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Biomedical subjects

J E Fischer

Publications and source records attributed to J E Fischer.

At least 199 records · Page 11Linked to original sources
PubMed1991

Reduced levels of mRNA for myofibrillar proteins in skeletal muscle from septic rats.

The influence of sepsis on transcription of myofibrillar proteins in skeletal muscle was studied in rats. Sepsis was induced by cecal ligation and puncture (CLP); control rats were sham-operated. Sixteen hours later, muscle levels of mRNA for myofibrillar proteins were determined by using cDNA probes specific for transcripts for alpha actin and myosin heavy chain. Sepsis resulted in a 2-6 fold decrease in alpha actin mRNA levels and an even more pronounced reduction in myosin heavy chain mRNA levels. Results suggest that sepsis-induced reduction of muscle protein synthesis is at least partly regulated at the transcriptional level.

Actins↗
PubMed1991

Tumor-induced alterations in brain neurotransmitter and plasma ammonia concentrations are normalized twenty-four hours after tumor resection.

Tumor-induced anorexia was accompanied by significant elevations in plasma ammonia and lactate and by alteration of the plasma amino acid profile. The brains of anorectic tumor-bearing rats had increased levels of glutamine and most large neutral amino acids. Dopamine and serotonin metabolism were also increased in several brain regions of these rats. Resection of the tumor resulted in the normalization of most of these aberrations in blood and brain within 24 hrs. These results demonstrate a rapid reversal of tumor-induced biochemical alterations shortly after tumor removal and suggest that these aberrations may be secondary to hyperammonemia.

Amino Acids↗
PubMed1991

Influence of sepsis in rats on muscle protein turnover in vivo and in tissue incubated under different in vitro conditions.

We studied the influence of sepsis on muscle protein synthesis and degradation in vivo and in muscles, incubated flaccid or at resting length. Sepsis was induced in rats by cecal ligation and puncture (CLP). Control rats were sham-operated. A flooding dose of 14C-phenylalanine was used to determine muscle protein synthesis rate in vivo, and protein breakdown was calculated from the difference between protein synthesis and growth rates. Protein synthesis rate in vitro was assessed by determining incorporation of 14C-phenylalanine into protein in incubated extensor digitorum longus (EDL) and soleus (SOL) muscles. Total and myofibrillar protein breakdown rates were determined from release into incubation medium of tyrosine and 3-methylhistidine (3-MH), respectively. Muscle protein synthesis rate in vivo was reduced by 35%, similar to the reduction observed in muscles incubated flaccid or at resting length. The calculated protein breakdown rate in vivo was increased by 31% in septic rats. In incubated muscles, the increase in total protein breakdown (ie, tyrosine release) during sepsis was almost identical in muscles incubated flaccid or at resting length, ie, 83% to 88% in EDL and 47% to 49% in SOL. Myofibrillar protein degradation in vitro (ie, 3-MH release) was increased approximately 10-fold in EDL muscles incubated flaccid or at resting length, but was not significantly affected by sepsis in SOL. Results suggest that sepsis-induced changes in protein synthesis observed in muscles incubated either flaccid or at resting length reflect changes in vivo. Changes in protein breakdown were qualitatively similar in vivo and in vitro, but results in incubated muscles may overestimate the increase in muscle proteolysis caused by sepsis.

Adenosine Triphosphate↗
PubMed1991

Myofibrillar proteinase, cathepsin B, and protein breakdown rates in skeletal muscle from septic rats.

Muscle catabolism during sepsis is mainly caused by myofibrillar protein breakdown. The mechanism of this metabolic response is not known. We tested the hypothesis that increased protein breakdown in the extensor digitorum longus (EDL) muscle of septic rats is caused by increased activity of the so-called myofibrillar proteinase, which is a nonlysosomal proteolytic enzyme, and cathepsin B, which is a lysosomal proteinase. Sepsis, induced in male Sprague-Dawley rats (50 to 60 g) by cecal ligation and puncture (CLP), resulted in an approximately 50% increase in myofibrillar proteinase activity and an approximately 30% increase in cathepsin B activity. Concomitantly, both total and myofibrillar protein breakdown rates, measured as release of tyrosine and 3-methylhistidine (3-MH), respectively, by incubated EDL muscles, were substantially elevated. Treatment of septic rats with the mast cell degranulating compound 48/80 or the lysosomal protease inhibitor leupeptin significantly reduced myofibrillar proteinase and cathepsin B activities, but did not affect protein breakdown rates. The results suggest that increased protein breakdown in septic skeletal muscle is associated with, but not caused by, myofibrillar proteinase or cathepsin B activity. The data also support the concept of a mast cell origin of the myofibrillar proteinase activity, but do not suggest an obligatory involvement of mast cell proteinase in increased protein degradation during sepsis.

