Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Sciences, 1992. / Includes bibliographical references (leaves 183-207).

Thesis (Ph.D)--Murdoch University, 2007. / Thesis submitted to the Division of Health Sciences. Includes bibliographical references (leaves 232-267).

Thesis (M.S.)--Michigan State University. Dept. of Chemistry, 2006. / Title from PDF t.p. (viewed on Nov. 20, 2008) Includes bibliographical references (p. 83-88). Also issued in print.

Dissertation (Ph.D.)--University of Toledo, 2008. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Title from title page of PDF document. Bibliography: p. 126-146.

Sleep loss alters both the concentration and activity of various aspects of the immune system. These alterations lead to increased susceptibility to infection and the progression of pathologies such as insulin resistance and atherosclerosis. Two proposed mechanisms of this alteration in immune function are the changes in both cortisol and sympathetic nervous system activity that accompany sleep deprivation. This work reviewed literature that measured the effects of periods of sleep restriction upon both cortisol and catecholamine concentrations within human subjects. Furthermore, studies which measured the effects of sleep loss upon these hormone levels and the associated changes in immune parameters were included. This thesis asserts that there is no defined pattern in reference to alterations of cortisol levels as a result of sleep deprivation. Furthermore, more evidence must be collected before implementing cortisol as a main effector of sleep loss upon immune system function. This dissertation, although repeatedly noting increased levels of norepinephrine following periods of sleep restriction, similarly argues that more research must be completed in order to declare that altered catecholamine concentrations as a result of sleep loss is a mechanism for altered immune function.

A administração de catecolaminas por via intravenosa é uma prática comum no ambiente hospitalar, principalmente em Unidade de Terapia Intensiva (UTI), Hemodiálise e Pronto Socorro (PS). Apesar de se tratar de um procedimento que demanda cuidados de enfermagem bastante específicos, este pode ser realizado por qualquer membro da equipe de enfermagem, até mesmo sem supervisão direta de um enfermeiro. Para prestar cuidados de enfermagem adequados aos pacientes que recebem catecolaminas por via intravenosa é necessário que o profissional que realiza o procedimento disponha de conhecimento específico acerca da prática realizada. Em unidades como UTI, PS e Hemodiálise, espera-se que o enfermeiro exerça supervisão direta desses cuidados, já que são unidades em que os pacientes apresentam condições mais críticas e geralmente instáveis. Desta forma, é esperado que o enfermeiro detenha todo o conhecimento necessário para administrar as catecolaminas com segurança, minimizando assim os riscos para o paciente. Estes conhecimentos devem ser aprofundados englobando desde ciências básicas como anatomia e fisiologia, até aspectos mais específicos como a escolha do cateter, recomendações de uso dos materiais disponíveis, conhecimentos farmacológicos direcionados e recomendações e cuidados durante a infusão desse tipo de medicamento. Este estudo avaliou o grau de conhecimento dos enfermeiros do Hospital Universitário (HU) da Universidade de São Paulo (USP) quanto à administração de catecolaminas de infusão contínua por via intravenosa. Foram sujeitos deste estudo somente os enfermeiros que atuam em unidades onde a administração de catecolaminas é prática comum. A pesquisa limitou-se aos enfermeiros que atuam em unidades de cuidados de adultos por considerar que há peculiaridades existentes no cuidado do paciente adulto e pediátrico no que diz respeito à administração de drogas vasoativas e à necessidade de atualização e vivência prática da situação. Assim, através de questionário estruturado, procedeu-se a avaliação do conhecimento dos enfermeiros atuantes nas unidades de Hemodiálise, PS de adultos e UTI de adultos com relação à administração de catecolaminas por via intravenosa. Os dados obtidos com a aplicação dos questionários foram submetidos a análises estatísticas para definir se o conhecimento apresentado pelos enfermeiros avaliados é condizente com o preconizado pela literatura para realização segura de tal procedimento / Catecholamine management through intravenous route is a common practice in the hospital setting, mainly at the Intensive Care Unit (ICU), Hemodialysis and Emergency Room (ER). Although it\'s a procedure that demands very specific nursing care, this can be made by any member of the nursing staff, even without direct supervision of a nurse. For delivering optimal nursing care to patients who receive catecholamine through intravenous route, it\'s necessary the provider who makes the procedure to have specific knowledge on this practice. In settings like ICU, ER and Hemodialysis, the nurse is expected to have direct supervision in these procedures, once they are units where patients present more critical and generally unstable conditions. This way, the nurse is supposed to have all the knowledge necessary to manage catecholamine safely, thus minimizing the risks for the patient. This knowledge must be deepen involving from basic sciences such as anatomy and physiology, to more specific aspects, such as the catheter chosen, recommendations for use of available material, specified pharmacological knowledge and recommendations and care during infusion of this type of medication. This study evaluated the knowledge level of nurses from University Hospital (HU) of University of Sao Paulo (USP) regarding to catecholamine management of continuous infusion through intravenous route. Subjects of the study were only the nurses who work in setting where catecholamine management is a common practice. The research limited to nurses who work in adult care, considering that there are peculiarities in adult and pediatric care related to vasoactive medication management and the need of upgrade and practical experience of the situation. Thus, through a structured questionnaire, it was made an evaluation of knowledge of nurses who work in Hemodialysis units, adult ER and adult ICU regarding to catecholamine management through intravenous route. The data obtained through the questionnaires were submitted to statistic analyses to define if the knowledge presented by the evaluated nurses is according to what is advised by literature to make safely such procedure

