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Biomedical subjects

W T Chance

Publications and source records attributed to W T Chance.

At least 19 recordsLinked to original sources
PubMed1995

Anticatabolic effect of the beta 2-agonist cimaterol in vivo in tumor-bearing animals.

Loss of lean body mass occurs in cancer and may adversely affect outcome. The beta 2-agonist cimaterol increases muscle mass and protein content in tumor-bearing animals, in part by decreasing protein degradation, but the effect of the drug on protein synthesis remains uncertain. To determine the influence of cimaterol on protein synthesis, a methylcholanthrene sarcoma was transplanted sc into the dorsum of male Fischer-344 rats. After 3 weeks of tumor growth, tumor-bearing and control animals received daily sc injections of the beta 2-agonist cimaterol (0.15 mg/kg) for 5 days. Rate of protein synthesis was measured using iv [3H]-phenylalanine (25 microCi/100 g body wt) and cold phenylalanine (150 mumole/100 g body wt) in a flooding dose. Extensor digitorum longus muscles were harvested 10 min later, homogenized, and assayed for [3H]-phenylalanine uptake (bound) (dpm/mg muscle) and tissue-specific (free) radioactivity to determine protein synthesis rate (Ks: %/24 hr). There was a significant increase in protein synthesis rate in control and tumor-bearing animals receiving cimaterol compared to that in freely feeding, food-deprived, or matched-carcass-weight nontumor-bearing controls, as well as compared to that in tumor-bearing controls. We conclude that the anabolic effects of cimaterol are due to both decreased protein degradation and increased muscle protein synthesis. Therefore, beta 2-agonists may prove useful in prevention and/or treatment of cancer cachexia.

Adrenergic beta-Agonists↗
PubMed1995

Differential effects of tumor and parenteral nutrition on jejunal mucosal polyamines.

Nutritional repletion of tumor-bearing (TB) organisms by means of total parenteral nutrition (TPN) has been associated with gut atrophy, immunosuppression, and increased infection rate. To assess possible molecular mechanisms of intestinal atrophy during TPN, jejunal mucosal polyamine concentrations and biosynthetic activity were assessed in non-TB (NTB) and TB rats maintained on rat chow or TPN for eight days. As expected, jejunal mucosal protein content was decreased in both groups of rats maintained on TPN. Although mucosal concentration of putrescine was decreased in TB groups and in the NTB group maintained on TPN, levels of spermidine and spermine were decreased only in the NTB-TPN group. Spermidine levels were elevated significantly in both TB groups. The concentration of spermine was also elevated in the TB-TPN group but was not changed in the TB group maintained on chow. Activity of ornithine decarboxylase was increased in the NTB-TPN group but was not altered significantly in either TB group. S-adenosylmethionine decarboxylase activity was decreased significantly in TB rats maintained on chow and was increased back to control level in the TB-TPN group. These results suggest that jejunal mucosal polyamines are decreased in NTB rats maintained on TPN. Additionally, it appears that enzyme activity is induced in NTB-TPN rats, perhaps in response to the reduction in polyamines and gut atrophy. The absence of similar changes in TB rats maintained on TPN suggests that regulatory mechanisms of polyamine biosynthesis, such as product inhibition, may be refractory. In addition, polyamine biosynthesis from other sources, such as tumor tissue, may be affecting the control of intestinal polyamine biosynthesis.

Adenosylmethionine Decarboxylase↗
PubMed1995

Neuropeptide Y and the development of cancer anorexia.

OBJECTIVE: The authors determined whether radioligand binding of neuropeptide Y (NPY) to hypothalamus taken from nonanorectic and anorectic tumor-bearing rats was altered as compared with similar tissue taken from freely-feeding and food-restricted control rats. SUMMARY BACKGROUND DATA: Previous results indicate that tumor-bearing rats exhibit a refractory feeding response to NPY, the most potent feeding stimulus known. Additional studies indicate that the concentration of NPY in the hypothalamus of anorectic tumor-bearing rats is decreased as compared with freely-feeding or food-restricted control rats. METHODS: Because these observations of decreased response to exogenous peptide in the presence of decreased endogenous levels suggest an alteration in hypothalamic NPY receptors, this study investigated binding of 125I-NPY to hypothalamic membranes of tumor-bearing and control rats. RESULTS: Determinations of receptor affinity for NPY (half maximal concentration for displacement) indicated a 20-fold decrease in affinity with the development of anorexia, which changed to an 80-fold decrease during severe anorexia. Receptor density, as indicated by specific binding, exhibited only a 30% decrease, even during severe anorexia. CONCLUSIONS: These results suggest major alterations in NPY receptor mechanisms in experimental cancer anorexia, with receptor affinity being decreased progressively as the rats become more anorectic. The absence of a compensatory up-regulation in receptor density in the presence of decreased endogenous NPY concentrations indicate dysfunction in receptor regulatory mechanisms. This receptor aberration may be the central nervous system basis for the etiology of cancer anorexia.

