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Biomedical subjects

R B Sewell

Publications and source records attributed to R B Sewell.

At least 37 records · Page 2Linked to original sources
PubMed1987

Hepatic metabolism of neurotensin.

Neurotensin is released from the intestinal mucosa into the portal circulation and, to exert a systemic effect, it must traverse the liver intact. We examined the potential role of the liver in neurotensin clearance using the isolated perfused rat liver model. With N-terminal and C-terminal directed RIAs and HPLC, we demonstrated rapid metabolism of intact neurotensin to inactive N-terminal fragments in the isolated rat liver system. The disappearance half-lives of C-terminal and N-terminal immunoreactivity were 20.4 +/- 6.0 min and 82.7 +/- 7.7 min, respectively, (P less than 0.002). To assess whether this neurotensin disappearance might be due to metabolism within the perfusate itself by a peptidase released from liver, we further incubated neurotensin in perfusate previously circulated through liver. A rapid and progressive breakdown of intact neurotensin to N-terminal fragments was again shown. These data demonstrate that a substantial proportion of the hepatic clearance of neurotensin is attributable to release of a peptidase by the liver into the circulation.

Animals↗
PubMed1986

Ethanol-induced cell damage in cultured rat antral mucosa assessed by chromium-51 release.

We have developed an in vitro method for studying ethanol-induced injury to gastric mucosa using organ culture of rat antrum. Cell damage was assessed by measurement of the release of [51Cr]sodium chromate from preloaded cells, a method adapted from a standard immunologic technique. This system provided rapid and highly reproducible quantitation of tissue injury as assessed by 51Cr release into the culture medium. The threshold concentration for ethanol-induced damage was between 10 and 15% v/v, similar to in vivo thresholds observed by others. 51Cr release could also be induced by very short exposure to ethanol (5-15 min), and then continued despite ethanol removal. Interestingly, after continuous ethanol exposure, a plateau of maximum 51Cr release was reached 60 min after exposure to ethanol over the concentration range 20-50%, suggesting tissue adaptation to ethanol damage. This organ culture system, which allows precise control of experimental conditions, may be useful for studying mechanisms of gastric mucosal injury and protection.

Animals↗
PubMed1986

Effects of copper on dopaminergic function in the rat corpus striatum.

Copper-loading was produced in rats by administration of 0.125% CuSO4 in the drinking water for a period of 11 months from weaning. At conclusion of the treatment the animals had significant increases in liver (552%) and brain (26%) copper content relative to age-matched controls. Whereas the concentration of dopamine was unaffected, the concentration of 3,4-dihydroxyphenylacetic acid in the corpus striatum was found to be lower (25% decrease) in the copper-treated group. Saturation studies of the striatal D-2 dopamine receptors using [3H]spiperone indicated that in copper-loaded animals the affinity was significantly increased threefold, whereas there was a trend for the number of receptors to decrease. When included in the radioligand binding assay, copper salts (Cu2+) inhibited specific [3H]spiperone binding to untreated corpora striata. The inhibition produced by copper was competitive with a significant decrease in affinity, the 50% effective concentration of Cu2+ was 21 to 24 microM, and the potency of dopamine agonists was also decreased. These results are discussed in relation to the mechanism by which copper affects dopaminergic function and to the use of copper-loaded rats as a model of Wilson's disease.

Animals↗
PubMed1986

Ethanol impairs biliary lysosomal enzyme release in rats.

The effects of ethanol on hepatic lysosomes are poorly documented. This study examined the biliary release of lysosomal enzymes, a marker of the hepatocyte-to-bile excretory pathway, after ethanol administration in the isolated perfused rat liver model. At concentrations similar to those reached in human plasma during social drinking, ethanol markedly decreased biliary lysosomal enzyme output and bile flow in the rat. Ethanol did not affect hepatic activities or the release into perfusate of lysosomal and other subcellular marker enzymes. Hence, ethanol may potentially inhibit hepatocyte-to-bile excretion of other compounds processed through lysosomes.

Acetylglucosaminidase↗
PubMed1985

Zinc abnormalities in fulminant hepatic failure.

Zinc is an important trace metal and, in liver disease, abnormal zinc metabolism has been reported. In this study of patients with fulminant hepatic failure progressing to grade IV encephalopathy, plasma zinc concentrations fell during the illness to reach levels significantly below normal; during this time urinary zinc excretion was markedly elevated.

Acetaminophen↗
PubMed1984

A circulating inhibitor of leucocyte sodium transport in patients with advanced liver cirrhosis.

