Dr. Watson's goal is to become an independent investigator focused on the vascular biology of hypertension (HT) and other cardiovascular diseases. Through a class on concepts and techniques in molecular biology, a class on statistical methods, several annual conferences, journal clubs, and hands on research in mentors' laboratories, he will acquire the necessary technical and analytical skills. The overall goal of the research project is to study how endothelin (ET-1) (a potent vasoconstrictor and growth stimulator) controls blood pressure. HT is more common and severe in African-Americans (AA), and the HT in this group is more often salt-sensitive. In animal models, continuous infusion of ET-1 causes sustained, salt-sensitive HT. In salt-sensitive animal models, ET-1 receptor antagonists lower blood pressure. ET-1 levels are more elevated in AA hypertensives (8-fold). Also, ET-1 receptors vary by race. Does ET-1 play a significant role in the development, maintenance, and complications in the HT in this population? Studies suggest that the ET-1 system in AA hypertensives is similar to that in animal models of salt-sensitive hypertension. Dr. Watson will start by studying ET-1 effects on arteries and veins in the Dahl salt-sensive rat, an excellent model of salt-sensitive HT. These studies have never before been performed in this model. Once he has mastered these techniques, he plans to study human arteries and veins by similar techniques, comparing AA and white hypertensives in novel ways. No one has compared the distribution of ET-1 receptors or the expression of the ET-1 gene in these populations. In the rat, he will study the contractile responses of mesenteric arteries and veins to ET-1; ET-1 levels, gene expression, receptor protein and gene expression in arteries and veins; measure superoxide anion in arteries and veins; determine the effect of chronic treatment with ET-1 receptor antagonists; and evaluate venomotor tone in vivo and effect of ET-1 receptor antagonists. In human tissue, he will compare contractile reactivity to ET-1, measure ET-1 gene expression, vascular superoxide levels, and possibly receptor levels in AA and white hypertensives. Could this lead to the development of a new class of ET-1 receptor antagonists for the treatment of salt-sensitive HT and the prevention of vascular complications of HT?
