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Biomedical subjects

D Harry

Publications and source records attributed to D Harry.

At least 19 recordsLinked to original sources
PubMed2002

Endothelin is an important determinant of renal function in a rat model of acute liver and renal failure.

BACKGROUND AND AIMS: Renal failure occurs in approximately 55% of patients with acute liver failure. We have previously shown that plasma endothelin 1 concentrations are elevated in patients with acute liver failure and the hepatorenal syndrome. There are few reported satisfactory animal models of liver failure together with functional renal failure. In this study, a rat model of acute liver failure induced by galactosamine that also develops renal failure was first characterised. This model was used to investigate the hypothesis that endothelin 1 is an important mediator involved in the pathogenesis of renal impairment that occurs in acute liver failure. METHODS: Acute liver failure was induced in male Sprague-Dawley rats by intraperitoneal injection of galactosamine together with treatment with the endothelin receptor antagonist Bosentan. Twenty four hour urine collections were made using a metabolic cage. Renal blood flow was measured in anaesthetised animals. RESULTS: This model developed renal failure and liver failure in the absence of any significant renal pathology, and with an accompanying fall in renal blood flow. Plasma concentrations of endothelin 1 were increased twofold following the onset of liver and renal failure (p<0.05), and there was significant upregulation of the endothelin receptor A (ET(A)) in the renal cortex (p<0.05). Administration of Bosentan prevented the development of renal failure when given before or 24 hours after the onset of liver injury (p<0.05) but had no effect on liver injury itself, or on renal blood flow. CONCLUSIONS: This study demonstrates that this animal model has many of the features needed to be regarded as a model of renal failure that occurs in acute liver failure. The observation that plasma levels of endothelin 1 and ET(A) receptors are increased and upregulated, and that renal failure is prevented by an endothelin antagonist supports the hypothesis originally put forward that ET(A) is important in the pathogenesis of renal failure that occurs in patients with acute liver failure.

Acute Disease↗
PubMed2001

Increased formation of S-nitrothiols and nitrotyrosine in cirrhotic rats during endotoxemia.

Plasma S-nitrosothiols are believed to function as a circulating form of nitric oxide that affects both vascular function and platelet aggregation. However, the formation of circulating S-nitrosothiols in relation to acute and chronic disease is largely unknown. Plasma S-nitrosothiols were measured by chemiluminescence in rats with biliary cirrhosis or controls, and the effect of lipopolysaccharide (LPS) on their formation was determined. Plasma S-nitrosothiols were increased in rats with cirrhosis (206 +/- 59 nM) compared to controls (51 +/- 6 nM, p <.001). Two hours following injection of LPS (0.5 mg/kg) plasma S-nitrosothiols increased to 108 +/- 23 nM in controls (p <.01) and to 1335 +/- 423 nM in cirrhotic rats (p <.001). The plasma clearance and half-life of S-nitrosoalbumin, the predominant circulating S-nitrosothiol, were similar in control and cirrhotic rats, confirming that the increased plasma concentrations were due to increased synthesis. Because reactive nitrogen species, such as peroxynitrite, may cause the formation of S-nitrosothiols in vivo, we determined the levels of nitrotyrosine by gas chromatography/mass spectrometry as an index for these nitrating and nitrosating radicals. Hepatic nitrotyrosine levels were increased at 7.0 +/- 1.2 ng/mg in cirrhotic rats compared to controls (2.0 +/- 0.2 ng/mg, p <.01). Hepatic nitrotyrosine levels increased by 2.3-fold and 1.5-fold in control and cirrhotic rats, respectively, at 2 h following injection of LPS (p <.01). Strong positive staining for nitrotyrosine was shown by immunohistochemistry in all the livers of the rats with cirrhosis. We conclude that there is increased formation of S-nitrosothiols and nitrotyrosine in biliary cirrhosis, and this is markedly upregulated during endotoxemia.

Animals↗
PubMed1999

Lipoic acid prevents development of the hyperdynamic circulation in anesthetized rats with biliary cirrhosis.

