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The primary goal of my studies was to elucidate the mechanisms for the well-recognized interaction between two nutrients, vitamins E and K. The outcomes from my studies assess mechanisms for adverse effects of vitamin E and provide novel information on mechanisms for vitamin K homeostasis. These findings will provide information relevant for assessing optimal intakes of vitamins E and K. This dissertation presents studies aimed at evaluating three different mechanisms by which vitamin K status could be decreased by increases in whole body vitamin E concentrations in rats supplemented with vitamin E by subcutaneous injections (100 mg α-tocopherol (α-T)/ kg body weight per day), the model system developed in the Traber lab. The tested mechanisms by which vitamin E leads to reduced vitamin K status were: 1) increasing vitamin K metabolism, 2) decreasing menaquinone-4 (MK-4) synthesis from dietary phylloquinone (PK) and 3) potentiating vitamin K excretion through xenobiotic pathways. Two approaches were undertaken to evaluate the hypothesis that vitamin E increases vitamin K metabolism. In Aim 1.1, the in vitro omega-hydroxylation of vitamin K by human cytochrome P450 CYP4F2 (expressed in insect microsomes) was tested because CYP4F2 is considered the limiting step in the catabolism of both vitamins. Chapter 2 shows that CYP4F2 more rapidly hydroxylated vitamin K compared with vitamin E. Moreover, vitamin E did not stimulate vitamin K metabolism in vitro. Thus, it is unlikely vitamin E stimulates vitamin K metabolism in vivo by direct interaction with the CYP4F2 enzyme-substrate complex. In Aim 1.2, the in vivo urinary and biliary excretion of vitamin K metabolites was investigated. Chapter 3 shows that α-T-injected rats significantly increased urinary excretion of vitamin E catabolites, but no increases in urinary vitamin K catabolites were found. Chapter 4 shows that α-T-injected rats increased biliary excretion of 5C-aglycone, a major vitamin K catabolite shared by MK-4 and PK. However, the overall in vivo excretion of vitamin K catabolites was not changed when urinary excretion was also taken into account. Aim 2 evaluated the hypothesis that α-T interferes with the conversion of PK to MK-4 because α-T and PK have similar side-chains. In Aim 2.1, conversion of PK or MN to MK-4 was tested in vivo. Rats were fed semi-purified diets containing equimolar concentrations of either PK or MN for 10 days, then α-T injections were undertaken. Chapter 3 shows that extra-hepatic tissues from α-T injected rats contained significantly lower MK-4 concentrations irrespective of whether the rats were fed PK or MN. These findings show that if vitamin E is interfering with the metabolic mechanism of MK-4 synthesis, then it is not specific to the cleavage of PK's side chain. In Aim 2.2, conversion of deuterium-labeled PK (d₄-PK) to d₄-MK-4 was used to evaluate the extra-hepatic tissue uptake of d₄-PK in α-T-injected rats. Rats were fed semi-purified diets containing equimolar concentrations of d₄-PK similar to my previous study for 10 days then α-T injections were undertaken for 7 days. Chapter 5 shows that total (labeled and unlabeled) vitamin K concentrations decreased in extra-hepatic tissues from α-T injected rats fed d₄-PK. Both d₄-MK-4 and d₄-PK concentrations decreased, suggesting that MK-4 concentrations were dependent upon those of d₄-PK. These findings suggest that PK, and not MN, is the primary substrate for MK-4 synthesis in extra-hepatic tissues. Moreover, both d₄-MK-4 and d₄-PK decreased in α-T-injected rats demonstrating that vitamin E's untoward effect on vitamin K status is likely a mechanism that is shared by both vitamin K forms and not specific to MK-4 synthesis. Recycling of vitamin K from the epoxide was not examined in this study and interference with the recycling mechanism for either PK or MK-4 in α-T injected rats has not been examined. Vitamin E metabolism is greatly increased in α-T-injected rats by increasing various xenobiotic pathways. Thus, vitamin K status was hypothesized to decrease in α-T-injected rats as a result of the up-regulation of these pathways. As shown in Aim 1, urinary vitamin K metabolite excretion was not increased in α-T-injected rats. In Aim 3.1, the biliary excretion of vitamins E and K were examined to evaluate whether the increased expression in biliary transporters, such as MDR1, led to increased vitamin K and E excretion via the bile. Chapter 4 shows that α-T increased in bile over the week of vitamin E injections and α-CEHC was the major vitamin E form excreted in bile. Although biliary PK secretion was unchanged and biliary MK-4 was undetectable, increased excretion of a major catabolite of both PK and MK-4, 5C-aglycone, was observed. In Aim, 3.2, the gene expression of enzymes and transporters in liver and extra-hepatic tissues as mechanisms involved in regulating their concentrations in these tissues was assessed. In Chapters 3 and 5, increased expression of biliary transporters were observed, one of which is known to bind the vitamin K intermediate MN as its substrate. It is possible other vitamin K catabolites, in addition to 5C-and 7C-aglycone, may have been excreted that were unaccounted for, e.g. MN or vitamin K epoxide metabolites. In summary, my studies have shown vitamin K status is decreased in α-T-injected rats because PK and MK-4 concentrations are decreased in many extra-hepatic tissues. Although metabolism of vitamin K was not stimulated in response to α-T injections, increased excretion of a vitamin K catabolite was measured in the bile; however it may not account for all of the vitamin K loss observed in tissues. Alternatively, transport of PK and MN to extra-hepatic tissues or MK-4 recycling may have been inhibited in response to vitamin E. Further studies are needed to distinguish between these mechanisms. / Graduation date: 2013

