Project: Research project

Project Details


DESCRIPTION (Adapted from the 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.
Effective start/end date7/1/006/30/06


  • Medicine(all)