Chronic bile duct ligation is associated with the development of oxidant injury, biliary cirrhosis, portal hypertension, and a hyperdynamic circulation. We have previously demonstrated that the hyperdynamic circulation in the partial portal vein-ligated rat can be prevented by the administration of N-acetylcysteine. To extend these findings, we have examined the effect of lipoic acid, a thiol-containing antioxidant, on hemodynamics, oxidative stress, and nitric oxide (NO) production in bile duct-ligated (BDL) cirrhotic rats. Lipoic acid was given continuously in drinking water to normal and BDL rats; control rats received ordinary drinking water, and animals were studied at 24 days following surgery. Lipoic acid prevented the development of the hyperdynamic circulation (cardiac index [CI]: 15.7 +/- 2.0 vs. 29.5 +/- 2.1 mL x min-1 x 100 g-1; P <. 05) and significantly attenuated the rise in portal pressure (PP) (12.7 +/- 0.8 vs. 15.2 +/- 0.5 mm Hg; P <.05). Hepatic nitric oxide synthase (NOS) activity and plasma nitrite/nitrate concentration increased significantly following bile duct ligation, and both of these were prevented by lipoic acid. Lipoic acid had no effect on the biochemical or histological parameters of liver function in the cirrhotic group. We conclude that lipoic acid prevents the development of the hyperdynamic circulation in the rat model of biliary cirrhosis, and that this is associated with decreased synthesis of NO.

Animals↗
PubMed1999

Increased sensitivity to endotoxemia in the bile duct-ligated cirrhotic Rat.

Sepsis is a common complication of cirrhosis with a high mortality. In this study, we have investigated some of the pathways that may be involved in tissue injury and death. Bile duct-ligated (BDL) cirrhotic and control rats were challenged with lipopolysaccharide (LPS). Sensitivity to LPS was markedly enhanced in the BDL group, and was associated with increased liver injury and mortality. There was a 5-fold constitutive activation of nuclear factor kappa B (NFkappaB) in the liver of BDL rat controls (P <.001), and this was activated further, but to a similar extent, in the liver of both sham and BDL rats after injection of LPS. Plasma tumor necrosis factor alpha (TNF-alpha) increased more markedly in the BDL cirrhotic rats (2,463 +/- 697 pg/mL in BDL rats versus 401 +/- 160 pg/mL in the controls at 3 hours; P <.01). Plasma nitrite/nitrate concentrations were increased in the BDL controls at baseline, and increased further after LPS (P <.05), but did not differ from sham controls at 6 hours. Plasma F(2)-isoprostanes increased 6-fold in the cirrhotic rats and 2-fold in the controls (P <.01) indicative of lipid peroxidation. Esterified F(2)-isoprostanes in the liver increased 2- to 3-fold at 1 hour in control and BDL rats, but returned to baseline levels by 3 hours. Esterified F(2)-isoprostanes in the kidney increased by 2-fold in the BDL rats after LPS administration, but remained unchanged in sham controls. We conclude that there is a marked increase in sensitivity to LPS in BDL cirrhotic rats. This is associated with an enhanced TNF-alpha response and increased lipid peroxidation. These may be directly and causally related to mortality.

Animals↗
PubMed1999

Acute cholestasis-induced renal failure: effects of antioxidants and ligands for the thromboxane A2 receptor.

BACKGROUND: Acute biliary obstruction is associated with the development of renal impairment and oxidative stress. The F2-isoprostanes, formed during oxidant injury, are renal vasoconstrictors acting via thromboxane (TX)-like receptors. We determined whether the formation of F2-isoprostanes is increased in experimental cholestasis and whether thiol containing antioxidants or ligands for the TXA2 receptor could improve renal function. METHODS: The effects on renal function of acute bile duct ligation (BDL) in the rat were studied for two days. The consequences of administration of N-acetylcysteine (NAC), alpha-lipoic acid (LA), the TX receptor antagonist (TXRA) BAYu3405, or placebo were then examined. RESULTS: BDL caused a reduction in creatinine clearance from 1.10 +/- 0.05 to 0.55 +/- 0.05 ml/min and sodium excretion from 52 +/- 3 to 17 +/- 3 micromol/hr. Urinary F2-isoprostanes increased from 14 +/- 2 to 197 +/- 22 pg/ml following BDL. Renal functional changes were ameliorated by NAC (creatinine clearance 0.73 +/- 0.05 ml/min), LA (0.64 +/- 0.03 ml/min), and a TXRA (0.90 +/- 0.15 ml/min); P < 0.05. Similarly, sodium excretion was increased from 17 +/- 3 micromol/hr (placebo) to 34 +/- 3 micromol/hr (NAC), 29 +/- 3 micromol/hr (LA), and 38 +/- 5 micromol/hr (TXRA); P < 0.005. Hepatic glutathione concentrations increased from 6.5 +/- 0.3 micromol/g (normal liver) to 8.8 +/- 0.5 micromol/g (NAC) and 7.7 +/- 0.3 micromol/g (LA), P < 0.01. However, only LA markedly inhibited F2-isoprostane formation (197 +/- 22 to 36 +/- 11 pg/ml creatinine clearance; P < 0.05). Urinary TXB2 excretion was elevated after BDL (2.2 +/- 0.5 to 111.1 +/- 20.3 pg/min) but was unaffected by NAC and LA. CONCLUSION: NAC, LA, and TXRA can partially prevent renal dysfunction in experimental cholestasis. The effects of the antioxidants are independent of their ability to inhibit lipid peroxidation or TX synthesis.