Animals↗
PubMed1994

Possible role of neuropeptide Y in experimental cancer anorexia.

The efficacy of NPY to elicit feeding in TB rats was reduced prior to the onset of overt anorexia, with the feeding response decreasing further as anorexia developed. Hypothalamic concentration of NPY was reduced in TB rats, with the magnitude of the decrease paralleling the degree of anorexia. Binding affinity of NPY to hypothalamic membranes taken from TB rats suggested decreased binding affinity with no change in receptor number. Infusing ammonium salts at a concentration and rate necessary to increase blood ammonia levels to the degree observed in TB rats, produced anorexia and decreased NPY feeding. These results suggest that NPY feeding systems are abnormal in TB rats and that hyperammonemia may be of primary importance in this dysfunction.

Ammonia↗
PubMed1994

Insulin reverses ammonia-induced anorexia and experimental cancer anorexia.

Previous experiments suggest that experimental cancer-induced anorexia is associated with hyperammonemia and that daily injections of insulin may attenuate the anorexia for several days. In the present study, we determined whether similar daily insulin treatments would correct anorexia induced by the infusion of ammonium salts and compared this feeding response with that of insulin-treated tumor-bearing (TB) rats. Daily treatment of control and anorectic TB rats with systemically administered insulin for six days increased feeding in all control rats and 40% of the TB rats. All insulin-treated groups exhibited equal degrees of hypoglycemia irrespective of anorexia. Basal concentrations of lactate and glucagon were elevated in saline-treated TB rats. Plasma lactate levels were normalized by insulin treatment, whereas glucagon was normalized only in the TB rats that fed to insulin and increased further in TB rats that did not feed to insulin. Elevated hypothalamic tyrosine was reduced in insulin-treated TB rats that ate, and 5-hydroxy-indoleacetic acid was increased further when the rats did not eat. Insulin also blocked anorexia resulting from the intravenous infusion of ammonium salts. Hypothalamic concentrations of tyrosine and tryptophan were increased by the ammonia infusion and reduced significantly in insulin-treated infused rats. These results indicate that insulin treatment can reverse experimental cancer-induced anorexia and hyperammonemia-induced anorexia. Neurochemical changes associated with these treatments are also similar, but not identical.

Ammonia↗
PubMed1993

Effects of increased beta 2-agonist dose in tumor-bearing animals.

Cachexia and malnutrition are major contributing causes of significant morbidity and mortality in the cancer patient. Although supplemental nutrition alone does not reverse the cachectic process, the use of anabolic beta 2-adrenergic agonists in conjunction with supplemental nutrition does significantly reverse cachectic processes in tumor-bearing (TB) animals. To determine the most efficacious dose of the beta 2-agonist cimaterol (CIM), male Fischer-344 rats with dorsal subcutaneous methylcholanthrene sarcomas were maintained on supplemental enteral nutrition via surgically placed gastrostomy tubes. TB rats were given daily subcutaneous injections of either saline (Sal) or one of three doses of CIM for seven days. TB-Sal animals demonstrated significant cachexia with decreased extensor digitorum longus and gastrocnemius muscle dry weight and protein content. There was a significant increase in both extensor digitorum longus and gastrocnemius muscle dry weight and protein content in all treatment groups compared with TB controls. The greatest increase was in the 0.30 mg/kg CIM treatment group. Increased cardiac mass was associated with increasing dosage, with the greatest effect being observed in the 0.60 mg/kg CIM treatment group. This dosage, however, was associated with a decreased effect on muscle weight and protein content compared with the 0.30 mg/kg CIM dose. Thus the peak anabolic effect in TB animals was reached with the 0.30 mg/kg dose of CIM. Therefore, use of the beta 2-agonist CIM may prove useful in the treatment of cancer-induced cachexia.

