L-ethionine, inhibitors of protein synthesis, stimulated calcium and magnesium transport in liver independently of the effects of thyroxine. These data present the possibility that certain actions of thyroid hormone may be mediated or modulated by associated, direct changes in the cellular transport and intracellular concentrations of divalent cations.

Authors

Stanley Wallach, J. V. Bellavia, P. J. Gamponia, P. Bristrim

Solubilized myocardial adenylate cyclase: Restoration of histamine responsiveness by phosphatidylserine

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We have recently described the preparation of a solubilized cat myocardial adenylate cyclase which is unresponsive to histamine, norepinephrine, glucagon, and thyroxine, the hormones which activate the particulate enzyme. Since hormone receptors may consist of proteins and phospholipids, we determined the effect of several phospholipids on restoring the responsiveness of the solubilized adenylate cyclase to histamine. The addition of phosphatidylserine completely restored the histamine-mediated activation of the solubilized enzyme in contrast to phosphatidylethanolamine and phosphatidylinositol which were without effect. The concentration of histamine producing half-maximal activation of adenylate cyclase, 2 × 10-5 M, was virtually identical with that observed in the particulate preparation. The antihistamine, diphenhydramine, 8 × 10-5 M, abolished activation of adenylate cyclase by histamine in both the solubilized and particulate preparations. Phosphatidylserine also restored glucagon responsiveness, but did not restore norepinephrine responsiveness. It would appear that phosphatidylserine produced the necessary molecular configuration of the adenylate cyclase for histamine binding and activation of the enzyme.

Authors

Gerald S. Levey, Irwin Klein

Ouabain-specific antibodies: immunochemical properties and reversal of Na⁺, K⁺-activated adenosine triphosphatase inhibition

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Antibodies with high affinity and specificity for the cardiac glycoside ouabain were raised in rabbits. The antigen used was a conjugate of ouabain linked through its rhamnose moiety to terminal α-amino groups of poly D,L alanyl-human serum albumin. Ouabain-specific antibodies were present as early as 3 wk, and rose steadily in titer over the initial 20-33 wk of immunization. Levels as high as 6.5 mg specific immunoglobulin per ml antiserum were reached in one rabbit at the end of 45 wk. The average intrinsic association constants for ouabain were 1.3 × 109 M-1 and 1.6 × 109 M-1 in antisera studied in detail, and there was evidence of restricted heterogeneity of binding site affinities. A high degree of specificity was demonstrated. Significant cross-reactivity occurred only with other cardioactive steroid compounds such as acetyl strophanthidin, digoxin, and digitoxin, while endogenous steroids did not cross-react even when present in 1000-fold excess. A rapid and convenient radioimmunoassay procedure for plasma or urine ouabain concentrations was developed using these antibodies. Competition between ouabain-3H tracer and unlabeled ouabain for specific antibody binding sites allowed the measurement of ouabain concentrations as low as 0.1 ng/ml or less without need for extraction procedures. The high association constants observed in these studies permit antibody reversal of established myocardial effects of ouabain. Both blockade and reversal of ouabain inhibition of canine myocardial microsomal Na+, K+-activated ATPase by antibody were documented, suggesting a possible mechanism for reversal of cellular effects.

Authors

Thomas W. Smith

Unstable variant of NADH methemoglobin reductase in puerto ricans with hereditary methemoglobinemia

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Abstract

The electrophoretic mobility of erythrocyte NADH methemoglobin reductase in five hereditary methemoglobinemia patients from three Puerto Rican kindreds was 118% of normal at pH 8.6. The methemoglobin ferrocyanide reductase activity of the enzyme in erythrocyte hemolysates was 3.2-6.4% of normal. Electrophoresis of hemolysates prepared from the blood of patients from two different families at six pH values between 4.6 and 9.3 did not differentiate between the variant enzymes. Examination of the deficient enzymes extracted from the erythrocytes of one patient from each kindred revealed altered affinity for NADH and dichloroindophenol dye and decreased thermal stability. The quantitative similarity of the abnormal findings, together with the Puerto Rican origin of the kindreds, suggested that the cyanotic patients possessed the same abnormal enzyme and were thus homozygous for the same rare mutant gene. Consanguinity of the kindreds could not be established.

Authors

Joel M. Schwartz, Philip S. Paress, Jonathan M. Ross, Frank DiPillo, Rafael Rizek

Predominance of histocompatibility antigen HL-A8 in patients with gluten-sensitive enteropathy

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Abstract

HL-A phenotypes were determined in 24 unrelated patients with gluten-sensitive enteropathy (GSE) using a lymphocyte microcytotoxicity test. 21 of the 24 patients had HL-A8 in the second segregant series, a frequency of 0.875. In contrast, the HL-A8 frequency in 200 normal individuals was 0.215 (difference significant at P < 0.002), and in 6 patients with villous atrophy due to tropical sprue or hypogammaglobulinemia the HL-A8 frequency was 0.17 (difference from normal not significant). The HL-A types in the families of three HL-A8 positive patients with GSE indicated that the HL-A8 antigen was inherited as an autosomal dominant. Frequencies of the other HL-A antigens in the GSE group did not differ significantly from that of the normal group. These findings are compatible with the hypothesis that GSE is due to the presence of an abnormal “immune response (Ir) gene,” leading to the production of pathogenic antigluten antibody or, alternatively, to the presence of a particular membrane configuration leading to the binding of gluten to epithelial cells with subsequent tissue damage.

Authors

Z. Myron Falchuk, G. Nicholas Rogentine, Warren Strober