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D Goodier

Publications and source records attributed to D Goodier.

12 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↗
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

A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure.

Muscle injury (rhabdomyolysis) and subsequent deposition of myoglobin in the kidney causes renal vasoconstriction and renal failure. We tested the hypothesis that myoglobin induces oxidant injury to the kidney and the formation of F2-isoprostanes, potent renal vasoconstrictors formed during lipid peroxidation. In low density lipoprotein (LDL), myoglobin induced a 30-fold increase in the formation of F2-isoprostanes by a mechanism involving redox cycling between ferric and ferryl forms of myoglobin. In an animal model of rhabdomyolysis, urinary excretion of F2-isoprostanes increased by 7.3-fold compared with controls. Administration of alkali, a treatment for rhabdomyolysis, improved renal function and significantly reduced the urinary excretion of F2-isoprostanes by approximately 80%. EPR and UV spectroscopy demonstrated that myoglobin was deposited in the kidneys as the redox competent ferric myoglobin and that it's concentration was not decreased by alkalinization. Kinetic studies demonstrated that the reactivity of ferryl myoglobin, which is responsible for inducing lipid peroxidation, is markedly attenuated at alkaline pH. This was further supported by demonstrating that myoglobin-induced oxidation of LDL was inhibited at alkaline pH. These data strongly support a causative role for oxidative injury in the renal failure of rhabdomyolysis and suggest that the protective effect of alkalinization may be attributed to inhibition of myoglobin-induced lipid peroxidation.

Animals↗
PubMed1995

Patellar tendon rupture in identical twins.

We report on identical traumatic injuries in a pair of monozygotic (identical) twins treated at the same unit, one year apart. Both had sustained a complete tear of the patellar tendon and were treated surgically.

Diseases in Twins↗
PubMed1994

Tibial tuberosity avulsion associated with patellar tendon avulsion.

We report an adolescent boy with avulsion of the tibial tuberosity associated with avulsion of the patellar tendon. He underwent open reduction and internal fixation of his bone injury, and the patellar tendon was successfully reattached. The boy experienced a full recovery.

Adolescent↗
PubMed1994

Tibial tuberosity avulsion associated with patellar tendon avulsion.

We report an adolescent boy with avulsion of the tibial tuberosity associated with avulsion of the patellar tendon. He underwent open reduction and internal fixation of his bone injury and the patellar tendon was successfully reattached. The boy experienced a full recovery.

Adolescent↗