Thesis (Ph. D.)--University of Wisconsin--Madison, 1962. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1959. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph.D.) - University of Glasgow, 1999. / Ph.D. thesis submitted to the Department of Medicine and Therapeutics, University of Glasgow, 1999. Includes bibliographical references. Print version also available.

The pathophysiology of cardiac failure involves activation of the renin-angiotensinaldosterone system that contributes to adverse left ventricular remodelling. This is a complex pathologic process that has been shown to be stimulated by haemodynamic and humoral factors including aldosterone. The precise mechanisms by which aldosterone contributes to this process are not known. In a mouse animal model of pressure overload induced cardiac hypertrophy and failure, the treatment with selective mineralocorticoid receptor, eplerenone, was shown to attenuate adverse left ventricular remodelling. This was associated with decreases in myocardial apoptosis, collagen turnover, oxidative stress and inflammation, in the absence of a significant blood pressure change. Furthermore, we administered aldosterone infusion and high salt diet to uninephrectomised mice deficient in the gp91phox subunit of NADPH oxidase and to the wild type strain. It was demonstrated that the increase in the blood pressure did not occur in the gp91phox deficient mice and that both wild-type and knock-out strains developed cardiac hypertrophy, but not interstitial fibrosis. Additionally, patients with chronic stable heart failure were also studied. We found that plasma aldosterone level was independently associated with levels of markers for oxidative stress (of 8- isoprostaglandin F2??), inflammation (soluble intercellular adhesion molecule-1) and matrix turnover (tissue inhibitor of metalloproteinase-1). High plasma osteopontin levels were also noted. Our experiments suggest that myocardial apoptosis, collagen turnover, oxidative stress and inflammation may be involved in mediating the adverse effects of mineralocorticoid receptor activation in pressure overload. In addition, the development of cardiac hypertrophy may be a haemodynamically independent process, but gp91phox subunit deficiency did not attenuate the hypertrophic response to aldosterone infusion when administered in conjunction with high salt diet, suggesting that there may be another mechanism that mediates aldosterone-induced hypertrophy. The state of increased oxidative stress and inflammation, seen in animal models, may also play an important role in chronic heart failure subjects. The importance of local factors in the regulation of myocardial tissue remodelling has become increasingly evident, but future investigations are required to clarify the role of aldosterone, oxidative stress and inflammation in heart failure.

Water and salt homeostasis is tightly controlled by both central and peripheral mechanisms. Angiotensin II (ANGII) and Vasopressin (VP) have long been known to be essential in this regulatory process. Recent studies have found that secretin (SCT) can regulate water homeostasis by playing osmoregulatory functions redundant as ANGII to stimulate VP expression and release in the hypothalamus. However, the functional role of secretin in salt homeostasis, which is closely related to water homeostasis, remains unclear. This study therefore aims to investigate the modulating function of secretin in the synthesis of aldosterone, which is known to be critical in salt regulation. Using immunohistochemical staining, expression of secretin receptor (SCTR) was detected in the zona glumerulosa of adrenal cortex. In mouse adrenal gland, real time quantitative polymerase chain reaction showed that both intraperitoneal (IP) and intracerebral ventricular (ICV) injections of SCT significantly increased aldosterone synthase (cyp11b2) expression levels. This effect was determined to be secretin-specific as it is not observed in SCTR knockout (SCTR-/-) mice. The increase of aldosterone synthase expression levels was further confirmed by Western blot analysis. In circulation, the serum level of aldosterone was also increased by ICV SCT injection, supporting the activation of aldosterone synthase by both central and peripheral SCT. Further studies showed the ICV-SCT induced aldosterone synthase can be significantly reduced by conivaptan, a VP receptor antagonist, indicating that the stimulatory effect of SCT on aldosterone synthesis is VP-related. In low sodium diet-fed mice, both SCTR and aldosterone synthase expression level were significantly increased and elevated serum SCT level was also observed. Western blot analysis also found an increase in aldosterone synthase expression in wild type mice but not in SCTR-/- controls. These results warrant the further study of the role of SCT in sodium retention. In summary, SCT facilitates the synthesis of aldosterone through the up-regulation of aldosterone synthase. This effect can be triggered by both central and peripheral administration of SCT. The central effect of SCT on aldosterone synthesis is vasopressin-related. SCT may also participate in the sodium retention under low-salt conditions. Taken together, this study suggests a potential function of SCT in regulating body sodium homeostasis. / published_or_final_version / Biological Sciences / Master / Master of Philosophy

The pathophysiology of cardiac failure involves activation of the renin-angiotensinaldosterone system that contributes to adverse left ventricular remodelling. This is a complex pathologic process that has been shown to be stimulated by haemodynamic and humoral factors including aldosterone. The precise mechanisms by which aldosterone contributes to this process are not known. In a mouse animal model of pressure overload induced cardiac hypertrophy and failure, the treatment with selective mineralocorticoid receptor, eplerenone, was shown to attenuate adverse left ventricular remodelling. This was associated with decreases in myocardial apoptosis, collagen turnover, oxidative stress and inflammation, in the absence of a significant blood pressure change. Furthermore, we administered aldosterone infusion and high salt diet to uninephrectomised mice deficient in the gp91phox subunit of NADPH oxidase and to the wild type strain. It was demonstrated that the increase in the blood pressure did not occur in the gp91phox deficient mice and that both wild-type and knock-out strains developed cardiac hypertrophy, but not interstitial fibrosis. Additionally, patients with chronic stable heart failure were also studied. We found that plasma aldosterone level was independently associated with levels of markers for oxidative stress (of 8- isoprostaglandin F2??), inflammation (soluble intercellular adhesion molecule-1) and matrix turnover (tissue inhibitor of metalloproteinase-1). High plasma osteopontin levels were also noted. Our experiments suggest that myocardial apoptosis, collagen turnover, oxidative stress and inflammation may be involved in mediating the adverse effects of mineralocorticoid receptor activation in pressure overload. In addition, the development of cardiac hypertrophy may be a haemodynamically independent process, but gp91phox subunit deficiency did not attenuate the hypertrophic response to aldosterone infusion when administered in conjunction with high salt diet, suggesting that there may be another mechanism that mediates aldosterone-induced hypertrophy. The state of increased oxidative stress and inflammation, seen in animal models, may also play an important role in chronic heart failure subjects. The importance of local factors in the regulation of myocardial tissue remodelling has become increasingly evident, but future investigations are required to clarify the role of aldosterone, oxidative stress and inflammation in heart failure.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1958. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

No description available.

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references. Available also from UMI/Dissertation Abstracts International.

No description available.