Thesis (M.S.)--University of Wisconsin--Madison, 1968. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

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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.

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 (M. Phil.)--Hong Kong University of Science and Technology, 2004. / Includes bibliographical references (leaves 84-87). Also available in electronic version. Access restricted to campus users.

Thesis (Ph.D.) - University of Glasgow, 1987. / Includes bibliographical references. Print version also available.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1981. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 304-333).

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2007. / Includes bibliographical references (leaves 130-141). Also available in electronic version.

An investigation was made into one aspect of the molecular control of cardiac contractility, namely, the putative role of the two endogenous cyclic 3',5'-nucleotides, adenosine cyclic 3',5' monophosphate (cyclic AMP) and guanosine cyclic 3',5' monophosphate (cyclic GMP) in regulating the capacity of the heart to produce force. It began as a study of a poorly understood but well documented effect of exogenous adenosine 5'-triphosphate (ATP) on the electrical and mechanical properties of the isolated frog ventricle. In common with several related purine and pyrimidine nucleotides, treatment of the ventricle with ATP elicits a characteristic triphasic response which is not blocked by either atropine or propranolol. Preliminary experiments with ATP led to the hypothesis that it exerts a dual effect on the heart. The two effects were attributed tentatively to the induction of elevated levels of intracellular cyclic AMP and cyclic GMP respectively. Indirect evidence for the involvement of cyclic nucleotides in mediating the ATP-induced response comes from studies with agents which are known to influence cyclic 3',5'-nucleotide metabolism on the form of the ATP-induced response. Measurements of endogenous cyclic 3',5'-nucleotides during the development of the hypodynamic state is associated by a gradual decline in intracellular cyclic AMP and a progressive increase in cyclic GMP. This gradual loss in contractility is also accompanied by the release of prostaglandins E1 and E2 and one or more prostaglandin-related substances into the perfusate. Subsequent experiments with exogenous ATP elicits profound changes in cyclic 3',5'-nucleotides. Both cyclic AMP and cyclic GMP are affected as had been postulated. A third series of experiments with the -agonist isoprenaline (isoproterenol) was undertaken to investigate the generality of the relationship between intracellular cyclic nucleotide levels and contractility, and this produced similar results. The most significant feature to emerge from the results was the finding that in all three responses, which on the face of it appear to be physiologically distinct and quite unrelated, changes in the ratio of intracellular cyclic AMP / cyclic GMP almost exactly parallel the observed changes in contractile force. This observation has led to the formulation of a hypothesis which postulates that both endogenous cyclic 3',5'-nucleotides are integral components of an intracellular control mechanism which is responsible for regulating the contractility of the amphibian ventricle.

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