Animals↗
PubMed1991

Tissue metabolite levels in different types of skeletal muscle during sepsis.

The effect of sepsis on energy and metabolite levels in the white, fast-twitch extensor digitorum longus (EDL) and the red, slow-twitch soleus (SOL) muscles was studied in rats. Sepsis was induced by cecal ligation and puncture (CLP). Control rats were sham-operated. Sixteen hours later, metabolite levels in muscle tissue were determined. Adenosine triphosphate (ATP) levels and energy charge were reduced during sepsis in SOL, but were unchanged in EDL muscles. In contrast, phosphocreatine (PCr) concentration was reduced during sepsis in EDL, but not in SOL. Tissue glycogen levels were reduced and lactate concentrations were increased in both muscles during sepsis. Results suggest that sepsis affects energy metabolism differently in different types of skeletal muscle. Tissue lactate accumulation may be consistent with muscle hypoperfusion following CLP, although other mechanisms may also be involved.

Adenosine Triphosphate↗
PubMed1991

Hyperammonemia and anorexia in Morris hepatoma-bearing rats.

Inoculation of Buffalo rats with Morris hepatoma produced significant anorexia within four weeks and reduced body weight within two weeks. Blood ammonia concentration was increased by 113% when the rats were euthanized, five days after the development of anorexia. Infusing ammonium salts into normal Buffalo rats also induced anorexia at a blood ammonia concentration comparable to that observed in the tumor-bearing rats. Although ammonia-infused rats exhibited expected increases in brain tyrosine, tryptophan, and metabolites of dopamine and serotonin, these alterations were attenuated in the tumor-bearing rats. These results indicate that hyperammonemia may be a general consequence of experimental cancer and that the increase in ammonia concentration may be of primary importance in the development of experimental cancer-induced anorexia. The rather small alterations in neurotransmitter metabolism in anorectic tumor-bearing rats deemphasize the role aberrations in DA and 5-HT systems in the development of experimental cancer anorexia.

Ammonia↗
PubMed1991

The effects of in vivo administration of endotoxin on the functions and interaction of hepatocytes and Kupffer cells.

It was the purpose of this study to determine the effects of the in vivo administration of endotoxin on certain in vitro hepatocyte and Kupffer cell functions. An Alzet osmotic pump that contained endotoxin (LPS, 2.5 mg/100g) was implanted into the peritoneal cavity of 300g guinea pigs and delivered the endotoxin over a period of four days. In vivo administration of LPS did not cause a change in the in vitro release of albumin by isolated hepatocytes. However, when hepatocytes were co-cultured with Kupffer cells there was a significant decrease in albumin release for both control and LPS-treated animals. There was no difference between control and LPS-treated animals in the release of C3 by hepatocytes. However, there was a significant increase over the control group in C3 release by Kupffer cells from LPS-treated animals. When hepatocytes and Kupffer cells were cultured together, their release of C3 was not additive. Kupffer cells from LPS-treated animals released significantly greater amounts of PGE2 than control animals when stimulated in vitro with LPS. Thus, these Kupffer cells appeared to be primed to respond to an in vitro challenge of LPS. Kupffer cells from LPS-treated animals had significantly depressed antibody dependent cellular cytotoxicity (ADCC). This endotoxin model is useful for determining the in vivo effects of endotoxin on cellular function and gives some indirect evidence for the detrimental effects of LPS on the immune system and host defense.

Animals↗
PubMed1991

Methionine sulfoximine intensifies cancer anorexia.

Consistent anorexia was first observed 33 days after inoculating Fischer 344 rats with methylcholanthrene-induced sarcoma. Daily treatment of a similar group of rats with the glutamine synthetase inhibitor, methionine sulfoximine, elicited significant reductions of feeding by day 29 at a dose that had no effect on nontumor-bearing rats. Blood concentrations of ammonia were elevated in both groups of tumor-bearing rats and brain ammonia level was increased in the methionine sulfoximine-treated tumor-bearing rats. Forebrain concentrations of tyrosine, tryptophan, DOPAC and 5-HIAA were elevated in both groups of tumor-bearing rats. Since ammonia is detoxified through the glutamine synthetase reaction, these results suggest that blood and brain ammonia concentrations are more important than the neurochemical consequences of ammonia detoxification for the etiology of cancer anorexia.

