This project tests the hypothesis that blacks differ from whites in the cellular regulation of the cytosolic free Ca (Ca-i). Such racial difference is expressed by enhanced Ca-i turnover and hyperresponsiveness of American blacks to agonists that act through Ca-i and protein kinase C (PKC) and it contributes to the increased propensity of blacks to essential hypertension. Since a rise in Ca-i or increased Ca-i turnover is associated with an alkaline shift in the cytosolic pH (pH-i) set point for activation of the Na/H antiport (Xi), it is expected that blacks would differ from whites not only in Ca-i homeostasis but also in cellular and systemic Na regulation. Using platelets as a cellular model, this project focuses on the cellular pathways in control of Ca-i, PKC and the Na/H antiport in normotensive and hypertensive blacks and whites of both genders. The following platelet parameters will be studied in resting platelets and after platelet stimulation with thrombin, the thromboxane A2 analogue U46619, thymeleatoxin and phorbol 12-myristate 13-acetate (PMA): a) Ca-i, pH-i and cytosolic free Na (Na-i) profiles, b) Ca influx (using Mn as a Ca surrogate), c) the kinetics of Ca extrusion (using thapsigargin), d) Xi and activity index of the Na/H antiport (Zi), e) PKC activity in platelet cytosol and platelet plasma membranes, and f) density of membrane bound PKC units, derived from the specific receptors of phorbol 12,13-dibutyrate (PdBu). These parameters will be examined to elucidate racial and gender-related differences in Ca-i and their link to altered activities of both PKC and the Na/H antiport. They will be correlated with the blood pressure profile, glucose metabolic status, age, indices of body mass and fat distribution, plasma renin-activity (PRA) and microalbuminuria. Insight into the cellular mechanisms that predispose blacks to essential hypertension is instrumental for formulating measures to prevent hypertension in this racial group and for developing specific therapeutic interventions to attenuate its cardiovascular and renal complications.
Showing the most recent 10 out of 22 publications
