Renal Tubular Transport of Organic Acids: STUDIES WITH OXALATE AND PARA-AMINOHIPPURATE IN THE RAT

• Text
• PDF

Abstract

The renal handling of oxalate was examined by free-flow micropuncture, intratubular microinjection, and droplet precession techniques in the rat. After the sustained i.v. infusion of [14C]oxalate, the fractional delivery of oxalate from the early portions of the proximal tubule was 120.1±4.4%, indicating net secretion. Fractional delivery rates from the late proximal tubule (124.6±6.1), distal tubule (120.9±2.9), and final urine (126.2±2.9%) were not different from that of the early proximal tubule. Direct intratubular microinjections of oxalate into the early proximal tubule and late proximal tubule yielded urinary recovery rates of 85±3% and 101±2%, respectively, suggesting that oxalate absorption does occur in the mid-portions of the proximal tubule. Droplet precession studies confirmed a secretory flux for oxalate. In contrast to oxalate, para-aminohippurate (PAH), the more traditional marker for organic acid transport, was secreted in the late portions of the proximal tubule and in large measure at a site between the late proximal and distal tubules, presumably the pars recta. Probenecid inhibited PAH secretion but was without effect on net oxalate transport, oxalate absorption, or oxalate secretion.

Authors

E. J. Weinman, S. J. Frankfurt, A. Ince, S. Sansom

Cardiac and Renal Prostaglandin I₂: BIOSYNTHESIS AND BIOLOGICAL EFFECTS IN ISOLATED PERFUSED RABBIT TISSUES

• Text
• PDF

Abstract

Both the isolated perfused rabbit heart and kidney are capable of synthesizing prostaglandin (PG) I2. The evidence that supports this finding includes: (a) radiochemical identification of the stable end-product of PGI2, 6-keto-PGF1α, in the venous effluent after arachidonic acid administration; (b) biological identification of the labile product in the venous effluents which causes relaxation of the bovine coronary artery assay tissue and inhibition of platelet aggregation; and (c) confirmation that arachidonic acid and its endoperoxide PGH2, but not dihomo-γ-linolenic acid and its endoperoxide PGH1, serve as the precursor for the coronary vasodilator and the inhibitor of platelet aggregation. The rabbit heart and kidney are both capable of converting exogenous arachidonate into PGI2 but the normal perfused rabbit kidney apparently primarily converts endogenous arachidonate (e.g., generated by stimulation with bradykinin, angiotensin, ATP, or ischemia) into PGE2; while the heart converts endogenous arachidonate primarily into PGI2. Indomethacin inhibition of the cyclo-oxygenase unmasks the continuous basal synthesis of PGI2 by the heart, and of PGE2 by the kidney. Cardiac PGI2 administration causes a sharp transient reduction in coronary perfusion pressure, whereas the intracardiac injection of the PGH2 causes an increase in coronary resistance without apparent cardiac conversion to PGI2. The perfused heart rapidly degrades most of the exogenous endoperoxide probably into PGE2, while exogenous PGI2 traverses the heart without being metabolized. The coronary vasoconstriction produced by PGH2 in the normal perfused rabbit heart suggests that the endoperoxide did not reach the PGI2 synthetase, whereas the more lipid soluble precursor arachidonic acid (exogenous or endogenous) penetrated to the cyclooxygenase, which apparently is tightly coupled to the PGI2 synthetase.