Encontramos no bulbo diversos núcleos, assim como diversos neurotransmissores, relacionados com a manutenção da pressão arterial. Dentre os núcleos, o núcleo do trato solitário se destaca por ser um dos principais moduladores do sistema nervoso autônomo, sendo o primeiro a receber aferências dos barorreceptores e encaminhá-los para diversos outros núcleos. Dentre estes neurotransmissores, encontramos o glutamato e as catecolaminas, sendo ambos essenciais para a manutenção da pressão arterial. É sabido que a atuação de transmissores em células do sistema nervoso pode levar a alterações em outras vias de neurotransmissão, alterando assim a resposta das células a estímulos. Levando em consideração a importância do glutamato e das catecolaminas na modulação da pressão arterial, e que tanto os receptores glutamatérgicos quanto catecolaminérgicos podem interferir no metabolismo celular e gerar mudanças estruturais nos neurônios, cogitamos que a atuação do sistema glutamatérgico poderia modular o sistema catecolaminérgico. Neste trabalho, avaliamos se o sistema glutamatérgico e catecolaminérgico podem interagir em culturas de células do bulbo de ratos neonatos, a partir de tratamentos das culturas com glutamato ou noradrenalina. Observamos que o tratamento destas culturas com glutamato leva a uma redução nos níveis de proteína e de mRNA da enzima tirosina hidroxilase e do receptor _2 adrenérgico. A modulação do sistema glutamatérgico a partir de tratamentos com noradrenalina não mostrou variações significativas. Concluímos que o sistema glutamatérgico pode modular o sistema catecolaminérgico em células do bulbo de ratos neonatos, e que esta modulação pode ser importante na regulação da pressão arterial pelos núcleos bulbares. / It is found in the medulla oblongata several nuclei, as well as several neurotransmitters, related with the maintenance of the arterial pressure. Among these nuclei, the nucleus of the solitary tract stands aside for being one of the main modulators of the autonomic nervous system, being the first to receive afferences from baroreceptors and to send their stimuli to other nuclei. Among these neurotransmitters, glutamate and the catecholamines are both essentials to the maintenance of the arterial pressure. It is known that the stimulation of brain cells by neurotransmitters can result in changes in other neurotransmitter pathways, changing the cell response to certain stimuli. Taking in consideration the importance of glutamate and the catecholamines in the modulation of the arterial pressure, and that both of them can interfere in the cellular metabolism and create structural changes in neurons, we have speculated that the stimulation of the glutamatergic system could modulate the catecholaminergic system. In this work, it was evaluated if the glutamatergic and catecholaminergic systems could interact in cell cultures of the medulla oblongata of newborn rats, from treatments of the cultures with glutamate or noradrenaline. It was found that the treatment of these cultures with glutamate leads to a reduction in the protein and mRNA levels of the enzyme tyrosine hydroxylase and the receptor _2 adrenergic. The modulation of the glutamatergic system from treatments with noradrenaline did not show significative variation. We concluded that the glutamatergic system can modulate the catecholaminergic system in medulla oblongata cell cultures, and that this modulation can be important in the regulation of the arterial pressure by nuclei present in the medulla oblongata.

Abstract The heart responds to increased hemodynamic stress by increased cardiac myocyte size, enhanced protein synthesis and altered gene expression. Regulation of hypertrophic adaptation involves a number of neural and hormonal factors, which act on the cardiovascular system. The aim of the present study was to elucidate the regulation of gene expression of natriuretic peptides and adrenomedullin (AM) in cardiac overload in vivo. Furthermore, the interactions of AM and angiotensin II (Ang II) in cardiac function and development of left ventricular hypertrophy were studied both in vivo and in vitro. The effects of cardiac hypertrophy on the regulation of natriuretic peptides (atrial natriuretic peptide, ANP and B-type natriuretic peptide, BNP) and AM gene expression were studied during pressure overload in the hearts of two hypertensive rat strains, angiotensinogen-renin transgenic rats and spontaneously hypertensive rats as well as their normotensive control strains. Increased workload resulted in rapid upregulation of both BNP and AM gene expression in all rat strains; the response of AM was, however, augmented in hypertensive rats. Direct left ventricular wall stretch induced AM gene expression in isolated, perfused rat hearts, whereas stretching of cultured cardiac myocytes downregulated AM mRNA levels. In cultured cardiac cells exposed to Ang II, endothelin-1 or the α-agonist phenylephrine, Ang II-induced myocyte hypertrophy was selectively inhibited by AM. In vivo, AM interacted with Ang II in circulation by attenuating the hypertensive effects of Ang II, and in the heart by augmenting the Ang II-induced improvement in cardiac systolic function. However, AM had no direct modulatory effects on Ang II-induced left ventricular hypertrophy. These results show that cardiac wall stretch is a major stimulus for the early induction of AM gene expression in both normal and hypertrophied ventricle, and the response in hypertrophied myocardium is augmented. Furthermore, cardiac non-muscle cells may be involved in mediating effects of direct stretch. In vitro, AM acts as a selective inhibitor of Ang II-induced myocyte hypertrophy, suggesting a cardioprotective role for AM to counteract the local renin-angiotensin system and Ang II in cardiac hypertrophy and heart failure. Circulating AM appears to act mainly as a regulator of vascular tone and cardiac function.

