published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

Thermoregulatory, analgesic and respiratory depressive responses as well as tolerance to morphine were investigated in young (3 to 5 months), mature (10 to 12 month) and senescent (26 to 28 month) male Fischer 344 rats. The thermoregulatory system of senescent rats was not able to maintain body temperature in hot and cold environments as well as the thermoregulatory system of young rats. Additionally, senescent rats had basal rectal temperatures which were approximately one degree lower than basal temperatures in young rats. Subcutaneous morphine caused biphasic effects on body temperature ie. hyperthermia at low doses and hypothermia at high doses. Senescent rats were less responsive to the hypothermic effects of subcutaneous morphine than young rats, but this was not due to decreased subcutaneous blood flow or inability to lose heat. Morphine injections intracerebroventricularly showed no age-related differences. A two site model for the actions of morphine on thermoregulation was proposed and it was suggested that the age-related differences are due to changes in a non periventricular site. Previously reported increased lethality of intravenous morphine in aged rodents was shown to be due to decreased respiratory reserve rather than increased sensitivity to respiratory depression. Senescent rats were also found to acquire tolerance to the thermic effects of morphine less readily than young rats regardless of the route of administration. Normal aging has been characterized as a decrease in adaptability, and it was suggested that senescent rats were less able to compensate for the thermic effects of morphine as well as young rats. In order to determine the mechanisms of decreased adaptability, neurotransmitters proposed to be involved in thermoregulation were injected intracerebroventricularly in morphine tolerant rats. The results suggested a shift from catecholaminergic to cholinergic transmitters with aging.

The effects of TCDD on hepatic ornithine decarboxylase (ODC) activity and endocrine function in rats were investigated. Sixteen hours after partial hepatecomy, rats which had been pretreated with TCDD for one week exhibited a 3- to 4-fold increase in ODC activity, while vehicle controls exhibited an 8- to 10-fold increase. ODC induction after either aminophylline or dexamethasone administration, agents which act via cAMP-mediated and direct nuclear events, respectively, also was inhibited by pretreatment with TCDD. RNA polymerase I activity, which positively correlates to ODC activity in growth and development, decreased concomitant with decreased induction of ODC. In unstimulated liver, RNA polymerase I activity, as well as protein, DNA and RNA levels, remained unchanged one week after TCDD. However, TCDD administration resulted in decreased liver concentrations of putrescine and spermidine, but not spermine. Within 2 days following administration of TCDD (45 or 90 μg/kg), rats exhibited hypothermia, hypothyroidism and decreased growth rate compared to pair-fed controls and rats fed ad libitum. Within 2 weeks of the administration of 90 μg TCDD/kg, body temperature had fallen to below 35°C with a low mean value 34.5°C recorded on day 16. Mean body temperatures for control rats ranged from 36.8°C to 37.5°C. One week after the administration of TCDD (45 μg/kg) to rats, serum thyroxine (T₄) and triiodothyronine (T₃) levels declined to 42% and 82% of control, respectively. Mild hypoglycemia occurred subsequent to hypothyroidism and hypothermia. At 1 week after administration of 45 μg TCDD/kg to rats, serum and pancreatic insulin levels were reduced to 25% and 76% of control, respectively. Hypophagia was determined to be responsible for decreased growth rate and hypoinsulinemia, but it could not account for hypothyroidism, hypothermia or hypoglycemia following administration of TCDD. No changes in glucagon or pancreatic, hepatic or serum somatostatin levels were found. Decreased somatostatin in the gastric antrum coincided with a 29% increase in stomach weight. The delayed toxicity of TCDD may be related to these striking hormonal alterations.

The metabolism and distribution of three commonly occurring PCB congeners, 4,4'-dichlorobiphenyl (4-DCB), 2,2',3,3',6,6'-hexachlorobiphenyl (236-HCB) and 2,2',4,4',5,5'-hexachlorobiphenyl (245-HCB), each displaying different structural features, were investigated at their principal metabolic site, the hepatocyte. Hepatocytes, isolated from male Sprague-Dawley rats (200-250 g) by collagenase perfusion, were suspended in medium 199 and maintained at 37°C in a gyratory shaker. The radiolabeled ¹⁴C-PCB congeners were added to the hepatocyte suspensions as a DMSO-albumin mixture. Each congener was rapidly taken up by the cells with less than 10% of the congener remaining in the medium. The congeners accumulated within the hepatocytes without being fully metabolized. Metabolism followed first order Michaelis-Menten kinetics for 20 min and plateaued by 90 min at which point only 32% of 4-DCB (0.01-100 uM) and 60% of 236-HCB (0.01-100 uM) was metabolized, while 245-HCB (0.1-200 uM) was not metabolized. Readdition of congener once metabolism had plateaued resulted in a reinitiation of metabolism with the same proportion of metabolites produced indicating that product inhibition was not the cause for the plateau. A partitioning of the PCB congeners within subcellular compartments and binding to cytosolic proteins influenced the extent of metabolism by decreasing the availability of congener for the drug metabolizing enzymes, cytochrome P-450. Spectral binding studies further revealed that the ability of a PCB congener to bind to the cytochrome P-450 system correlated with the extent of metabolism observed, with 236-HCB 4-DCB 245-HCB. The metabolic potential of the PCB congeners was influenced by both the affinity of the congener for cytochrome P-450 and the partitioning of congener within the hepatocyte, and not by product inhibition.

by Kwok-Ping Ho. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1980. / Bibliography: leaves 111-118.

by Wong Siu-Kuen. / Thesis (M.Phil.)--Chinese University of Hong Kong. / Bibliography: leaves 76-92.

No description available.

Bibliography: leaves 152-170.

Bibliography: leaves 80-106. / 106, [11] leaves, [33] leaves of plates : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Studies the phagocytic function of regenerated splenic tissue to determine its potential for protection against overwhelming post-splenectomy infection, using an in vivo model established in rats. / Thesis (M.D.)--University of Adelaide, Dept. of Surgery, 1996

Bibliography : leaves 162-181. / xvi, 186, [19] leaves, [13] leaves of plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines the gene expression of the renin-angiotensin system (RAS) in the spontaneously hypertensive rat and the normotensive Wistar-Kyoto rat. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1994