Project 3 is designed to evaluate the relationships between sympathetic outflow from the central nervous system to the kidneys and the subsequent alterations in renal function which may prevent the adequate buffering of the controllers of renal function resulting in arterial hypertension. We have developed a new model of hypertension derived from low level intrarenal infusion of norepinephrine. The development of hypertension must result from acute homeostatic changes in renal function when intrarenal norepinephrine is only slightly increased since the intravenous infusion of equivalent dosages of neurotransmitter have no effect on renal or cardiovascular function. The focus of the proposed studies is to identify the intrarenal mechanisms responsible for the acute elevation of arterial pressure after small increases in intrarenal neurotransmitter. We hypothesize that low level elevation of intrarenal norepinephrine may lead to arterial hypertension by: 1) selective constriction of the medullary/papillary vasculature causing a chronic resetting of the renal function curve to higher perfusion pressure, 2) elevation of intrarenal AII causing altered renal vascular and/or tubular responses to arterial pressure or 3) alterations in the normal vascular smooth responses to arterial pressure and/or other vasoactive stimuli.
The specific aims for Project 3 are: 1) to determine and compare the effects of low-level intrarenal norepinephrine infusion with very low frequency renal nerve stimulation on renal function and the intrarenal distribution of blood flow. 2) to determine the relationship between the development of intrarenal neuroadrenergic hypertension nd the distribution of intrarenal blood flow in conscious dogs. 3) to determine the effects of intrarenal adrenergic stimulation on the chronic regulation of renal function and arterial pressure. 4) to evaluate the influence of intrarenal vasoactive angiotensin on the development of renal neuroadrenergic hypertension. 5) to determine the effects of """"""""long-term"""""""" elevation of intrarenal norepinephrine on renal function and arterial pressure in conscious dogs. All experiments will be conducted in chronically instrumented dogs utilizing a unique servocontrol system for the intrarenal infusion of norepinephrine. In this system, the level of intrarenal norepinephrine is maintained at maximal concentrations without changing whole kidney blood flow or GFR. The data obtained from these studies will begin to identify the mechanisms by which low level elevation of intrarenal neurotransmitter may produce chronic alterations in intrarenal function and the development of arterial hypertension. Thus, the hypothesis that selective elevation of renal sympathetic neurotransmitter may serve as a mediator of neurogenic hypertension by directly altering renal functional responses to elevated arterial pressure will be carefully studied in order to begin to determine the intrarenal interactions between renal sympathetic outflow and the long term control of arterial pressure by the kidney.
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