Acetylcysteine↗
PubMed1998

N-acetylcysteine prevents development of the hyperdynamic circulation in the portal hypertensive rat.

Partial portal vein ligation (PPVL) leads to the development of a hyperdynamic circulation. It is associated with elevated levels of tumor necrosis factor (TNF-alpha) and nitric oxide (NO) production, both of which can result in oxidant injury. In this study, we have investigated whether PPVL is associated with the development of oxidative stress, by measuring urinary F2-isoprostanes. In addition, we have examined whether N-acetylcysteine (NAC) can ameliorate oxidant injury and prevent the development of the hyperdynamic circulation. Urinary excretion of F2-isoprostanes increased sixfold following PPVL together with a significant increase in plasma nitrite and nitrate. Treatment with NAC inhibited the formation of F2-isoprostanes as well as the increase in plasma nitrite and nitrate. Hemodynamic studies in anesthetized rats showed that following PPVL, cardiac output and portal pressure increased, and systemic vascular resistance decreased, consistent with the development of a hyperdynamic circulation. These changes were prevented by chronic administration of NAC. We conclude that NAC prevents the development of the hyperdynamic circulation and that the formation of reactive oxygen species may be important in the pathogenesis of these hemodynamic changes.

Acetylcysteine↗
PubMed1998

The efficacy of FP 736-04 in experimental liver cirrhosis.

PURPOSE: To determine whether the uptake of FP 736-04, a hepatocyte-specific CT contrast agent, is influenced by cirrhotic changes in the liver. MATERIAL AND METHODS: Liver cirrhosis was induced by bile duct ligation (BDL) in Sprague-Dawley rats. Seventy-four animals were divided into three groups comprising: rats with acute BDL; rats with chronic BDL; and normal controls. CT was performed after i.v. infusion of FP 736-04 or saline at a dose of 2 ml/kg b.w., and the mean attenuation in the liver and spleen was measured. The livers from the chronic BDL group were taken for histopathological examination and the extent of the disease was graded according to an arbitrary scale. RESULTS AND CONCLUSION: There was a significant reduction of the native liver attenuation in both chronic and acute BDL groups as compared with the normal controls. FP 736-04 was taken up by the liver parenchyma with a similar degree of enhancement in all three groups.

Animals↗
PubMed1997

8-Isoprostaglandin F2 alpha, a product of lipid peroxidation, increases portal pressure in normal and cirrhotic rats.

BACKGROUND & AIMS: The F2-isoprostanes are a recently described class of prostaglandins formed by free radical-mediated lipid peroxidation. 8-Isoprostaglandin F2 alpha (8-iso-PGF2 alpha), an F2-isoprostane, has previously been shown to be a potent renal vasoconstrictor acting via a thromboxane-like receptor. The aim of this study was to investigate whether 8-iso-PGF2 alpha increases portal pressure. METHODS: Livers from normal and bile duct-ligated cirrhotic rats were perfused, and portal pressure response to infused agonist was monitored continuously. RESULTS: Infusion of 8-iso-PGF2 alpha increased portal pressure in both groups, with a significantly greater response in cirrhotic rats. At a dose of 2.5 nmol/min, the mean portal pressure increased from a baseline of 8.2 +/- 0.6 to 9.8 +/- 1.3 mm Hg, whereas in cirrhotic animals, the increase was from 12.0 +/- 0.9 to 18.6 +/- 1.8 mm Hg. This response was completely blocked by SQ29548, a thromboxane receptor antagonist. A similar response pattern was observed with the thromboxane receptor agonist U46619. CONCLUSIONS: 8-iso-PGF2 alpha can increase portal pressure in cirrhotic rats. If extrapolated to patients with cirrhosis, lipid peroxidation secondary to alcoholic liver injury, sepsis, or other liver pathology may cause an acute increase in portal pressure such as that observed in acute liver injury.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1994

Activity-dependent mobilization of the adhesion molecule polysialic NCAM to the cell surface of neurons and endocrine cells.

