The overall goal of this project is to establish the angiogenic efficacy of two pharmacological interventions in the postinfarcted and ischemic heart: a thyroxine analog, diiodothyropropionic acid (DITPA), and the bradycardic drug, alinidine. This goal is based on the rationale that these two agents stimulate mechanical or metabolic factors which then trigger the cascade of angiogenic events which will enhance myocardial perfusion in surviving, hypertrophic myocardium, or in tahe ischemic myocardium. The first three aims will be based on data from male rats, while the fourth aim will utilize beagles.
Aim 1 will test the hypothesis that treatment with these agents will stimulate not only the capillary network, but also the growth of resistance vessels, thus normalizing coronary reserve.
This aim will include a variety of angiogenic assays, as well as myocardial perfusion and ventricular function measurements under various conditions.
Aim 2 will identify the spatial and temporal expression of growth factors which regulate the angiogenic response, e.g., basic fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor-beta by utilizing in situ hybridization, blotting, and immunohistochemical techniques.
Aim 3 focuses on tahe role of aging in the postinfarcted heart's ability to vascularize in response to the two therapeutic interventions. The use of aged rats in this proposal is of particular importance since myocardial infarction occurs most frequently in older individuals. The experimental protocols in the first two aims will be utilized to explore this aim in middle-aged and senescent rats.
Aim 4 will test hypotheses regarding the efficacy of DITPA and alinidine in stimulating growth of collaterals as well as capillaries and arterioles during ischemia, induced by gradual coronary artery occlusion. These studies in beagles compliment the rat studies, by providing a model of ischemia in a non-hypertrophic heart. Our studies addresss non-invasive therapies which may be readily used in humans with ischemic heart disease or with compensatory hypertrophy and remodeling resulting from myocardial infarction. Such interventions have a number of advantages over more invasive interventions, e.g., the delivery of oxogenous growth factors or gene therapy.
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