Biomedical subjects

W T Chance

Publications and source records attributed to W T Chance.

At least 37 records · Page 2Linked to original sources

PubMed1995

Refractory hypothalamic adenylate cyclase in anorectic tumor-bearing rats: implications for NPY-induced feeding.

Although isoproterenol stimulated adenylate cyclase activity in hypothalamic membranes taken from freely-feeding, food-restricted or nonanorectic tumor-bearing rats, the response was greatly reduced in anorectic tumor-bearing rats. The addition of NPY to the membrane preparation inhibited adenylate cyclase activity in hypothalamus taken from freely-feeding and food-restricted rats, but NPY-inhibitory activity was significantly reduced in both groups of tumor-bearing rats. These results suggest that cyclic AMP formation is refractory in anorectic tumor-bearing rats, and that NPY-induced inhibition of hypothalamic adenylate cyclase is reduced in tumor-bearing rats prior to the onset of significant anorexia. Therefore, NPY-induced feeding may be reduced in tumor-bearing organisms due to a dysfunction in the cyclic AMP second messenger system.

Adenylyl Cyclases↗

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

Effects of electromagnetic fields and gender on neurotransmitters and amino acids in rats.

Epidemiological studies have linked electromagnetic field (EMF) exposure to certain forms of cancer, however only limited laboratory evidence supports a connection between EMF and biological effects. In the present study we exposed male and female rats to low level, 1000 milli-Gauss (mGs), direct current EMF generated with Helmholtz coils for 1 mo or 4 mo. The effects of these EMF exposures on regional brain neurotransmitter metabolism and circulating amino acid concentrations were determined. After 1 mo of EMF exposure the concentration of serotonin was elevated in the hypothalamus of male rats. Levels of the dopamine metabolite, 3-methoxytyramine, were increased in the corpus striatum of male and female rats that were exposed to EMF for 1 mo. Hypothalamic concentration of norepinephrine was elevated in both groups of male rats, as compared to respective female groups, but was not affected by EMF. Similarly, levels of tyrosine were increased in hypothalamus, corpus striatum and nucleus accumbens of male rats, but were not affected by EMF exposure. Following 4 mo of EMF exposure, no significant effect of EMF was observed. Significant sex differences in plasma amino acid concentrations were observed in both studies, with female rats exhibiting decreases in a majority of the amino acids measured. These results are suggestive that short-term exposure may cause small alterations in neurotransmitter metabolism and in circulating amino acids, which dissipate when exposure duration is increased.

Amino Acids↗

PubMed1995

Anorectic and neurochemical effects of pituitary adenylate cyclase activating polypeptide in rats.

Pretreatment of rats with intrahypothalamic injections of pituitary adenylate cyclase activating peptide (PACAP) 10 min prior to the injection of neuropeptide Y (NPY) significantly reduced food and water intake during the 4-h measurement period. Intrahypothalamic injection of PACAP in schedule-fed rats also reduced food and water intake for 2 h. A smaller 1-h reduction of water intake was observed in water-deprived rats, suggesting that the anticonsummatory effects of PACAP were primarily against food intake. PACAP treatment did not alter hypothalamic concentration of NPY, nor were neurotransmitters, precursors, or metabolites altered substantially in corpus striatum or nucleus accumbens regions. These results demonstrate primary anorectic effects of intrahypothalamic injection of PACAP. The demonstration of these anorectic effects may suggest a role of cyclic AMP activation and inhibition in the control of satiety and hunger.

Adenylyl Cyclases↗

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

[D-TRP32]neuropeptide Y: a competitive antagonist of NPY in rat hypothalamus.

Neuropeptide Y (NPY) is a potent orexigenic peptide. Structure-activity studies have revealed that nearly the entire sequence of NPY is required to elicit feeding responses. Therefore, in order to develop antagonistic peptides for NPY-induced feeding, we synthesized full-length analogs of NPY, substituting D-Trp in the C-terminal receptor binding region, and screened their activity in rat hypothalamus. Although [D-Trp36]NPY and [D-Trp34]NPY inhibited isoproterenol-stimulated hypothalamic membrane adenylate cyclase activity, [D-Trp32]NPY exhibited no intrinsic activity. Furthermore, [D-Trp32]NPY inhibited [125I]NPY binding to rat hypothalamic membranes with a potency comparable to that of NPY. The presence of 30 and 300 nM concentrations of [D-Trp32]NPY shifted the inhibitory dose-response curve of NPY on isoproterenol-stimulated hypothalamic membrane adenylate cyclase activity parallel to the right with comparable KB values. Moreover, in vivo experiments in rats revealed that [D-Trp32]NPY (10 micrograms) significantly attenuated the 1-h feeding response induced by NPY (1 microgram). Several other substitutions at position 32 including 2-D-Nal resulted in agonist activity, suggesting that there are strict structural requirements to induce the antagonistic property in NPY. These findings confirm that [D-Trp32]NPY is a competitive antagonist of NPY in both in vitro and in vivo systems. Analogs based on [D-Trp32]NPY may have potential clinical application, since NPY has been implicated in the pathophysiology of a number of feeding disorders including obesity, anorexia, and bulimia.

Adenylyl Cyclase Inhibitors↗

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

Hypothalamic concentration and release of neuropeptide Y into microdialysates is reduced in anorectic tumor-bearing rats.

Hypothalamic concentration of neuropeptide Y was decreased significantly in anorectic tumor-bearing rats, while NPY level was increased significantly in matched carcass weight control rats as compared with freely-feeding controls. In vivo microdialysis of the perifornical hypothalamic area of tumor-bearing rats prior to the development of anorexia revealed no alteration in NPY in dialysates. Following the development of anorexia, however, tumor-bearing rats exhibited significant reduction in NPY concentration in dialysates as compared with either matched carcass weight or freely-feeding control group. These results suggest that hypothalamic NPY concentration and release are decreased selectively in anorectic tumor-bearing rats. Since NPY also elicits less feeding in tumor-bearing rats, dysfunction of hypothalamic NPY feeding mechanisms may be of primary importance in cancer anorexia.

Animals↗

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

Anorexia following the systemic injection of amylin.

The intravenous injection of 100 micrograms/kg of rat amylin reduced food intake in schedule-fed rats for 1 h of an 8 h measurement period. Associated with this brief anorexia was a hyperglycemic response, observed 30 min after a subsequent amylin administration. Determination of neurochemical alterations revealed increased concentration of serotonin in the hypothalamus and decreased level of the dopamine metabolite, 3-methoxytyramine, in the corpus striatum. Since similar neurochemical alterations were observed following the systemic injection of glucose, both the neurochemical changes and anorexia following intravenous amylin treatment may be secondary to hyperglycemia.

Amyloid↗

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↗