Thesis (M.S.)--Brandeis University, 2009. / Title from PDF title page (viewed on May 29, 2009). Includes bibliographical references.

Thesis (M.S.)--University of British Columbia, 2005. / Includes bibliographical references (leaves 89-97). Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (M.S.)--University of British Columbia, 2005. / Includes bibliographical references (leaves 89-97).

Thesis (Ph. D.)--Georgia State University, 2005. / Timothy Bartness, committee chair; Elliott Albers, Ruth Harris , Sarah Pallas, committee members. Electronic text (181 p. : ill.)) : digital, PDF file. Description based on contents viewed July 17, 2007. Includes bibliographical references (p. 148-181).

Methyldopa (L-alpha-Methyl-3,4-dihydroxyphenylalanine) is a catecholamine used as an antihypertensive agent.1 Alpha-Methyldopa is not used as frequently anymore due to side effects, but it is still used especially in developing countries due to its low cost. Indications are mostly for the management of pregnancyinduced hypertension (PIH), as it is relatively safe in pregnancy compared to other antihypertensive drugs. This project is intended to increase the already-existing knowledge base of the mechanism of pharmacological action and to stimulate further investigation through research. The sympathetic nervous system is a division of the autonomic nervous system and it is responsible for the “flight-or-fight” response. It is involuntary and constantly active to maintain homeostasis in the human body. Sympathetic responses include an increase in heart rate, blood pressure and cardiac output, dilation of pupils and bronchioles, constriction of blood vessels, contraction of sphincters and inhibition of gut motility and secretions. The purpose of this study is to evaluate the activity of the sympathetic nervous system of volunteers by three different techniques (QT interval and Heart rate variability and Skin conductance) after a week of a bi-daily dosage of alphamethyldopa. All volunteers received either 250mg alpha-methyldopa orally or a placebo tablet in a randomized, double blind, placebo controlled study design. The correlation between the following techniques was also evaluated: Skin conductance as measured by the ProComp Infiniti Biofeedback apparatus, QT interval on ECG and HRV measured with Viport apparatus. A salivary sample was collected to evaluate the effect of alpha-methyldopa on salivary cortisol using an ELISA kit for analysis. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Pharmacology / unrestricted

Diabetes mellitus (DM) and hyperglycemia contribute to sympathetic nervous system (SNS) activation and cardiovascular dysfunction. SNS activation and increased norepinephrine levels downregulate cardiac β-adrenergic receptors (β-AR). The ADMIRE-HF trial identified reduced cardiac SNS innervation as an independent prognostic marker in heart failure. The β-AR antagonist [3H]-CGP12177 was used to quantify cardiac β-AR in ex vivo biodistribution studies in streptozotocin (STZ)-treated rats after 8 weeks of sustained hyperglycemia, and in the Zucker Diabetic Fatty (ZDF) rat model of type-2 diabetes at the onset of hyperglycemia (10 weeks of age) and after a sustained period of hyperglycemia (16 weeks of age). In some STZ rats, insulin was provided at the onset of hyperglycemia, or after a sustained period of hyperglycemia. Insulin treatment at both time points prevented reduced [3H]-CGP12177 binding (33-38% compared to controls) observed in STZ hyperglycemics. ZDF β-ARs were intact at 10 weeks but became reduced (16-25% relative to the Zucker leans) following 6 weeks of hyperglycemia. This work supports that cardiac β-AR are reduced in models of DM and that restoring insulin signalling to maintain glycemic control can normalize β-AR density whether provided early or after a period of sustained hyperglycemia.