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder that affects 11% of children in the US alo­ne. Methylphenidate (MPH) is the most commonly prescribed drug for the treatment of ADHD. Given the fact that ADHD symptoms persist in up to 50% of patients, many children receive MPH from childhood to early adulthood. Unfortunately, most of the scientific literature focuses on the short-term consequences of MPH, even though individuals are taking MPH for many years. Previous research has shown that long-term exposure to MPH causes dopamine-releasing neurons within the nigrostriatal pathway to die when exposed to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPH acts by blocking dopamine transporters and norepinephrine transporters, preventing the reuptake and removal of these neurotransmitters following release and increasing the time outside of the protective environment of the neuron’s vesicles. We hypothesize that spontaneous oxidation of excess dopamine to a quinone metabolite is rendering these neurons within this particular pathway to be more sensitive to MPTP. The dopamine quinone may be bound by the antioxidant glutathione (GSH) in an effort to protect the cell against oxidative stress. However, as the finite amount of GSH is depleted, the quinone may lead to the production of highly reactive molecules, leading to mitochondrial damage and cell death which may be accelerated by MPTP. In order to examine this hypothesis, we chose to study adolescent male Swiss-Webster mice, which have been shown to be resistant to MPTP’s toxic effects. They were divided into 3 cohorts and administered either saline (control), 1 mg/kg MPH (therapeutic dose) or 10 mg/kg (abusive dose) via intraperitoneal (IP) injections for 12 weeks. Mice were injected twice daily, Monday through Friday, mimicking a school-week dosing schedule. After 12 weeks, all animals received a drug washout period of 7 days. Then, half of each cohort was treated with MPTP (4 x 20 mg/kg, every 2 hours), while the other half was administered 4 injections of sterile saline. Either 3 or 7 days after MPTP or saline treatment, the mice were sacrificed, brains were removed, and the substantia nigra (SN) and striatum (STR) were collected. These areas of the brain make up the nigrostriatal pathway and are affected by Parkinson’s disease. Oxidative stress related to increased dopamine levels was determined using the glutathione assay to measure GSH content, near-infrared fluorescence dot blots to measure free and protein-bound ortho-quinones, and an ATP luciferase assay to measure mitochondrial function. Interestingly, there was a significant decrease in GSH as the dose of MPH was increased with both saline and MPTP samples. Furthermore, a significant increase in quinones was observed as the dose of MPH increased. We also expect to see a decrease in ATP inversely proportional to the dose of MPH indicating increased oxidative stress. In conclusion, it appears that long-term exposure to MPH sensitizes dopaminergic neurons within the nigrostriatal pathway to oxidative stress, rendering them vulnerable to further insults, such as MPTP exposure. As such, these studies provide insight into the risks of long-term psychostimulant exposure.

The cardiac ryanodine receptor (RyR2) is a Ca2+ ion channel found in the sarcoplasmic reticulum (SR), an intracellular membranous Ca2+ storage system. It is well known that a destabilization of RyR2 can lead to a Ca2+ flux out of the SR, which results in an overload of intracellular Ca2+; this can also lead to arrhythmias and heart failure. The catecholamines play a large role in the regulation of RyR2; stimulation of the Beta-adrenergic receptor on the cell membrane can lead to a hyperphosphorylation of RyR2, making it more leaky to Ca2+. We have previously shown that strong electron donors will inhibit RyR2. It is hypothesized that the catecholamines, sharing a similar structure with other proven inhibitors of RyR2, will also inhibit RyR2. Here we confirm this hypothesis and show for the first time that the catecholamines, isoproterenol and epinephrine, act as strong electron donors and inhibit RyR2 activity at the single channel level. This data suggests that the catecholamines can influence RyR2 activity at two levels. This offers promising insight into the potential development of a new class of drugs to treat heart failure and arrhythmia; ones that can both prevent the hyperphosphorylation of RyR2 by blocking the Beta;-adrenergic receptor, but can also directly inhibit the release of Ca2+ from RyR2.