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This application is to provide support for Jose R. Romero, Ph. D. to allow him protected time for further supervised patient‑oriented research and training to become an independent biomedical scientist. To this end, a formal career development plan and curriculum for his development have been designed. The scientific focus of this application is to study sodium and calcium transport abnormalities at the cellular level that are present in blood cells from insulin resistant hypertensive patients. Various groups have independently shown that insulin resistance and the compensatory hyperinsulinemia are associated with essential hypertension. Erythrocytes, lymphocytes and platelets have been widely used as surrogate cells to what happens in cells that are more closely involved in the hypertensive process. Elevated Na/H exchanger (NHE), hyperinsulinemia and altered cytosolic calcium (Cacyt) handling are frequent abnormalities associated with essential hypertension. Genetic and epidemiological studies have characterized elevated NHE activity in blood cells as an intermediate phenotype in the hypertensive process. Our preliminary findings suggest that NHE activity in red blood cells (RBC) from these patients is insulin resistant but can still modulate sodium transport at high insulin levels. However this response is blunted in comparison to the effect on normotensives. In addition, we have seen that insulin levels correlate with sodium/lithium countertransport, a mode of operation of the NHE. Furthermore, our preliminary data show that incubation of lymphocytes with insulin causes Cacyt to increase in hypertensive patients. These findings have led us to the hypothesis to be tested in this project: insulin resistance is associated with functional defects in sodium and/or calcium transport pathways in hypertensive patients and these pathways are similarly abnormal in target tissues (endothelial cells) of the hypertensive process. To address this problem we have identified the following specific objectives. We will study the effects of insulin and Cacyt on the kinetics of NHE activation in RBC and lymphocytes from hypertensive individuals that have been characterized by markers of insulin resistance. We propose that the phosphorylation state and/or the turnover rate of NHE are enhanced by either Cacyt and/or insulin. We will also study the effect of insulin on Cacyt in lymphocytes from hypertensives with varying degrees of insulin sensitivity. Finally, we will investigate whether the cation alterations observed in blood cells can be seen in primary cultures of vascular endothelial cells obtained from subjects that have been characterized by markers of insulin resistance. Through these mechanisms the insulin resistance and hyperinsulinemia in hypertensive individuals may be linked to NHE abnormalities and/or elevated Cacyt levels. The information obtained from this project will demonstrate the role of insulin resistance in sodium and calcium transport.

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