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.
Hamlyn JM, Lu Z, Manunta P, Ludens JH, Kimura K, Shah JR, Laredo J, Hamilton JP, Hamilton MJ, Hamilton BP. Observations on the Nature, Biosynthesis, Secretion and Significance of Endogenous Ouabain. Clin & Exper. Hypertension 1998, 20(5&6) 523-533.
Shah JR, Laredo J, Hamilton BP, Hamlyn JM. Effects of Angiotensin II on sodium potassium pumps, endogenous ouabain and aldosterone in Bovine Zona Glomerulosa Cells. Hypertension 1999, 33 (Part II) 373-377.
Manunta P, Hamilton J, Hamilton BP, Hamlyn JM,. Chronic Hypertension Induced by Ouabain but not Digoxin in the Rat: Antihypertensive Effect of Digoxin and Digitoxin. Hypertension Research. 2000, 23 Suppl:S77-S85.
Manunta P, Hamilton BP, Hamlyn JM. Structure-Activity Relationships for the Hypertensinogenic Activity of Ouabain: Role of the Sugar and Lactose Ring. Hypertension 2001.;37 (part 2): 472-477.
Ward SC, Hamilton BP, Hamlyn JM. Novel Receptors for Ouabain Studies in Adrencortical Cells and Membranes. Hypertension. 2002; 39 (part 2): 536-542.
Hamlyn JM, Laredo J, Shah JR, Lu ZR, Hamilton BP, 11 – Hydroxylation in the Biosynthesis of Endogenous Ouabain: Multiple Implications. Ann. NY Acad. Sci. 2003; 986: 685-693.
Lighthall G, Hamilton BP, Hamlyn JM, Identification of salt-sensitive genes in the kidneys of Dahl rats. J. Hypertension, 2004: 22:1487-1494.
Mordecai P Blaustein, Jin Zhang, Ling Chen, Bruce P. Hamilton, Molecular Mechanisms Linking Salt to Hypertension, Am J Physiol Regul Integr Comp Physiol 290: R514-R523, 2006.
Bruce P. Hamilton, Mordecai P. Blaustein “Molecular Mechanisms Linking Sodium to Hypertension: Report of a Symposium” J. Invest. Med. 54: 86-94. 2006.
Manunta P, Hamilton BP, Hamlyn JM. “Salt Intake and Depletion Increase Circulating Levels of Endogenous Ouabain in Normal Men” Am J Physiol Regul Integr Comp Physiol 290: R553-R559, 2006.
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981-2997.
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002; 288: 2998-3007.
Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, Black HR, Hamilton BP, Holland J, Nwachuku C, Papademetrou V, Probstfield J, Wright JT, Alderman MH, Weiss RJ, Piller L, Bettencourt J, Walsh SM for the ALLHAT Collaborative Research Group. Success and predictors of blood pressure control in diverse North American settings: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens 2002; 4:393-404.