Authors

Philip Needleman, Sue D. Bronson, Angela Wyche, Mark Sivakoff

Interaction of Polymorphonuclear Neutrophils with Escherichia Coli: EFFECT OF ENTEROTOXIN ON PHAGOCYTOSIS, KILLING, CHEMOTAXIS, AND CYCLIC AMP

• Text
• PDF

Abstract

Enterotoxigenic Escherichia coli are associated with noninflammatory diarrhea and stimulate adenylate cyclase activity of mammalian cells, thereby increasing intracellular cyclic adenosine 3′,5′-monophosphate (cyclic AMP). Increased concentrations of cyclic AMP in polymorphonuclear neutrophils (PMN) inhibit phagocytosis, candidacidal activity, granule discharge, and chemotactic responsiveness. We examined the effect of enterotoxin on the interaction of human PMN with E. coli. Enterotoxigenic and nonenterotoxigenic strains, including serotypes of E. coli identical except for the presence or absence of the plasmid coding for enterotoxin production, were utilized. Enterotoxigenic and nonenterotoxigenic E. coli, tumbled with PMN, were phagocytized and killed (>97%) equally well, and these strains stimulated PMN hexose monophosphate shunt activity equivalently.

Authors

Mark J. Bergman, Richard L. Guerrant, Ferid Murad, Stephen H. Richardson, David Weaver, Gerald L. Mandell

Control of the Acute Phase Response: SERUM C-REACTIVE PROTEIN KINETICS AFTER ACUTE MYOCARDIAL INFARCTION

• Text
• PDF

Abstract

In order to investigate the magnitude and kinetics of the C-reactive protein (CRP) response after differing degrees of tissue injury, we studied changes in serum concentration of this acute phase protein in 19 patients after mild or extensive acute myocardial infarction. An increase in serum CRP concentration was seen in all patients. The rate of increase in concentration was found to be exponential, with a mean hourly rate constant for the entire group of patients of 0.085 (doubling time, 8.2 h). Patients with extensive infarction attained mean serum CRP levels about 4 times as great as did patients with mild infarction. No difference could be shown in the mean rate constant between these groups, the greater CRP response in the former group resulting principally from a more protracted period of rise in serum CRP concentration. A lag period before serum CRP levels began to rise was noted in only 4 of the 13 patients in whom this could be assessed. 7 of 10 patients with presumed unstable angina (coronary insufficiency) showed no rise in CRP concentration, while a small increase as noted in 3 patients. The data suggest that acute tissue injury, such as myocardial infarction, rapidly leads to acceleration in synthesis of CRP, and that the duration of this period of acceleration is related to the extent of tissue injury.

Authors

Irving Kushner, Martin L. Broder, David Karp

Multicompartmental Analysis of Cholesterol Metabolism in Man: CHARACTERIZATION OF THE HEPATIC BILE ACID AND BILIARY CHOLESTEROL PRECURSOR SITES

• Text
• PDF

Abstract

The present report has presented the first clear evidence in man for the existence of specific hepatic cholesterol precursor sites associated with the formation and secretion of bile acids and biliary cholesterol. These hepatic compartments derive virtually all their cholesterol from newly synthesized and lipoprotein free cholesterol. The model which is presented was formulated on current concepts of cholesterol metabolism in man and is concerned, at this initial stage, with the elucidation of the bile acid and biliary cholesterol compartments. The complexity of cholesterol metabolism in man necessitated an initial approach that would minimize the number of inputs of cholesterol into the system, allow for the sampling of several cholesterol compartments, and permit the simultaneous labeling of newly synthesized cholesterol and preformed cholesterol. To achieve these objectives, we studied the patient with a total bile fistula. Six patients were administered simultaneously pulse injections of labeled mevalonic acid and [14C]cholesterol. The qualitative features of the specific activity time course curves after labeled mevalonic acid revealed no precursor-product relationship between bile acid, biliary cholesterol, and plasma free cholesterol. The peak specific activity of the bile acids was reached in approximately 100 min and was higher than the biliary cholesterol, which was higher than the plasma free cholesterol. The plasma free cholesterol specific activity became higher than the other lipids after 12 h and remained higher throughout the period of study. Similar related observations were made with [14C]cholesterol. The data were then subjected to simulation analysis and modeling using the SAAM-27 computer program. Computer least-square fits of the data were obtained after the model was evolved. During the model development, the least number of compartments and transport pathways were introduced consistent with a good fit of the data. Of particular importance was the constraint that the model fit the data obtained from both [14C]cholesterol and labeled mevalonic acid. The same parameter values were used to fit the data from both tracers. The fluxes arrived at in the model indicate that 31% and 20%, respectively, of the cholesterol input into the bile acid and biliary cholesterol precursor sites were derived directly from the newly synthesized hepatic cholesterol. The remainder had its origin predominantly from lipoprotein free cholesterol. Plasma esterified cholesterol (as free) made a small contribution (11%) to the bile acid compartment. Similarly, 10% of the biliary cholesterol arose from an unknown hepatic site.

