This is a new RO1 submission with the overall goal of determining the role of abnormally functioning amiloride-sensitive sodium channels (ASSCs) in the etiology of severe salt-sensitive hypertension in a subset of African Americans. The proposal builds on a substantial knowledge base established by the investigators and others concerning the role of mutant ASSCs in the severe, salt-sensitive hypertension of affected individuals with Liddle's disease. Due to a beta subunit mutation in the ASSC, these individuals have severe hypertension responsive to the K-sparing diuretic amiloride and/or triamterene. This is associated with a constitutively activated ASSC conductance in renal epithelial cells. Importantly, the investigator has established that ASSCs are expressed in human lymphocytes and that the lymphocytes can serve as surrogate markers of the primarily affected cells. Furthermore, it has been established that abnormal ASSCs are seen in a subset of African American hypertensives. Based on this preliminary data, the following specific aims are proposed. The first specific aim is to isolate peripheral blood lymphocytes (PBLs) from hypertensive African Americans, as well as hypertensive individuals from other races and normal controls, followed by characterization and comparison of the function of the ASSCs. The second specific aim is to determine whether abnormalities of regulation exist in transformed lymphocytes from individuals with abnormal basal ASSC conductances. Specifically, regulation via cAMP analogs, via G-protein mediated ADP ribosylation, via mechanical stimulation, and via alpha receptors will be characterized and compared to the established body of data concerning these regulatory pathways in normally functioning ASSCs. Finally, the efficacy of amiloride, triamterene, prazosin, and terazosin on abnormal lymphocyte ASSCs will be evaluated. The latter specific aim has important therapeutic implications for the individuals who are being studied. An addendum adds an IRB-approved clinical study based on these findings, in which a trial with the effective agent, identified in the in vitro studies, will be compared to standard antihypertensives, in the affected individuals.
