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Biomedical subjects

C J Lote

Publications and source records attributed to C J Lote.

At least 19 recordsLinked to original sources
PubMed2001

The evaluation of novel mixed metal hydroxy-carbonates as phosphate binders: an in-vivo study in the rat.

A number of novel phosphate binders based on mixed metal hydroxide structures incorporating Fe and Ca, or Fe and Mg (classified as CT, Crosfield test compounds), were compared with the established phosphate binders Mg(OH)2, Al(OH)3, CaCO3 and a commercial hydrotalcite (Al- and Mg-based) using a rat model. The changes in urine and soluble faecal phosphate were used to evaluate efficacy of phosphate binding. The binders were mixed into a standard rat maintenance food at a concentration of 1% (w/w). Four rats were used for each binder study group and fed over 7 days. Urine and faeces were collected (in a metabolic cage) over the last 24-h study period and the phosphate content measured. The urinary phosphate was significantly reduced (P < 0.001) with CTFeCa (72+/-44 microm), CTFeMg (13+/-4 microm), CT100 (26+/-11 microm), and Mg(OH)2 (65+/-53 microm), compared with control (766+/-188 microm), Al(OH)3 (1,256+/-279 microm), and CaCO3 (857+/-25 microm). The soluble phosphate content of the faeces was significantly reduced (P < 0.05) by up to 60 % with CTFeCa, CTFeMg and Mg(OH)2, and up to 40% with CT100 and Al(OH)3, compared with 30% in controls and 10% with CaCO3. The new mixed metal hydroxy-carbonate compounds based on FeCa or FeMg are effective phosphate binders in-vivo and warrant further testing in patients.

Animals↗
PubMed2000

Role of nitric oxide in a toxin-induced model of haemolytic uraemic syndrome.

The role of nitric oxide in the pathogenesis of glomerular thrombotic microangiopathy was explored using an established rat model in which ricin with or without lipopolysaccharide induced glomerular thrombosis. Ricin alone caused a small rise in the plasma concentration of nitric oxide (control 9.2+/-0.7 microM, ricin 23.3+/-6.3 microM at 7 h). This increase occurred after the development of glomerular thrombosis. Nitric oxide synthase (NOS) activity in the kidney showed no significant change from control values (control 5.66+/-2.7 pmol/min per ml homogenate, ricin 7.52+/-1.8 pmol/min per ml homogenate, total activity). When ricin and lipopolysaccharide were administered together, calcium-independent NOS activity increased whereas calcium-dependent activity decreased (1.22+/-2.6 pmol/min per ml homogenate). The increase in calcium-independent NOS activity correlated with a high plasma concentration of interleukin-1beta in the ricin plus lipopolysaccharide group (4,036.83+/-1,001.5 pg/ml). These data indicate that thrombus formation in a rat model of haemolytic uraemic syndrome is independent of the effects of nitric oxide.

Animals↗
PubMed2000

The hypomagnesaemic action of FK506: urinary excretion of magnesium and calcium and the role of parathyroid hormone.

A side-effect of the immunosuppressive drug FK506 (Prograf; tacrolimus) is hypomagnesaemia. We have investigated the effects of short-term (7-day) treatment of rats with FK506, using a protocol designed to indicate whether there are modifications in the renal tubular handling of magnesium and other electrolytes, or in the tissue deposition of magnesium, which may account for the hypomagnesaemia. We have also investigated whether parathyroid hormone has a role in the observed hypomagnesaemia. Two studies have been performed; in the first we administered FK506 (0.5 mg x kg(-1) body weight x day(-1)) or vehicle by intraperitoneal injection for 7 days, and then housed the rats in metabolic cages for the 24 h collection of urine. At the end of the metabolic cage period, the animals were anaesthetized, and blood and tissue samples were taken for analysis. In the second set of experiments the dosage regime was identical, but at the end of the treatment period the animals were anaesthetized for implantation of arterial and venous cannulae, and then received a saline (plus inulin) infusion for 6 h, during which time blood and urine samples were collected. The dose of FK506 employed did not decrease the glomerular filtration rate. FK506 elicited hypomagnesaemia in both sets of experiments, accompanied by inappropriately high fractional excretion of magnesium. There was also evidence of disruption of the normal renal reabsorption of calcium, but this did not result in hypocalcaemia. Plasma parathyroid hormone activity was not significantly different between the two groups, and there was no evidence of altered tissue content of magnesium in kidney, liver, heart, skeletal muscle or bone. The study confirms that hypomagnesaemia is a significant side-effect of FK506, even at a relatively low dose which did not decrease the glomerular filtration rate. The effect is not due to a decrease in parathyroid hormone release, or to translocation of magnesium from plasma to tissues, but does reflect decreased renal tubular magnesium (and calcium) reabsorption.