Leucocyte sodium efflux was measured in control leucocytes pre-incubated for 90 min with serum from patients with advanced liver cirrhosis. Serum from patients with advanced alcoholic liver cirrhosis was inhibitory to sodium transport in control leucocytes. The degree of inhibition was similar to that seen in the patients' own leucocytes; the defect induced by patient serum was primarily inhibition of ouabain-insensitive sodium efflux, whereas in the patients' own leucocytes, inhibition was seen in both ouabain-sensitive and -insensitive sodium efflux, as shown previously. The results suggest that a circulating factor, present in patients with advanced cirrhosis, is capable of inhibiting sodium transport in leucocytes.

Adult↗
PubMed1984

Microtubule modulation of biliary excretion of endogenous and exogenous hepatic lysosomal constituents.

We tested the hypothesis that hepatocyte microtubules modulate the biliary excretion of endogenous and exogenous constituents of hepatocyte lysosomes. We collected bile via bile fistulas from male rats before and after acute administration of colchicine and vinblastine, agents known to bind to hepatocyte microtubules; rats were then killed and livers were homogenized for biochemical analyses or processed for electron microscopy. Colchicine caused biphasic, parallel alterations in the biliary excretion of three lysosomal enzymes compared with control rats given saline or lumicolchicine; a peak rise in enzyme outputs of approximately 175% at 45-60 min after colchicine administration was followed by a sustained fall to approximately 25% of control values, which persisted for 2-4 h. When hepatocyte lysosomes were prelabeled in vivo by administration of [3H]Triton WR-1339, a nonionic detergent that is sequestered in hepatic lysosomes, the biliary excretion of radiolabel in response to colchicine paralleled the biliary excretion of the three lysosomal enzymes. Vinblastine also induced a biphasic response in biliary lysosomal enzyme output that was similar to that produced by colchicine administration. Morphometric analysis of electron micrographs of rat livers demonstrated changes in the number of lysosomelike vesicles in the vicinity of bile canaliculi after colchicine and vinblastine administration; the initial increase in lysosomal enzyme secretion was associated with a significant decrease in the number of pericanalicular lysosomes after both agents, while the subsequent decrease in enzyme secretion coincided with an increase in the number of pericanalicular lysosomes after vinblastine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Apolipoproteins of high, low, and very low density lipoproteins in human bile.

We tested the hypothesis that apolipoproteins, the protein constituents of plasma lipoproteins, are secreted into bile. We examined human gallbladder bile obtained at surgery (N = 54) from subjects with (N = 44) and without (N = 10) gallstones and hepatic bile collected by T-tube drainage (N = 9) after cholecystectomy. Using specific radioimmunoassays for human apolipoproteins A-I and A-II, the major apoproteins of high density lipoproteins, for apolipoproteins C-II and C-III, major apoproteins of very low density lipoproteins, and for apolipoprotein B, the major apoprotein of low density lipoproteins, we found immunoreactivity for these five apolipoproteins in every bile sample studied in concentrations up to 10% of their plasma values. Using double immunodiffusion, we observed complete lines of identity between bile samples and purified apolipoproteins A-I, A-II, or C-II. Using molecular sieve chromatography, we found identical elution profiles for biliary apolipoproteins A-I, A-II and B and these same apolipoproteins purified from human plasma. When we added high density lipoproteins purified from human plasma to lipoprotein-free solutions perfusing isolated rat livers, we detected apolipoproteins A-I and A-II in bile. Similarly, when we added low density lipoproteins purified from human plasma to lipoprotein-free solutions perfusing isolated livers of rats treated with ethinyl estradiol in order to enhance hepatic uptake of low-density lipoproteins, we found apolipoprotein B in bile. These data indicate that apolipoproteins can be transported across the hepatocyte and secreted into bile.

Animals↗
PubMed1983

Effect of chloroquine on the form and function of hepatocyte lysosomes. Morphologic modifications and physiologic alterations related to the biliary excretion of lipids and proteins.

