The overall aim of the current proposal is to understand how endogenous endothelial derived relaxing factor, EDRF, influences local renal and peripheral vascular tone and controls kidney function. We will test the hypothesis that in the baseline state, endogenous EDRF provides significant regulation of glomerular hemodynamics, by influencing arteriolar resistances and also by modulating the state of contraction of the glomerular mesangial cells which in turn control glomerular capillary ultrafiltration coefficient (Kf). We will use EDRF synthesis blockers and EDRF-mimetics. Interactions between other vasoactive control systems (cyclooxygenase products, endothelin, ET, and the sympathetic nervous system, SNS) will be extensively studied. Since free oxygen radicals inactivate EDRF, we will investigate potentiation of endogenous EDRF by antioxidant enzymes. We will also investigate modulation of EDRF by changes in dietary sodium intake. Some studies will test the hypothesis that EDRF controls sodium excretion by directly enhancing sodium reabsorption. The influence of agonist-stimulated EDRF on glomerular hemodynamics will be investigated using acetylcholine, ACh, and bradykinin, Bk. Other studies will test the hypothesis that EDRF tonically modulates the action of various nonendothelial dependent vasoactive agents that influence the renal vasculature and/or the glomerular mesangial cell e.g., angiotensin II. Separate experiments will test the hypothesis that EDRF inhibits autoregulatory increases in renal vascular resistance during increases in blood pressure, BP, potentiates autoregulatory renal vasodilation during falls in BP and is inhibitory to tubuloglomerular feedback. Finally, extensive in vivo studies will investigate our newly described model of primary, progressive glomerular disease due to chronic systemic blockade of endogenous EDRF. We will investigate how prolonged systemic EDRF blockade influences the SNS and vasoactive control systems. We will also determine whether diet or drugs can slow progression in this model of primary glomerular disease and also investigate interactions between this and other models of primary, progressive glomerular injury. Whole kidney studies will be performed in both conscious and anesthetized rats; the glomerular microcirculation and tubular functions will be investigated using in-vivo micropuncture techniques; in-vitro studies will be conducted on cultured rat glomerular mesangial cells.
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