Addenda and corrigenda are tipped-in & numbered leaves 281-282. / Copies of author's previously published articles are inserted back end paper. / Bibliography: leaves 222-279. / xiv, 282 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Studies were performed in the Langendorff-perfused isolated rat heart, using a paradigm in which atrial distension was prevented. The release of natriuretic peptides and endothelin-1, along with cardiac function was monitored during periods of transient ischaemia or hypoxia. Additional studies were performed in patients undergoing cardiac catheterization. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1999?

Addenda and corrigenda are tipped-in & numbered leaves 281-282. Copies of author's previously published articles are inserted back end paper. Bibliography: leaves 222-279. Studies were performed in the Langendorff-perfused isolated rat heart, using a paradigm in which atrial distension was prevented. The release of natriuretic peptides and endothelin-1, along with cardiac function was monitored during periods of transient ischaemia or hypoxia. Additional studies were performed in patients undergoing cardiac catheterization.

viii, 88 leaves : ill. ; 29 cm Notes Typescript (Another copy on microfilm is located in Archives) Thesis (M.A.)--University of Oregon Includes vita Bibliography: leaves 83-88

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This study examined the extent to which physiological and psychological concomitants of aerobic terrestrial performance were affected by body cooling of varying degrees induced by cold water immersion (CWI). Thirteen male and 13 female subjects underwent three randomly assigned 30 min treadmill runs: a control run without prior manipulation of the subjects' thermal status and the same exercise after "central" (core temperature 1°C below pre-immersion) and "peripheral" cooling (skin heat loss 100kcal.m⁻².h⁻¹). During treadmill runs core temperature was measured, together with chest, leg, arm and hand temperatures, from which mean skin temperature (T [subscript]s[subscript]k) and mean body temperature (T[subscript]b) were calculated. Heart rate, oxygen consumption (VO₂,), carbon dioxide production (VCO₂), minute ventilation (V₂ (BTPS)), breathing frequency (f), cadence and ratings of perceived exertion (RPE) and thermal sensation (PTS) were also measured. Both central and peripheral cooling resulted in significantly reduced T[subscript]r[subscript]e (males : control 37.9±0. 3°C; central cooling : 36.8±0.5°C; peripheral cooling: 37.5±0.4°C; females: control: 37.9±0.4°C; central cooling: 37.2±0.5; p<0.05) during subsequent treadmill running, except following peripheral cooling for females (37.9±0.3°C) . For males and females T[subscript]s[subscript]k was lower following peripheral cooling than control values and lowest after central cooling (males: control: 30.0±1.3°C; central cooling: 36.8±0.5°C; peripheral cooling: 37.5±0.4°C; females: control: 30.5±1.2°C; central cooling: 25.9±1.8°C; peripheral cooling: 26.9±1.9°C; p<0.05). Female subjects experienced significantly higher T[subscript]r[subscript]e than males following central and peripheral cooling and a lower T[subscript]s[subscript]k following central cooling. Females experienced less of an increase in heart rate than males during exercise following central and peripheral cooling (control: l57.7±23.7b.min⁻¹; central cooling: 143.5±20.5b.min⁻¹; peripheral cooling 151.7±16.7b.min⁻¹; p<0 .05). Male responses were the same following central cooling but higher for peripheral cooling than control values (control: 139.1±7.3b.min⁻¹; central cooling 134.7±17.5b.min⁻¹; peripheral cooling: 145.0±16.4b.min⁻¹; p<0.05). These data indicate a depression in cardiovascular function for females following peripheral cooling that was not apparent for males. The VO₂ was not different between tests for males; only peripheral cooling resulted in a raised VO₂ of 28.6±3 .3ml.kg⁻¹.min⁻¹ (p<0 .05) for females compared to 27.6±2.6ml.kg⁻¹.min⁻¹ (control). A biphasic response was evident for VO₂ VCO₂ and V[subscript]B (BTPS). For both sexes overall RPE was lower for peripheral cooling (males: 9.4±1.9; females: 8.7±1.3; p<0 .05) than for control and central cooling. Central RPE was only changed for females following peripheral cooling. Changes in cadence and step length together with the effect of low skin and leg temperatures resulted in higher local RPE for females after central cooling (9.6±1.2; p<0.05) than control (9.4±1.9) and peripheral cooling (8.9±1.2 ). Males and females rated the same ambient temperature during the same exercise lower after peripheral cooling (males: 4.6±1.5; females : 5.3±1.3) than control values and lower still after central cooling (males: 3. 8±1.8; females: 2 .7±l. 5) In this study T[subscript]s[subscript]k was the primary determinant of PTS after precooling. / KMBT_363 / Adobe Acrobat 9.54 Paper Capture Plug-in

