Dr. Hamilton has a major research interest in the pathogenesis of essential hypertension at the molecular level. His work spans 25 years, performed in close collaboration with two basic scientists, John Hamlyn PhD and Mordecai Blaustein MD in the Physiology Dept. They have shown in a long series of paper over this time that (1) an excess of body salt stimulates the secretion from the adrenal of a steroid hormone closely related in structure to the cardenolide ouabain – a cardiotonic steroid obtained from a plant source in E. Africa. (2) This “endogenous ouabain” is a potent ligand and inhibitor of the α2 isoform of the sodium pump present on all cells. (3) The sodium pump is linked to the activity of a second ion transport system in the cell membrane – the Na+/Ca2+ exchanger. The research group has shown that when the sodium pump is inhibited by endogenous ouabain the resultant rise in intracellular sodium triggers, via the Na+/Ca2+ exchanger, a rise in Ca2+. In the smooth muscle cell, the result is a rise in myogenic tone and in the arteriole, a rise in peripheral resistance – the hemodynamic hallmark of hypertension. These molecular pathways have been confirmed in transgenic animals and specific inhibitors of ouabain’s action on the sodium pump and of the Na+/Ca2+ exchanger are in clinical studies for the treatment of hypertension and other cardiovascular disorders.
Dr. Hamilton and his wife Jennifer Hamilton, MD conduct a large clinical research program in their Hypertension & Endocrine Unit (HEU) in the VA Medical Center. The studies involve the investigation of therapeutic aspects for Hypertension, Diabetes & Dyslipidemia. They followed 350 patients in the (now completed) ALLHAT study and are following 180 patients in the NIH-funded ACCORD study in type-2 diabetes that will continue until 2009.