Authors

Charles C. Schwartz, Mones Berman, Z. R. Vlahcevic, L. Gregg Halloran, Daniel H. Gregory, Leon Swell

Influence of Basal Insulin and Glucagon Secretion on Potassium and Sodium Metabolism: STUDIES WITH SOMATOSTATIN IN NORMAL DOGS AND IN NORMAL AND DIABETIC HUMAN BEINGS

• Text
• PDF

Abstract

To examine the role of basal insulin and glucagon secretion in potassium and sodium homeostasis, somatostatin, a potent inhibitor of insulin and glucagon secretion, was infused for 5 h into healthy human subjects, maturity-onset diabetes, juvenile-onset diabetics, and normal dogs. Infusion of somatostatin resulted in an increase in serum potassium (0.5-0.6 meq/liter) in normal subjects and maturity-onset diabetics, but not in juvenile-onset diabetics despite equivalent reductions in plasma glucagon in all three groups. A similar rise in serum potassium was observed in normal conscious dogs given somatostatin and was reversed by insulin replacement. Urinary excretion of potassium was unaffected by somatostatin.

Authors

Ralph A. Defronzo, Robert S. Sherwin, Mark Dillingham, Rosa Hendler, William V. Tamborlane, Philip Felig

Studies in Porphyria: VII. INDUCTION OF UROPORPHYRINOGEN-I SYNTHASE AND EXPRESSION OF THE GENE DEFECT OF ACUTE INTERMITTENT PORPHYRIA IN MITOGEN-STIMULATED HUMAN LYMPHOCYTES

• Text
• PDF

Abstract

A 50% reduction in the activity of uroporphyrinogen-I (URO) synthase in liver, erythrocytes, and cultured skin fibroblasts characterizes all patients with clinically active acute intermittent porphyria (AIP). The same enzyme defect has also been demonstrated in the erythrocytes and skin fibroblasts of completely latent gene carriers of this disorder and presumably exists in the liver as well.

Authors

Shigeru Sassa, Gregory L. Zalar, Attallah Kappas

Antibody-Dependent Cellular Cytotoxicity in Primary Immunodeficiency Diseases and with Normal Leukocyte Subpopulations: IMPORTANCE OF THE TYPE OF TARGET

• Text
• PDF

Abstract

To gain insight into a possible role for antibody-dependent cell-mediated cytotoxicity in vivo, we examined the ability of leukocytes from 28 patients with primary immunodeficiency and from 20 normal controls to lyse three different types of antibody-coated targets in vitro. Mean cytotoxic indices ±1 SD elicited by unfractionated mononuclear cells from normal controls were 28.74±13.26 for human HLA antibody-coated lymphocyte targets, 42.79±8.27 for rabbit IgG antibody-coated chicken erythrocyte targets, and 47.58±10.34 for human anti-CD (Ripley)-coated O+ erythrocyte targets. Significantly (P=<0.05) lower than normal mean cytotoxic indices against lymphocyte targets were seen with effector cells from 10 patients with X-linked agammaglobulinemia (3.7±4.33), in 10 with common variable agammaglobulinemia (16.05±7.74), in 3 with immunodeficiency with hyper IgM (18.41±4.88), and in 2 with severe combined immunodeficiency (3.94±0.3). Antibody-dependent cytotoxicity against chicken erythrocytes was significantly (P=<0.05) lower than normal only in the common variable agammaglobulinemic group (33.33±12.3) and against human erythrocytes only in the common variable (34.36±9.59) and hyper IgM (27.54±0.66) groups. Rosette and anti-F(ab′)2 depletion studies with normal leukocytes indicated that a nonadherent, nonphagocytic, non-Ig-bearing, non-C receptor-bearing, Fc receptor-bearing lymphocyte was the only effector capable of lysing HLA antiboyd-coated lymphocyte targets. Patients with infantile X-linked agammaglobulinemia and severe combined immunodeficiency appear to have a marked deficiency in this type of effector cell function.