The alpha-2,8-linked sialic acid polymer (PSA) on the neural cell adhesion molecule (NCAM) is an important regulator of cell surface interactions. We have examined the translocation of PSA-NCAM to the surface of cultured cortical neurons and insulin secreting beta cells under different conditions of cell activity. Endoneuraminidase N, an enzyme that specifically cleaves PSA chains, was used to remove pre-existing PSA from the plasma membrane and the re-expression of the molecule was monitored by immunocytochemistry. Punctate PSA immunostaining was restored on the surface of 68% of neurons within 1 h. This recovery was almost completely prevented by tetrodotoxin, suggesting that spontaneous electrical activity is required. K+ depolarization (50 mM) allowed recovery of PSA surface staining in the presence of tetrodotoxin and this effect required the presence of extracellular Ca2+. Rapid redistribution of PSA-NCAM to the surface of beta cells was observed under conditions that stimulate insulin secretion. Ca2+ channel inhibition decreased both PSA-NCAM expression and insulin secretion to control, non-stimulated levels. Finally, subcellular fractionation of an insulin-secreting cell line showed that the secretory vesicle fraction is highly enriched in PSA-NCAM. These results suggest that PSA-NCAM can be translocated to the cell surface via regulated exocytosis. Taken together, our results provide unprecedented evidence linking cell activity and PSA-NCAM expression, and suggest a mechanism for rapid modulation of cell surface interactions.

Animals↗
PubMed1994

Alteration in vascular reactivity in isolated aortic rings from portal vein-constricted rats.

It has been suggested that increased production of nitric oxide by an inducible nitric oxide synthase isoenzyme is important in the pathogenesis of the vascular abnormalities seen in human beings and animals with portal hypertension. We investigated this hypothesis by studying the in vitro vascular reactivity of isolated aortic rings from portal vein-constricted and sham-operated rats. Aortic rings from portal vein-constricted rats exhibited significantly impaired contractility to phenylephrine and potassium chloride compared with control rats. Preincubation with the nitric oxide synthase inhibitor nitro-L-arginine methyl ester significantly increased contractility to phenylephrine and potassium chloride in both portal-hypertensive and control tissues, with greater effect in the portal-hypertensive rings. Despite nitro-L-arginine methyl ester, maximal contractions were still significantly smaller in the portal-hypertensive tissues. Vascular relaxation evoked by acetylcholine, but not by the endothelium-independent vasodilator glyceryl trinitrate, was significantly impaired in the portal-hypertensive group. Our results demonstrate significant impairment in vascular function in aortic rings in this model of portal hypertension. The addition of a nitric oxide synthase inhibitor partly corrected these changes, suggesting that although nitric oxide is likely an important mediator, other factors may also be involved in the pathogenesis of these alterations in vascular function.

Acetylcholine↗
PubMed1994

5-fluorouracil vs. epirubicin vs. 5-fluorouracil plus epirubicin in advanced gastric carcinoma.

From January, 1985, through January, 1987, 165 patients with advanced gastric cancer were randomized to receive epirubicin (E) alone (90 mg/m2 day 1), 5-Fluorouracil (5-FU) alone (500 mg/m2 days 1-5), or the combination of E (90 mg/m2 day 1) and 5-FU (400 mg/m2 days 1-5). Courses were repeated every four weeks. Patients were stratified by extent (locally advanced vs. metastatic), evaluability (measurable vs. nonmeasurable) and by history of prior radiotherapy (yes vs. no). Randomization to single arm epirubicin was stopped after 26 patients were enrolled. Objective responses occurred in only 1/16 (6%) of the patients treated with E alone, 1/40 (5%) with 5-FU alone and 4/33 (12%) with both 5-FU and E. There were no significant differences in all eligible patients with respect to time to progression or overall survival in the three treatment arms. Toxicity was primarily hematologic and more pronounced in the combination arm. Neither 5-FU alone, epirubicin alone, or the combination have a major impact in the treatment of gastric carcinoma.

Adenocarcinoma↗
PubMed1994

Altered prostacyclin synthesis by aortae from hepatic portal vein-constricted rats: evidence for effects on protein kinase C and calcium.