Animals↗
PubMed1999

A laboratory model of toxin-induced hemolytic uremic syndrome.

BACKGROUND: Verocytotoxin-producing (Shiga-like toxin-producing) Escherichia coli infection is the principal cause of hemolytic uremic syndrome (HUS). The pathogenesis is unclear, and there is a need for animal models. These are impeded by the different distribution of verocytotoxin receptors between species. We have circumvented this restriction using ricin, which gains entry into cells via various galactose receptors. Like verocytotoxin, ricin specifically cleaves a single adenine from ribosomal RNA. METHODS: Rats were given ricin at a dose of 6.7 micrograms/100 g body wt, with or without lipopolysaccharide at 10 micrograms/100 g body wt. Lipopolysaccharide alone or saline were used as controls. Changes in glomerular filtration rate, hematological parameters, histology, and plasma cytokine concentrations were measured. RESULTS: Extensive glomerular thrombosis, pyknotic nuclei, and an infiltration of ED1-positive cells into glomeruli were observed eight hours after an injection of ricin. Other vascular beds were unaffected. Histologic changes were preceded by oliguric renal failure, hemolysis, and thrombocytopenia. Ricin produced a rise in plasma concentrations of monocyte chemotactic protein-1, > tumor necrosis factor-alpha, > interleukin-1 beta, > interleukin-6. Interferon-gamma showed a small increase at the end of the experiment. CONCLUSIONS: Ricin induces glomerular thrombotic microangiopathy, closely resembling that which occurs in verocytotoxin-producing E. coli-induced HUS. As in HUS, high concentrations of proinflammatory cytokines are present, which are probably a result of cytokine superinduction by the toxin.

Animals↗
PubMed1996

A case of neonatal Bartter's syndrome.

We describe a child with a neonatal presentation of Bartter's syndrome. Unlike infants previously described with a similar clinical presentation, the urinary excretion rate of prostaglandin E2 in this child was similar to normal children and Tamm-Horsfall protein was distributed normally in the thick ascending limb of the loop of Henle. The child failed to respond to indomethacin alone, but thrived after the addition of the angiotensin converting enzyme inhibitor, captopril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Interactions between renal tubules and interstitium.

Renal tubules and interstitium have close physiological associations. Changes in both are often seen in renal disease. Damaged tubules can attract inflammatory cells and stimulate interstitial fibrosis, but do not always do so. Interstitial inflammation can damage tubules and can also stimulate fibrosis, and is probably always initiated by tubular events. Interstitial and tubular abnormalities are closely associated with changes in renal excretory function, but tubular events are more important. A main determinant of the outcome of renal disease is whether tubules can recover, not the extent of interstitial changes. If tubules are atrophic, they will not recover and renal function will be permanently impaired.

Extracellular Space↗
PubMed1995

Peripheral haemodynamic effects of inhibition of prostaglandin synthesis in congestive heart failure and interactions with captopril.