Ammonia↗
PubMed1991

Clenbuterol decreases catabolism and increases hypermetabolism in burned rats.

Following a 30% body surface area full-thickness open-flame burn, rats exhibited hypermetabolism, body weight loss, and muscle catabolism. Twenty-one days of treatment of one group of burned rats with the selective beta 2-adrenergic agonist, clenbuterol, increased resting energy expenditure and normalized body weight gain, muscle mass, and muscle protein content. Conversely, similar treatment of another group of burned rats with the long-acting beta-adrenergic antagonist, nadolol, reduced muscle mass, while having no effect on resting energy expenditure, body weight gain, or muscle protein content. These results demonstrate that hypermetabolism does not invariably result in loss of lean body mass and suggest that clenbuterol may be useful in preserving muscle mass and protein in catabolic diseases.

Amino Acids↗
PubMed1991

Factors influencing the concentrations of the large neutral amino acids in the brain and in the CSF of dogs after portacaval anastomosis.

Portal-systemic shunting of blood is associated with hyperammonemia, an increased glutamine concentration in brain, an altered plasma neutral amino acid pattern, and high levels of several of the large neutral amino acids in brain. Since some of these amino acids are precursors for neurotransmitters and for other potentially neuroactive substances, high CNS levels of these amino acids may contribute to the development of encephalopathy. In order to determine the relative importance of changes in brain glutamine levels and changes in competition among the neutral amino acids for blood-brain transport, we measured the concentrations of the large neutral amino acids in plasma, cisternal cerebrospinal fluid and in brain tissue from various regions of dogs after end-to-side portacaval shunt. Although the changes in CSF amino acid levels correlated partially with altered amino acid plasma competitor ratios, better correlations were observed with the elevation of CSF glutamine. These results suggest a model of blood-brain amino acid transport in which a high level of glutamine in brain extracellular fluid competes with other neutral amino acids for efflux from brain, thus raising brain amino acid levels after portal-systemic shunting.

Amino Acids, Essential↗
PubMed1991

Reversal of cancer cachexia in rats by cimaterol and supplemental nutrition.

The anabolic beta 2-agonist cimaterol was used in conjunction with supplemental nutrition to reverse cancer-induced cachexia and malnutrition in tumor-bearing rats. Cimaterol was administered to tumor-bearing rats receiving total parenteral nutrition or enteral nutrition for 10 days, beginning 2 weeks after subcutaneous transplantation of methylcholanthrene sarcoma. A significant increase occurred in both muscle weight and muscle protein in animals receiving cimaterol in conjunction with either enteral or parenteral feeding, compared to food fed tumor-bearing animals. Muscle protein content was increased significantly by 16% in cimaterol-treated rats maintained on parenteral nutrition and by 11% in cimaterol-treated enterally fed rats compared with the respective tumor-bearing controls. Urinary concentrations of 3-methylhistidine, an estimation of muscle turnover or catabolism, were significantly reduced in both tumor-bearing groups treated with cimaterol compared to 3-methylhistidine levels of the untreated tumor-bearing groups. The anabolic effects of cimaterol were expressed in the presence of a large tumor burden resulting in reversal of muscle depletion and muscle breakdown regardless of the route of supplemental nutrition. Thus, beta 2-agonists may be considered as a possible therapy for cancer cachexia.

Adrenergic beta-Agonists↗
PubMed1991

Effect of ischemia on protein synthesis in the septic liver.