Development of the sympathetic nervous system (SNS) tone onto peripheral organs has been shown to be susceptible to a wide range of external factors, such as temperature. Although it was initially postulated that the sympathetic signal is uniform across the body, there is growing evidence that there can be target-specific sympathetic signals. To date, evidence for a relationship between developmental influences on SNS tone and organ function is purely correlational. An obstacle to investigating the programming of SNS permanently altering physiology is that experimental manipulations of SNS activity during development would impact multiple organ functions simultaneously, which could affect the overall health of the animal and therefore confound interpretation of the results. Here we used brown adipose tissue (BAT) as a platform to define a critical period and identify molecules that contribute to the development of SNS outflow to peripheral organs. In addition, we explored the molecular target-specificity of sympathetic neurons by performing a single-cell RNA sequencing transcriptomic analysis of adult mouse stellate ganglion (SG) in conjunction with retrograde tracing from two of its targets, brown adipose tissue and forelimb. We discovered four molecularly distinct populations of SG neurons that express unique combinations of neuropeptides and receptors, but we did not find evidence of target specificity. The four distinct SG neuronal populations had marker genes that showed unique expression in each population, including genes encoding secreted peptides and receptors of circulating factors. Also, we found that the expression of some of the marker genes differs across the sympathetic chain, which could provide a means for coordinated regulation of SNS responses to specific types of homeostatic challenges.

ABSTRACT Chronic activation of the sympathetic nervous system, via β-adrenoreceptor (AR) stimulation, contributes toward progressive heart failure. However, in this regard there are some outstanding issues which require clarity. First, in addition to contributing toward progressive heart failure, it is not clear whether chronic β-AR activation can also initiate cardiac decompensation. If so, the mechanisms of this effect also need to be determined. Second, the role of functional variants of β-AR genes as determinants of either the development or progression of heart failure requires elucidation. Moreover, whether there is any practical value in genotyping of patients for these variants has yet to be determined. These questions were addressed in the present thesis. With respect to the question of whether chronic β-AR activation initiates cardiac decompensation, the mechanisms responsible for the transition from compensated cardiac hypertrophy to heart failure in pressure overload states, such as hypertension, are uncertain. In this thesis I explored whether chronic sympathetic nervous system activation, produced by daily administration of a β-AR agonist, could promote the transition to cardiac pump failure in spontaneously hypertensive rats (SHR) with compensated cardiac hypertrophy. After 5 months of daily administration of a β-AR agonist, SHR developed marked left ventricular pump dysfunction, whereas normotensive control rats maintained pump function. The pump dysfunction noted in SHR was attributed to marked chamber dilatation with wall thinning, whilst myocardial contractile function appeared to be intact. The changes in cardiac structure and function noted after chronic β-AR activation in SHR were similar to those noted in SHR with advanced heart failure. These data provided the first evidence to indicate that chronic β- AR activation can promote the transition to decompensated cardiac hypertrophy in pressure overload states, and that this effect is principally mediated by adverse structural remodeling of the cardiac chamber. iii The mechanisms responsible for the effect of chronic β-AR activation on cardiac chamber dilatation were subsequently studied. The identified mechanisms included activation of an enzyme that degrades myocardial collagen (matrix metalloproteinase 2) and an increase of myocardial collagen of the type that is susceptible to collagen degradation (non-cross-linked collagen). I also excluded alternative potential mechanisms such as necrosis, apoptosis and an accumulation of type III collagen. However, previous studies have indicated that increases in myocardial collagen concentrations determine myocardial stiffness and not cardiac chamber dilatation. Hence, I performed a study to examine whether the impact of increases in myocardial collagen concentrations on cardiac structure and function depends on the qualitative changes in myocardial collagen. Indeed, using a variety of models of pressure overload hypertrophy associated with increases in myocardial collagen concentrations, I was able to provide evidence to support the theory that increases in myocardial collagen of the cross-linked phenotype will promote myocardial stiffness, whereas increase in myocardial collagen of the non-cross-linked phenotype promotes cardiac dilatation. With respect to the question of whether functional variants of β-AR genes contribute toward either the development or progression of heart failure, I studied the role of both functional β1-AR and β2-AR (together with a α2C-AR) gene variants in black South Africans with idiopathic dilated cardiomyopathy (IDC). In a prospective study I obtained data to indicate that the relationship between functional β2-AR genotypes and the progression to hospitalization, death or transplantation; a reduced exercise capacity, and left ventricular functional responses to b-blocker therapy, as described by other groups, is unlikely to be attributed to an independent effect of genotype on cardiac chamber dimensions and pump function. Moreover, I was able to show that contrary to what had previously been suggested, genotyping black subjects for functional α2C-AR iv and β1-AR gene variants is of little use when predicting the development or severity of IDC in this population group.

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