Adrenergic beta-Agonists↗
PubMed1992

Amylin increases transport of tyrosine and tryptophan into the brain.

Injection of amylin (diabetes-associated peptide) into the hypothalamus induces anorexia, increases brain metabolism of dopamine and serotonin and elevates brain level of tryptophan. When male Sprague-Dawley rats were treated with 50 mg/kg L-tryptophan and L-tyrosine ethyl ester 30 min prior to the intrahypothalamic injection of 2 micrograms amylin, brain tryptophan and tyrosine levels were selectively increased as compared to rats treated with amylin alone. Hypothalamic and striatal serotonin metabolism also appeared to be increased following the amino acid-amylin treatment combination. These results suggest that amylin may increase transport of tyrosine and tryptophan into the brain, and that the increased availability of tryptophan may contribute to increased serotonin turnover observed following intrahypothalamic amylin treatment.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Aphagic and adipsic effects of interleukin-1.

Intake of rat chow and water was reduced 4 and 8 h after the intrahypothalamic injection of 5 ng interleukin-1a (IL-1a). Although core body temperature was also elevated significantly for at least 4 h by the administration of this cytokine, resting energy expenditure was not altered. These results suggest that IL-1a may be involved in the reduction of feeding associated with trauma, infection or cancer, by inducing early satiety. Additionally, hyperthermia associated with the injection of IL-1a appears to be maintained by decreased heat dissipation rather than by increased thermogenesis.

Analysis of Variance↗
PubMed1991

Anorexia following the intrahypothalamic administration of amylin.

The intrahypothalamic injection of rat amylin reduced feeding in schedule-fed rats for eight hours. Specificity of this anorectic response was indicated by an appropriate dose-response relationship and the absence of effect of human amylin. Amylin-induced anorexia was accompanied by alterations in neurotransmitter metabolism similar to those observed in anorectic tumor-bearing rats. These results indicate that amylin may inhibit feeding by acting directly on hypothalamic neurons to alter metabolism of neurotransmitter systems known to affect feeding behavior.

Amyloid↗
PubMed1991

Clenbuterol plus acivicin decrease tumor growth and increase muscle mass in rats maintained on total parenteral nutrition.

Two problems associated with supplemental nutrition of tumor-bearing organisms are control of tumor growth and reduction of cachexia. To investigate these problems, rats bearing methylcholanthrene-induced sarcomas were maintained on total parenteral nutrition (TPN) for 10 to 12 days beginning 23 days after tumor inoculation. Combined treatment of one group of these rats with the glutamine antimetabolite, acivicin, and the beta 2-adrenergic agonist, clenbuterol, arrested tumor growth, increased skeletal muscle mass and protein content, increased gut mass, and decreased total plasma lipid levels. Resting energy expenditure and cardiac mass were increased by TPN and were increased further by acivicin plus clenbuterol. These results demonstrate that tumor growth and muscle wasting can be controlled during TPN of tumor-bearing organisms. Therefore, cachectic depletion of lean body tissue may not be obligatory in neoplastic disease.

Animals↗
PubMed1991

Decreased myofibrillar protein breakdown following treatment with clenbuterol.

Daily treatment of Fischer-344 rats for 14 days with the beta 2-adrenergic agonist, clenbuterol, increased gastrocnemius muscle mass and protein content. Coadministration with the beta-adrenergic antagonist, nadolol, significantly reduced these anabolic effects of clenbuterol. Although clenbuterol treatment reduced food intake during the first 4 days, clenbuterol-treated rats were hyperphagic during the second week of drug administration. Nadolol treatment also blocked these effects of clenbuterol on feeding. In a second experiment, in vitro incubation of extensor digitorum longus muscles taken from post weaning food-deprived rats demonstrated decreased release of 3-methylhistidine by clenbuterol-treated rats, suggesting decreased breakdown of myofibrillar protein. Protein synthesis was not increased in vitro in the soleus muscles taken from these rats. These experiments demonstrate that the anabolic effect of clenbuterol is due in part to beta-adrenergic activity and may involve reduced myofibrillar protein degradation. These results appear to have direct application to nutrition and protein repletion in various catabolic diseases.

Adrenergic beta-Antagonists↗
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

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

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↗