We propose to continue studies of kidney and nephron function and investigate mechanisms responsible for, or involved in, abnormalities in renal hemodynamic control systems we observe in young spontaneously hypertensive rats of the Okamoto-Aoki strain (SHR) as compared to Wistar-Kyoto normotensive controls: elevated renal vascular resistance; hyperreactive tubuloglomerular feedback control of glomerular function; hyper-reactive renal vasculature to angiotensin and thromboxane; and increased density of glomerular thromboxane receptors. Micropuncture and microperfusion techniques will be used to measure glomerular function and its control by tubuloglomerular feedback. Blood flow studies will evaluate steady-state and dynamic responses of renal vascular resistance to physical and hormonal influences. Radio-ligand studies will quantify glomerular receptors. Three protocols will investigate the mechanism(s) responsible for the excessive renal vasoconstriction; two protocols will examine exaggerated activity of tubuloglomerular feedback. Studies will evaluate the proposal that feedback activity is reset and more reactive due increased intrarenal activity of the vasoconstrictors hormone(s) such as angiotensin and thromboxane and/or a relative deficiency in the effects of vasodilator hormone(s) such as kinins. The relative contribution of myogenic responses and tubuloglomerular feedback to blood flow autoregulation in young SHR will be determined. The hypothesis that more efficient autoregulation of renal blood flow is due to exaggerated tubuloglomerular feedback activity and/or a stronger myogenic response will be investigated. The influence of vasoactive hormones/autacoids on the relative strengths of the intrinsic controllers of vasomotor tone will be examined. Studies will test the postulate that exaggerated renal vascular reactivity is due to greater responses to constrictor systems or weaker responses to dilator systems. Vascular reactivity to, and interactions among, the vasodilator prostanoids PGE2 and PGl2 and the vasoconstrictors angiotensin II and thromboxane will be determined in blood flow studies. Receptors for PGE2 and PGl2 will be characterized in glomeruli isolated from young SHR . Regulation of glomerular thromboxane receptors will be assessed as a function of intrarenal concentrations of thromboxane. Parallel studies in young genetically hypertensive rats and appropriate normotensive controls should provide new, useful and important insights into the role of renal function, and its regulation by intrinsic mechanisms and hormonal and autacoid systems in the development of hypertension in a standard model of human essential hypertension.
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