OBJECTIVES: To investigate the role of prostaglandins in maintaining circulatory homoeostasis in chronic heart failure and the hypothesis that an increase in vasodilatory prostaglandin synthesis may contribute to the actions of angiotensin converting enzyme inhibitors in heart failure. DESIGN: Randomised, double blind, placebo controlled studies. Cardiac output and renal and limb blood flow were measured after oral indomethacin 50 mg or placebo followed by "open" intravenous infusion of prostaglandin E2 (study A). In a second study the same measurements were made after oral indomethacin 50 mg or placebo was given 30 min before "open" captopril (study B). METHODS: Blood pressure was measured using a mercury sphygmomanometer. Cardiac output was determined by Doppler interrogation of blood flow in the ascending aorta and echocardiographic measurement of aortic root diameter. Renal blood flow was calculated from the effective renal plasma flow measured by p-aminohippurate clearance and the haematocrit, and glomerular filtration rate by endogenous creatinine clearance. Limb blood flow was measured by venous occlusion plethysmography using mercury in silastic strain gauges. The concentration of plasma prostaglandin E2 was measured by radioimmunoassay. SETTING: University department of cardiovascular medicine. PATIENTS: 12 patients with chronic stable heart failure before starting treatment with angiotensin converting enzyme inhibitors. RESULTS: Indomethacin resulted in adverse effects on cardiac output, systemic vascular resistance, renal blood flow, glomerular filtration, urinary sodium excretion, and calf vascular resistance. Changes were reversed with infusion of prostaglandin E2. Pretreatment with indomethacin resulted in the attenuation of the acute increase in cardiac output and decrease in systemic vascular resistance that occurred with captopril. Similarly, an increase in renal blood flow with captopril was attenuated by indomethacin. CONCLUSIONS: The acute adverse effects of indomethacin on central and peripheral haemodynamic and renal function suggest that prostaglandins have a significant role in the regulation of peripheral blood flow and renal function in patients with stable chronic heart failure. The attenuation by indomethacin of captopril induced improvements in haemodynamic function and renal blood flow is consistent with the hypothesis that captopril may act in part via an increase in prostaglandin synthesis.

Aged↗
PubMed1995

Renal filtration and excretion of aluminium in the rat: dose-response relationships and effects of aluminium speciation.

The known toxicity of aluminium, and the toxicity of agents (such as desferrioxamine) used to remove aluminium from the body, has prompted us to investigate whether there may be ways of enhancing aluminium excretion by exploiting the normal renal handling of aluminium. Aluminium (as sulphate or citrate) was administered intravenously to conscious rats at doses ranging from 25 micrograms (0.93 mumol) to 800 micrograms (29.6 mumol) aluminium, and aluminium excretion was monitored over the following 2 h. Measurements of the filterability of aluminium from the rat plasma, and the glomerular filtration rate (inulin clearance), enabled us to calculate the filtered load of aluminium, and hence determine aluminium reabsorption. At all doses of administered aluminium, that administered as sulphate was excreted less effectively than that administered as citrate. This difference was attributable to the much greater filterability of aluminium administered as citrate. However, for any given filtered load, the excretion of aluminium administered as citrate was not significantly different (in either fractional or absolute terms) from the excretion of aluminium administered as sulphate. It seems likely that, following aluminium sulphate administration, the filtered aluminium may be an aluminium citrate form which is then reabsorbed in the same way as aluminium administered as citrate. It is thus apparent that aluminium removal from the body could be further enhanced if it were possible to prevent the tubular reabsorption of the aluminium species which is so effectively filtered following aluminium citrate administration.

Absorption↗
PubMed1995

Aluminium deposition in liver and kidney following acute intravenous administration of aluminium chloride or citrate in conscious rats.

1. Plasma, urinary, liver and kidney cell aluminium (Al) levels were monitored in the rat, 1h after intravenous administration of 29630 nmol (800 micrograms) Al as either Al chloride or as Al citrate (Al chloride plus excess sodium citrate). Al levels were measured in plasma, urine and liver by atomic absorption spectroscopy (AAS). Liver and kidney Al content was measured at the cellular and subcellular level by electron probe X-ray microanalysis (EPXMA). 2. Urinary excretion of Al was significantly higher (P < 0.01), when Al was given as the citrate than as the chloride. After 1h, plasma Al levels were significantly lower in the Al citrate group than the Al chloride group (59 +/- 3.7 vs 877 +/- 214 nmol ml-1, respectively; P < 0.01). 3. Al concentrations were significantly higher in the livers of rats receiving Al chloride (818 +/- 252 nmol g-1 wet weight; P < 0.05), than in either control or Al citrate groups (122 +/- 41 and 107 +/- 26 nmol g-1 wet weight, respectively). Al concentrations derived from EPXMA measurements were in agreement with AAS values for the three groups, with significantly higher Al concentrations in the Al chloride group (1.7 +/- 0.4 nmol mg-1 dry weight; P < 0.05) than in the control or Al citrate groups, where Al was not detectable. EPXMA analysis showed that Al was distributed in all liver organelles analysed (cytoplasm, mitochondria, nucleus, ER) and was not preferentially taken up by any one organelle in Al chloride treated rats. 4. Significant amounts of Al were found in cytoplasm and mitochondria of proximal tubule cells of rats given Al citrate (0.64 +/- 0.15 and 0.80 +/- 0.11 nmol mg-1 dry weight, respectively), but not in nuclei or lysosomes of these cells. Al levels were not detectable in control kidneys, in proximal tubule cells after Al chloride administration or distal tubule cells after either Al treatment.