In these experiments, we tested the hypothesis that chloroquine, a lysosomotropic agent which modifies protein and lipid metabolism by hepatocyte lysosomes, would alter the biliary excretion of lipids and lysosomal enzymes. We treated male rats for 5 days with intraperitoneal chloroquine (50 mg/kg body wt, n = 9) or saline (n = 8) and collected bile for 6 h via bile fistulas; rats were then killed and livers homogenized for biochemical analyses or processed for electron microscopy. Chloroquine markedly increased the biliary excretion of three lysosomal enzymes (mean +/- SEM) expressed as milliunits of activity per gram liver: N-acetyl-beta-glucosaminidase (24.4 +/- 2.7 vs. 12.5 +/- 1.4, p less than 0.01), beta-glucuronidase (26.4 +/- 4.7 vs. 10.9 +/- 1.4, p less than 0.01), and beta-galactosidase (9.8 +/- 1.7 vs. 5.5 +/- 0.8, p less than 0.05). In contrast, biliary outputs of enzymes associated with other organelles (e.g., alkaline phosphodiesterase I and lactic dehydrogenase) were unaffected by chloroquine treatment. Biliary cholesterol secretion was decreased after chloroquine administration (0.28 +/- 0.02 mumol/g liver vs. 0.39 +/- 0.03 mumol/g liver, p less than 0.01), but bile acid and phospholipid secretion were not altered; as a result, cholesterol saturation of bile decreased by 22% (p less than 0.05). Hepatic activities of all three lysosomal enzymes were increased after chloroquine administration (p less than 0.04); activities of enzymes associated with mitochondria, plasma membrane, endoplasmic reticulum, and cell sap were not altered. Morphometric analysis of electron micrographs of rat livers demonstrated a marked increase (p less than 0.001) in the number of lysosomelike vesicles and autophagic vacuoles in the vicinity of bile canaliculi after chloroquine administration; also, the number of canalicular microvilli decreased (p less than 0.003) after chloroquine treatment. We conclude that altered hepatic lysosomal morphology and function after chloroquine is accompanied by marked changes in outputs of lipids and lysosomal enzymes into bile. These findings call attention to a possible role for hepatic lysosomes in modulating biliary protein and lipid secretion.

Acetylglucosaminidase↗
PubMed1982

Effects of serum from patients with fulminant hepatic failure on leucocyte sodium transport.

1. Serum from patients with fulminant hepatic failure inhibits the ouabain-sensitive sodium efflux in leucocytes. A 1 : 100 dilution of the serum was necessary before the inhibition became undetectable. 2. Dialysates of the serum through cuprophane in vitro and polyacrylonitrile haemodialysis in vivo were inhibitory in small amounts. 3. Ultrafiltrates ( less than 10 000 daltons) of serum were chromatographed on Sephadex G-25 and the elution profile obtained from patients with fulminant hepatic failure was both qualitatively and quantitatively different from that of normal controls. Material from peaks 3, 4, 5 and 7 in patients with fulminant hepatic failure inhibited leucocyte sodium transport. 4. dialysate from haemodialysis with the polyacrylonitrile membrane contained most peaks, particularly peaks 4 and 5. Adsorption of serum with polymer coated charcoal in vitro largely removed peaks 5-8.

Biological Transport↗
PubMed1982

Sodium transport during the natriuresis of volume expansion; a study using peripheral blood leucocytes.

1. Leucocyte sodium transport was investigated as a possible assay for the small molecular weight natriuretic material isolated from the urine of normal subjects who had undergone volume expansion by saline infusion. 2. This fraction (fraction four or FIV), inhibitory to sodium transport in several other assays, was also found to inhibit leucocyte sodium transport. 3. FIV isolated from the urine of five normal subjects undergoing the natriuresis of mineralocorticoid 'escape' was also found to be inhibitory to leucocyte sodium transport. 4. Leucocytes isolated from the blood of the same subjects during mineralocorticoid escape showed decreased sodium transport.

Adult↗
PubMed1982

Fetal bile salt metabolism: placental transfer of dihydroxy bile salts in sheep.

The bidirectional placental transfer of sodium [11,12-di-3H]chenodeoxycholate and sodium [14C]deoxycholate was studied in conscious pregnant sheep near term. In fetal-to-maternal studies, radiolabeled bile salt was injected into the fetal portal vein, and the daily excretion of radiolabel in maternal hepatic bile was measured over 3-4 days. In maternal-to-fetal studies, the mother received daily injections of radiolabeled bile salt, and the accumulation of label in the fetal pool was measured after 6-9 days. Bile salts were transferred predominantly as the taurine conjugate. Transfer rates were 1) fetus to mother; chenodeoxycholate, 6.7 mumol/24 h and deoxycholate, less than 0.5 mumol/24 h and deoxycholate, 1.4 mumol/24 h. We conclude that, in sheep near term, deoxycholate derived from the mother slowly accumulates in the fetus, while the placenta acts as an excretory route for fetal chenodeoxycholate.

Animals↗
PubMed1981

Evidence for a circulating sodium transport inhibitor in essential hypertension.

The active sodium transport of white cells and red cells obtained from patients with essential hypertension was impaired. Incubating white cells from normotensive subjects in serum obtained from patients with essential hypertension caused an impairment in sodium transport in the white cells of normotensive subjects similar to that found in the white cells of hypertensive patients. The impairment in sodium transport was due to a fall in the ouabain-sensitive component of the total sodium efflux rate constant. These results show that the serum of patients with essential hypertension contains a substance which influences sodium transport and that it has ouabain-like activity. They also suggest that it is this substance which causes the impairment in sodium transport in the leucocytes of patients with essential hypertension. These findings support the hypothesis that the rise in blood pressure in patients with essential hypertension is due to an increased concentration of a circulating sodium transport inhibitor which is continuously correcting a tendency for sodium retention by the kidney.