Authors

S. Ozden Sanal, Rebecca H. Buckley

Kinetic Analysis of Plasma Insulin Disappearance in Nonketotic Diabetic Patients and in Normal Subjects: A TRACER STUDY WITH ¹²⁵I-INSULIN

• Text
• PDF

Abstract

The studies so far reported on the metabolic clearance rate of insulin in human diabetes mellitus have given conflicting results, probably because they have been conducted on few patients and have used a variety of experimental techniques and data treatments. We investigated the kinetics of insulin distribution and degradation in 35 normal subjects and in 42 nonketotic, nonobese, overtly diabetic patients, of whom 26 were above 40 yr old and 16 were 40 yr old or less at diagnosis. The design of the study combined (a) the use of a tracer to perturb minimally the steady state and to avoid glucose infusion; (b) the preparation of purified [125I]-monoiodoinsulin, which has a metabolic behavior similar to that of native insulin; and (c) noncompartmental analysis of the plasma immunoprecipitable 125I-insulin disappearance curves, which were recorded for 2 h after pulse i.v. injection of the tracer.

Authors

Renzo Navalesi, Alessandro Pilo, Eleuterio Ferrannini, Paolo Cecchetti, Antonio Masoni

Activity of [Des-Aspartyl¹]-Angiotensin II and Angiotensin II in Man: DIFFERENCES IN BLOOD PRESSURE AND ADRENOCORTICAL RESPONSES DURING NORMAL AND LOW SODIUM INTAKE

• Text
• PDF

Abstract

This study was designed to compare the effect of [des-Aspartyl1]-angiotensin II ([des-Asp]-A II) and angiotensin II (A II) on blood pressure and aldosterone production in man under conditions of normal and low sodium (Na) intake. Seven normal male subjects in balance on constant normal Na intake (UNa V 160.3±5.0 meq/24 h) for 5 days received A II and [des-Asp]-A II infusions on two consecutive days; 1 mo later they were restudied after 5 days of low Na intake (UNa V 10.5±1.6 meq/24 h). Each dose was infused for 30 min, sequentially. During normal Na intake, [des-Asp]-A II from 2 to 18 pmol/kg per min increased mean blood pressure from 85.2±3 to 95.3±5 mm Hg and plasma aldosterone concentration from 5.2±1.1 to 14.3±1.9 ng/100 ml. During low Na intake, the same dose of [des-Asp]-A II increased mean blood pressure from 83.7±3 to 86.7±3 mm Hg and plasma aldosterone concentration from 34.4±6.0 to 51.0±8.2 ng/100 ml. In contrast, A II from 2 to 6 pmol/kg per min during normal Na intake increased mean blood pressure from 83.3±4 to 102.3±4 mm Hg and plasma aldosterone concentration from 7.0±2.2 to 26.8±2.0 ng/100 ml; during low Na intake, A II increased mean blood pressure from 83.0±3 to 96.0±4 mm Hg and plasma aldosterone concentration from 42.0±9.7 to 102.2±15.4 ng/100 ml. A II and [des-Asp]-A II were equally effective in suppressing renin release. Plasma cortisol and Na and K concentration did not change.

Authors

Robert M. Carey, E. Darracott Vaughan Jr., Michael J. Peach, Carlos R. Ayers