Aluminum↗
PubMed1995

Renal excretion of aluminium in the rat: effect of citrate infusion.

When aluminium is administered intravenously to rats, the speciation of the aluminium has a major effect on its renal excretion. Aluminium administered as citrate is much more effectively excreted than that administered as chloride or sulphate. This suggests that citrate could be therapeutically useful in patients who have been exposed to aluminium. Accordingly, we have performed two series of experiments in rats, in which a citrate infusion (intravenous), was begun either immediately after, or one hour after, the administration of an intravenous aluminium sulphate bolus. Both protocols led to markedly enhanced aluminium excretion compared to controls in which only 0.7% NaCl was infused. The enhancement of aluminium excretion was 783% if citrate infusion was begun immediately after aluminium administration, and 335% if the citrate infusion began after an hour delay. The increased excretion was due to an increase in the freely filterable fraction of aluminium. In the control experiments, in which aluminium sulphate administration was followed by 0.7% NaCl infusion, aluminium was found to be deposited in the liver. Administration of citrate one hour after the aluminium bolus did not reduce this liver deposition. The results indicate that a fraction of the plasma aluminium is accessible to the citrate infused and can thereby be converted into a filterable form which can be excreted. It appears that, for maximum therapeutic effect, citrate should be infused as rapidly as possible after an aluminium load, to limit aluminium binding to ligands which allow it to enter cells.

Alum Compounds↗
PubMed1993

Distribution of immunoreactive Tamm-Horsfall protein in various species in the vertebrate classes.

A sheep antibody to human Tamm-Horsfall protein, the major protein in normal urine, was used in an immunohistological study of organs of 48 species of vertebrate animals, representing the classes Mammalia, Aves, Reptilia, Amphibia, Osteichthyes and Chondrichthyes. Immunoreactivity was shown in the thick limb of the loop of Henle in the kidney of mammals, but there was no reactivity with tissues of birds or reptiles. Superficial layers of the skin of several amphibians and fish, superficial layers of the oral mucosa and gills of fish, and the distal tubules of the kidney of some amphibians, reacted with the antibody. Immunoreactivity with mammalian kidney was removed by passage of the antibody down an immunoadsorption column coated with human Tamm-Horsfall protein, and amphibian immunoreactivity was removed by incubation of the antibody with material prepared from frogs in the same way as Tamm-Horsfall protein. These findings suggest that immunoreactive Tamm-Horsfall protein appeared early in vertebrate phylogeny, initially in skin and gills and later in kidney, and that although conserved in evolution, it shows antigenic differences between amphibians and mammals. Its distribution is consistent with the hypothesis that is acts as a waterproofing agent.

Amphibians↗
PubMed1993

Prostacyclin in diarrhoea-associated haemolytic uraemic syndrome.

The role of prostacyclin (PGI2) in the pathogenesis of haemolytic uraemic syndrome (HUS) is controversial. In part, confusion has been caused by failure to distinguish between two main sub-types of the syndrome: extrinsic, diarrhoea-associated HUS (D+ HUS), usually caused by infection with verocytotoxin-producing Escherichia coli or Shigella dysenteriae, and the heterogeneous group of non-prodromal forms where intrinsic factors predominate (D- HUS). This paper critically reviews data confined to D+ HUS. Two methods have been used to assess PGI2 synthesis; the generation of PGI2 from endothelium in the presence of HUS plasma in vitro and the measurement of stable metabolites in body fluids. No concensus could be reached with regard to the former. The reported increase of PGI2 stable metabolites in plasma may represent reduced clearance or increased carriage by plasma lipids. Apparent differences between studies of urinary excretion of PGI2 metabolites may reflect the way excretion was expressed. If the metabolite concentration is factored for urinary creatinine, it appears that renal excretion and thus renal synthesis of PGI2 is reduced. However, these are insufficient data on which to attribute the pathogenesis of D+ HUS to disordered PGI2 metabolism.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Renal filtration, reabsorption and excretion of aluminium in the rat.