Adult↗
PubMed1981

Abnormalities in the leukocyte sodium pump in advanced cirrhosis.

Previous studies have demonstrated abnormalities of intracellular electrolyte content and sodium transport in leukocytes of patients with fulminant hepatic failure. The current study was undertaken to establish whether similar abnormalities were present in patients with encephalopathy from advanced cirrhosis. Results from 19 patients with advanced cirrhosis showed values for the leukocyte total sodium efflux-rate constant were significantly reduced in patients, 3.02 +/- 1 SEM 0.12 h-1, compared to control values, 3.80 +/- 0.06 h-1. This reduction was due primarily to a lowering of the ouabain-sensitive component of sodium efflux, a measure of Na,K-ATPase activity. In comparison, leukocytes from patients with fulminant hepatic failure show a greater inhibition of the ouabain-sensitive component of sodium efflux with a raised ouabain-insensitive efflux. Although cirrhosis has generally been associated with potassium depletion, the intracellular potassium content of the cirrhotic patients' leukocytes was normal. Since the leukocyte is considered to be a good cell model and because abnormalities of sodium transport have been shown in the leukocytes of these patients, it is likely that similar abnormalities of sodium transport are present in other organs, including the brain.

Cholesterol↗
PubMed1980

Bile acid metabolism in fetal sheep; perinatal changes in the bile acid pool.

1. A chronic fetal bile fistula model was developed in sheep which allowed observations on fetal bile for periods of up to 10 days. A comparison of fetal, lamb and adult bile acids was made in bile fistula animals. 2. Bile was analysed by thin layer chromatography, gas liquid chromatography, and high pressure liquid chromatography. Fetal bile contained a much greater proportion of chenodeoxycholic acid (42.0 +/- 1. S.E. of mean 3.0% of total bile acids by high pressure liquid chromatography) than lamb bile (8.1 +/- 1.9%) or adult bile (5.4 +/- 0.6%). The corresponding figures for cholic acid were fetal: 45.8 +/- 2.9%, lamb: 89.1 +/- 2.9%, and adult: 75.2 +/- 2.6%. Deoxycholic acid, a secondary bile acid, was present in fetal bile (12.2 +/- 4.9%). In the lamb, deoxycholic acid comprised only 2.8 +/- 1.1% of total bile acids, compared with 19.3 +/- 2.9% in adult sheep. Taurine conjugates predominated in sheep bile, but this predominance was least marked in lamb bile. 3. The fetal bile acid pool (101 +/- 13 mu mole/kg) was significantly smaller than the neonatal pool (214 +/- 26 mu mole/kg, P < 0.01). This increase in pool size, together with the increased proportion of cholic acid, suggests a rapid rise in cholic acid synthesis soon after birth. 4. Bile acid synthetic rates were estimated from bile acid secretion rates at the nadir of the washout curves. The values obtained were 0.71 +/- 0.18 mu mole/kg.hour (adult), 0.47 +/- 0.16 mu mole/kg.hour (lamb), and 0.35 +/- 0.08 mu mole.hour (fetus). 5. In the fetus and in pregnant adult sheep, the normal increase in bile acid synthesis in response to depletion of the bile acid pool was much less marked. 6. In the fetus, biliary secretion of cholesterol and phospholipid ran parallel with bile acid secretion. Bile lipid composition was similar to that in the adult. 7. Fetal bile water production was higher, relative to bile acid secretion, than lamb or adult bile water secretion.

Animals↗
PubMed1980

Bile acid structure and bile formation: a comparison of hydroxy and keto bile acids.

The effect of four bile acids, taurocholic (TC), taurochenodeoxycholic (TCDC), tauro-3 alpha,7 alpha-dihydroxy-12-keto-5 beta-cholanoic (T12K), and cholic (C), on bile lipid and water secretion was studied in the bile fistula cat over a 20-fold range of bile acid secretion rates. The critical micellar concentration (CMC) and lecithin-solubilizing capacity of TC, TCDC, and T12K were measured in vitro. T12K and C produced a greater choleresis than TC or TCDC; phospholipid secretion was strikingly reduced with T12K; and cholesterol secretion strikingly increased with TCDC, with a high cholesterol-phospholipid ratio. The estimated CMCs of TC, TCDC, and T12K were 3.3, 0.7, and 6.2 mM respectively; the relative lecithin-solubilizing capacities were 4.4:2.6:1. We conclude that the micellar characteristics of the bile acids studied do not explain the differences in water and lipid secretion observed, and that effects within the hepatocyte may be equally important.

Animals↗