The effect of ischemia on hepatic protein synthesis during sepsis is not known, but is of clinical relevance, since hepatic blood flow decreases during the late phase of sepsis. In this study, synthesis of acute-phase proteins was measured in perfused livers of rats 16 hours after sham operation or cecal ligation and puncture. Livers from each group had 45 minutes of complete ischemia or control perfusion. Protein synthesis was measured during two hour perfusion after the ischemia or control period, by determining incorporation of 3H-leucine into total secreted trichloracetic acid precipitated proteins, immunoprecipitated complement component C3 and albumin and phosphotungstenate-precipitated alpha 1-acid glycoprotein. Lactate, glutamine-oxalacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) levels in the perfusate were measured during preischemic and postischemic perfusion. Tissue glutathione levels were measured at the end of the perfusion. Synthesis of alpha 1-acid glycoprotein was increased by 100 per cent and albumin synthesis decreased by 46 per cent in septic livers, consistent with an acute-phase response and apparent downregulation of albumin synthesis during early sepsis. Synthesis rates were reduced by 50 to 60 per cent after ischemia in perfused livers from sham operated rats and 70 to 80 per cent in livers from septic rats. Hepatic production of interleukin-1 was not different between the groups during perfusion. GOT and GPT levels increased significantly during ischemia of both nonseptic and septic livers and rapidly returned toward baseline during reperfusion. Lactate levels were higher in perfusate of septic than of nonseptic livers before ischemia and increased further during ischemia. The results suggest that ischemia inhibits production of secreted hepatic proteins similarly in nonseptic and septic livers, but perhaps to a slightly greater extent in septic livers.

Acute-Phase Proteins↗
PubMed1991

Pathogenesis of hepatic steatosis during total parenteral nutrition.

The hepatic toxicity of TPN that is seen clinically appears to be multifactorial in origin. Most patients develop a combination of hepatic steatosis with evidence of cholestasis and abnormalities in liver function. The model that we have studied is one of pure hepatic steatosis since, on repeated study, these rats do not develop any liver function abnormalities. It is unclear whether this is related to the fact that these are short-term experiments, that rat livers respond differently from humans, or that rats do not have gallbladders. It has not been possible to carry these experiments out beyond 3 weeks since the rats develop bacterial colonization of the central lines as well as evidence of line sepsis. thus confounding the issue of hepatic toxicity being due to the TPN or to sepsis. One hypothesis is that hepatic steatosis is an early marker of liver toxicity and that prevention or reversal of hepatic steatosis may protect the liver from further abnormality. Insulin and glucagon seem to play a critical role in the development of TPN-associated hepatic steatosis. Specifically, an elevated portal venous insulin-glucagon molar ratio appears to be the primary stimulus and any treatment that lowers this ratio should diminish hepatic steatosis. The use of glucagon as a treatment modality is new. We have found no evident side effects of low dose glucagon in rats when it is added to the TPN solution. Glutamine has received much attention recently as a nutritional pharmacological agent in ameliorating some of the intestinal complications of parenteral nutrition and is well tolerated when administered appropriately. Intravenous lipid administration is an important nonprotein calorie source, especially when a high dextrose base cannot be used, and plays a role as well in preventing the development of hepatic steatosis. Thus, it is suggested that the clinical treatment of hepatic steatosis during TPN can be safely performed using any one, or a combination, of these modalities and without having to discontinue the TPN infusions. Since we observed no deterioration of liver function in rats receiving TPN for up to 2 weeks, we cannot completely relate these findings and recommendations to the hepatic dysfunction seen clinically with the use of TPN. Additional study will be required before this can be conclusively determined.

Animals↗
PubMed1991

The effects of calcium and calcium channel blockade on peptide YY and neuropeptide Y release.

The secretory response of many gastrointestinal hormones has been demonstrated to be mediated by way of calcium-dependent pathways. The present study was done to assess the effects of infusions of calcium (15 milligrams per kilogram per hour) and verapamil (5 milligrams per kilogram per hour) on circulatory and ileal intraluminal release of peptide YY and neuropeptide Y. Five dogs weighing 25 kilograms had distal ileal Thiry-Vella segments of 25 centimeters surgically created. After a two week recovery period, each dog was tested after overnight fasting. The dogs were given one hour infusions of either calcium or verapamil after basal measurements. One hour of postinfusion measurements completed the study. Intravenous calcium did not affect circulating peptide YY or neuropeptide Y, but did significantly increase recoverable ileal peptide YY. Verapamil administration significantly increased both circulating peptide YY and neuropeptide Y levels. The results of our data suggest an independent release of intraluminal and intravascular peptide YY as well as modulation of the circulatory release of both peptide YY and neuropeptide Y by cell membrane calcium channel blockade.

Animals↗
PubMed1991

Effect of the glucocorticoid receptor antagonist RU 38486 on muscle protein breakdown in sepsis.