1. Plasma and urinary aluminium levels, and renal function, were investigated in a control group of rats (n = 5) and in two groups that received an intravenous bolus dose of aluminium chloride (either 25 micrograms or 800 micrograms of aluminium, n = 7 and 5, respectively). 2. In the control group (plasma aluminium concentration 76.8 +/- 14.2 ng/ml), 59.4 +/- 3.5% of the plasma aluminium was ultrafilterable. The percentage ultrafilterable after the administration of 25 micrograms of aluminium was 41.9 +/- 7.8 (plasma concentration 154.3 +/- 18.6 ng/ml). However, after administration of 800 micrograms of aluminium, to give a plasma concentration of 19,800 +/- 2956 ng/ml, only 1.06 +/- 0.13% was ultrafilterable. 3. Such results have generally been interpreted as indicating an increase in protein-binding of aluminium with increasing aluminium concentration. In buffered aqueous solutions of aluminium chloride at pH 7.4, with an aluminium concentration of 189 +/- 6 ng/ml, 96.12 +/- 0.02% was ultrafilterable (n = 6). This concentration is comparable with that attained in the low-dose (25 micrograms) aluminium group of animals and suggests that the difference between the ultrafilterable percentage of aluminium in plasma compared with that in aqueous solution is indeed due to the binding of aluminium to high Mr material (proteins). In contrast, however, in an aqueous buffered (pH 7.4) solution containing 28,200 ng of aluminium/ml, only 1.05 +/- 0.09% was ultrafilterable. This indicates insolubility (i.e. colloid formation) of the aluminium at this high concentration. The same percentage (1.06 +/- 0.13) was ultrafilterable from plasma from the high-dose (800 micrograms) aluminium group with a plasma aluminium concentration of 19,800 +/- 2956 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum↗
PubMed1992

Effect of citrate on plasma aluminium concentration and aluminium excretion in the rat.

1. Plasma aluminium concentration and urinary aluminium excretion were monitored for 4.5 h in rats after the administration of 25 micrograms or 800 micrograms of aluminium as an intravenous bolus, either as aluminium chloride or as aluminium citrate (i.e. aluminium chloride together with sodium citrate). 2. Immediately after the bolus aluminium administration, the plasma aluminium concentration was higher in the groups given aluminium chloride than in those which received aluminium citrate, although the difference was significant (P < 0.05) only for the 25 micrograms dose. This difference between aluminium chloride and citrate indicates that the citrate form has a higher volume of distribution (i.e. is able to leave the plasma). The calculated volume of distribution for the 25 micrograms of aluminium chloride (17.5 ml) was similar to the plasma volume of the rats used (15 ml). 3. In experiments in vitro, the ultrafilterability of aqueous solutions of aluminium chloride and aluminium citrate were compared. Only 1.05 +/- 0.09% of the aluminium chloride solution was ultrafilterable (aluminium concentration 28,200 +/- 730 ng/ml), whereas 97.3 +/- 2.4% of the aluminium citrate was ultrafilterable (aluminium concentration 42,000 +/- 370 ng/ml). When the filterability of aluminium in plasma was examined, the aluminium chloride ultrafilterability was identical with that in aqueous solution (1.06 +/- 0.13%, aluminium concentration 19,800 +/- 2956 ng/ml), but the aluminium citrate was 79.8 +/- 7.1% ultrafilterable (aluminium concentration 10,125 +/- 591 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum↗
PubMed1991

Immunoreactive Tamm-Horsfall protein in the kidney and skin of the frog Rana temporaria.

Tamm-Horsfall protein (THP) is the main protein in normal human urine, and is found in the thick limb of the Loop of Henle in human kidney, and in other mammalian species. The skin of the frog. Rana temporaria, has similar physiological properties to this mammalian kidney tissue. In the present study, an immunohistological method involving an antibody to human THP was used to investigate the distribution of this distinctive protein in frog kidney and skin, and to compare its distribution with that found in the kidney tubules of rat and rabbit. THP-positive material was detected in the distal renal tubules and nephric duct of frogs, and was also located in the superficial epidermis of skin. It is suggested that its presence in amphibian skin is consistent with the hypothesis that THP is an important component of tissues that absorb sodium and chloride ions, but remain impermeable to water.

Animals↗