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Apparatus has been designed and developed for determining the response of the plankton Crustacean Simocephalus serrulatus (Koch) to horizontal gradients of light and temperature. These factors were varied independently or combined under standardized conditions. The temperature preferendum for this organism, cultured in a constant environment, was found to be 19.13°C, for animals previously held at 19°C. for 14 hours. The steepness of a temperature gradient was shown to influence the rate of aggregation at a preferendum temperature. At a constant temperature (temperature preferendum) reactions to light were then studied. Light intensity, gradients of light intensity, light quality, and gradients of light quality were considered. Animals were positively phototactic to the range of visible light intensities considered, but became indifferent to light on the addition of chemical substances to the water medium. An absolute optimum light intensity was demonstrated, at which the response to light is greatest in magnitude. The rate of rise of light intensity was shown to be directly related to the magnitude of the response and indirectly related to the time for the response to reach a peak up to the absolute optimum light intensity. The intensity of illumination was inversely related to the time for adaptation to occur. The magnitude of the light response was inversely related to the intensity of a pre-adaptation light stimulus. Wave lengths in the region of 3000 to 3500 Å, with a mean value of approximately 3300 Å, were shown to reverse the primary sign of the phototactic response. The spectral sensitivity curve for the positive phototactic response to visible light extended from 4000 to 6400 Å. Finally, light factors were applied to the animals in a temperature gradient and quantitative data on the response obtained. The interaction of the two factors produced a response which is the resultant of the factors acting in opposition. / Science, Faculty of / Zoology, Department of / Graduate

This study was undertaken to determine and compare the rates of oxygen consumption and carbon dioxide elimination during normal and hyperventilated breathing at progressive work rates. Three subjects stepped at 18, 24, 30, 36 and 40 steps per minute on an eighteen inch bench for a duration of ten minutes or until exhaustion. All exercises were performed inside a 6,900 liter closed circuit respirometer. The volume of each subject obtained from hydrostatic weighings was subtracted from the chamber volume as was the volume of the bench. Net volume was corrected to STPD. The respirometer was equipped with Beckman oxygen and carbon dioxide analyzers, an internal cooling system as well as wet and dry thermocouples on three sides . Oxygen and carbon dioxide concentrations were continuously analyzed and automatically recorded against time. A resting metabolic rate was established prior to each work task. Completion of the exercise was followed by a fifteen minute recovery period. Curves of cumulative oxygen consumption (VO₂) and carbon dioxide elimination (VCO₂) were plotted against time. By determining the gradients of these curves at different points it was possible to plot the corresponding velocity curves [formula omitted]. The acceleration curves [formula omitted] were derived from the velocity curves. An IBM computer program was used to determine the velocity and acceleration values. When compared to normal breathing, hyperventilating at the higher work loads increases the VO₂ and VCO₂ during the early phase of exercise. This is generally followed by decreased VO₂ during the recovery period. There are well defined differences in the derivative curves between normal and hyperventilated breathing. Implications for athletic performance are indicated. Derivative curves of oxygen consumption and carbon dioxide elimination appear to be highly individual. Their use as a fitness criterion is indicated. / Education, Faculty of / Curriculum and Pedagogy (EDCP), Department of / Graduate