The role of glucocorticoids in muscle catabolism during sepsis was tested with the glucocorticoid receptor antagonist RU 38486. Sepsis was induced in male Sprague-Dawley rats (40 to 60 gm) by cecal ligation and puncture (CLP). Other animals underwent sham operation. Two hours before CLP or sham operation, rats received RU 38486 (5 mg/kg) or a corresponding volume of vehicle by gavage. Sixteen hours after CLP or sham operation, protein synthesis rate was determined by measuring incorporation of 14C-phenylalanine into protein in incubated extensor digitorum longus muscles. Total and myofibrillar protein breakdown rates were determined by measuring net release of tyrosine and 3-methylhistidine, respectively. The protein synthesis rate was approximately 30% lower in rats with sepsis than in sham operated rats and was not affected by treatment with RU 38486. The total protein breakdown rate was increased by approximately 70% and myofibrillar protein degradation was increased more than fivefold in muscle from rats with sepsis. Treatment with RU 38486 resulted in a 28% reduction of total and a 44% reduction of myofibrillar protein breakdown in rats with sepsis but did not affect proteolysis in muscle from sham-operated animals. The results support a role of glucocorticoids in accelerated muscle proteolysis during sepsis. It is not clear whether glucocorticoids are the only required mediator or they interact with other substances to induce muscle protein breakdown during sepsis.

Animals↗
PubMed1990

Prostaglandin E2 does not regulate total or myofibrillar protein breakdown in incubated skeletal muscle from normal or septic rats.

The role of prostaglandins in the regulation of muscle protein breakdown is controversial. We examined the influence of arachidonic acid (5 microM), prostaglandin E2 (PGE2) (2.8 microM) and the prostaglandin-synthesis inhibitor indomethacin (3 microM) on total and myofibrillar protein breakdown in rat extensor digitorum longus and soleus muscles incubated under different conditions in vitro. In other experiments, the effects of indomethacin, administered in vivo to septic rats (3 mg/kg, injected subcutaneously twice after induction of sepsis by caecal ligation and puncture) on plasma levels and muscle release of PGE2 and on total and myofibrillar protein breakdown rates were determined. Total and myofibrillar proteolysis was assessed by measuring production by incubated muscles of tyrosine and 3-methylhistidine respectively. Arachidonic acid or PGE2 added during incubation of muscles from normal rats did not affect total or myofibrillar protein degradation under a variety of different conditions in vitro. Indomethacin inhibited muscle PGE2 production by incubated muscles from septic rats, but did not lower proteolytic rates. Administration in vivo of indomethacin did not affect total or myofibrillar muscle protein breakdown, despite effective plasma levels of indomethacin with decreased plasma PGE2 levels and inhibition of muscle PGE2 release. The present results suggest that protein breakdown in skeletal muscle of normal or septic rats is not regulated by PGE2 or other prostaglandins.

Animals↗
PubMed1990

Regulation of total and myofibrillar protein breakdown in rat extensor digitorum longus and soleus muscle incubated flaccid or at resting length.

The present study characterized total and myofibrillar protein breakdown rates in a muscle preparation frequently used in vitro, i.e. incubated extensor digitorum longus (EDL) and soleus (SOL) muscles of young rats. Total and myofibrillar protein breakdown rates were assessed by determining net production by the incubated muscles of tyrosine and 3-methylhistidine (3-MH) respectively. Both amino acids were determined by h.p.l.c. Both total and myofibrillar protein breakdown rates were higher in SOL than in EDL muscles and were decreased by incubating the muscles maintained at resting length, rather than flaccid. After fasting for 72 h, total protein breakdown (i.e. tyrosine release) was increased by 73% and 138% in EDL muscles incubated flaccid and at resting length respectively. Net production of tyrosine by SOL muscle was not significantly altered by fasting. In contrast, myofibrillar protein degradation (i.e. 3-MH release) was markedly increased by fasting in both muscles. When tissue was incubated in the presence of 1 munit of insulin/ml, total protein breakdown rate was inhibited by 17-20%, and the response to the hormone was similar in muscles incubated flaccid or at resting length. In contrast, myofibrillar protein breakdown rate was not altered by insulin in any of the muscle preparations. The results support the concepts of individual regulation of myofibrillar and non-myofibrillar proteins and of different effects of various conditions on protein breakdown in different types of skeletal muscle. Thus determination of both tyrosine and 3-MH production in red and white muscle is important for a more complete understanding of protein regulation in skeletal muscle.

Animals↗