application): The current application serves as a natural extension of the principal investigator's previous KO-8, which focused on endothelin in the coronary circulation in humans. Previous studies have focused on the vasodilator and its contribution to the development of coronary atherosclerosis. However, there is a void of information about the role of the endothelium-derived vasoconstrictor factors in the early stages of the disease state. A growing body of evidence suggests that endothelin plays a significant role in the regulation of vascular tone under normal conditions and in pathophysiological states. The PI's broad working hypothesis is that in early atherosclerosis the activity of the endogenous coronary endothelin system is enhanced and is associated with coronary artery disease risk factors. Moreover, administration of chronic endothelin receptor antagonist in this patient population will improve coronary endothelial function. This improvement of coronary endothelial function will result in restoration of myocardial perfusion, which is impaired in early atherosclerosis with coronary endothelial dysfunction. These beneficial effects are partially mediated by the enhancement of the endogenous coronary nitric oxide system. To address the PI's working hypothesis, three Specific Aims are proposed:
Aim I : To determine the activity of the endogenous endothelin system in the coronary circulation in humans with coronary endothelial dysfunction and atherosclerosis risk factors.
Aims II : To assess the potential of chronic endothelin receptor antagonists to improve preexisting coronary endothelial dysfunction and myocardial perfusion in humans and Aim III: To assess the effect of chronic endothelin receptor antagonism on the endogenous nitric oxide system in humans with early coronary atherosclerosis. The studies will be performed in patients with coronary endothelial dysfunction and coronary artery disease risk factors. Coronary endothelin, big endothelial and nitric oxide will be measured and myocardial perfusion will be assessed with SPECT. The patients with endothelial dysfunction will be randomized to chronic administration of an endothelin receptor antagonist. Coronary endothelial function and myocardial perfusion will be assessed at six-month follow up. The activity of endothelin also will be assessed in human vessels in vitro and immunohistochemistry will be performed. The functional interaction between endothelin and the nitric oxide pathway also will be addressed in vivo in humans by assessing the physiological response to the acute inhibition of nitric generation and also assessing NO production. The current application will contribute to our understanding of the role of the endogenous endothelin in modulating endothelial function in early coronary atherosclerosis in humans and may have a significant therapeutic potential for this disease process.
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