To investigate the mechanisms causing reduced systemic vascular reactivity to vasoconstrictor agents in portal hypertension, we studied receptor- and signal-transduction-linked PGI2 (a vasodilator) synthesis (measured as 6-oxo-PGF1 alpha by radioimmunoassay) in the aorta (ex vivo) of portal vein-constricted rats. PGI2 synthesis was stimulated by adrenaline (via heterogeneous alpha-adrenoceptors), phorbol ester dibutyrate (a protein kinase C activator), arachidonic acid (the substrate for PGI2 synthesis) and the Ca2+ ionophore A23187 (A23187) and thapsigargin (both of which elevate intracellular Ca2+, which in turn elicits the release of arachidonic acid). The release of PGI2 by the aortae of rats with portal hypertension in comparison to sham-operated controls was: 1) enhanced in response to adrenaline, 2) reduced in response to phorbol ester dibutyrate, A23187 and thapsigargin and 3) unchanged in response to arichidonic acid. These data indicate that in aortae from rats with experimental portal hypertension: i) there are no changes in the enzymes involved in PGI2 synthesis (cyclooxygenase, PGI2 synthase), ii) there is a specific increase in adrenoceptor-linked PGI2 synthesis in aortae which may contribute to arterial vasodilation in this experimental model and 3) the diminished response of PGI2 synthesis to A23187, phorbol ester dibutyrate and thapsigargin indicates that there is a generalised attenuation of protein kinase C activator activity and of Ca2+. Since Ca2+ is a key component of excitation-contraction coupling and protein kinase C activator has been implicated in mediating this event, attenuation of these systems may also explain, at least in part, the known reduced vasoactivity of aortae from rats with portal hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The effect of an eucaloric high carbohydrate diet on circulating levels of glucose, fructose and non-esterified fatty acids in patients with cirrhosis.

Twelve cirrhotic patients and six controls were fed an eucaloric high carbohydrate (CHO) diet for 3 days. Fasting serum triglyceride (TG), non-esterified fatty acids (NEFA), glucose, insulin and glycerol were estimated daily. On the 3rd day of the study we measured NEFA, glucose, insulin, and fructose every 45 min from 07:45 h until 19:45 h, and then every 4 h until 07:45 h the next day. The patients were divided into two groups of six on the basis of plasma lecithin-cholesterol acyltransferase (LCAT) activity: group A cirrhotics (with good liver function--LCAT activity: 40.6-65.7 nmol.ml-1.h-1; mean 48.5), and group B (poor liver function--LCAT: 23.7-32.3; mean 27.4). On the high CHO diet there was an increase in the fasting serum TG with a peak after 2 or 3 days. The increase in serum TG in controls was greater (p less than 0.01) than in either group of cirrhotics. In the controls and in group A most of the extra TG was carried in VLDL; in group B only 39% of the TG increment was found in VLDL. Fasting NEFA fell with 3 days of CHO feeding in the control group (p less than 0.01); they were unchanged in group A, and rose in group B to a significantly higher level than in controls (p less than 0.01). During day 3 when a high CHO diet was fed plasma NEFA levels fell in cirrhotics, and for most of the day the mean NEFA concentration in group B patients was significantly (p less than 0.05) lower than in normals. On day 3 glucose and fructose levels rose after each meal--much more in cirrhotics than in controls (and more in group B than in group A), and for most of the day they were significantly higher in group B patients as compared to the controls (glucose p less than 0.01, fructose p less than 0.001). Our results supported the hypothesis that plasma NEFA would be lower following high CHO meals in cirrhotics than in controls. This suggests that a high NEFA utilisation, which occurs in fasting cirrhotics, is not present throughout the day. Following a CHO meal, we suggest that tissues derive energy directly from the dietary sugars which are present in high concentration during the period of absorption and that this reduces the post prandial requirement for NEFA.

Adult↗
PubMed1981

Computed tomography attenuation values in fatty liver.

The accuracy of CT diagnosis of increased fat deposition in the liver was assessed in 11 alcoholic patients with suspected fatty liver. Single-energy CT attenuation values were compared with histological assessment of fatty liver and chemical analysis of liver triglyceride concentrations, obtained from liver biopsy specimens. Measured attenuation values showed an inverse correlation with the degree of fatty change assessed histologically (r =--0.90; p Less Than 0.0001) and with that assessed chemically (r=--0.57; p Less Than 0.05). CT scanning may provide a useful non-invasive method for detecting and following patients with fatty liver, particularly when liver biopsy is contraindicated.

Adult↗