Theoretical and transplantation studies have indicated that renal dysfunction underlies the development and maintenance of hypertension; however, the factors that """"""""reset the kidney in hypertension"""""""" are unknown. This proposal focuses on the hypothesis that an elevation in renal medullary vascular resistance is responsible for the abnormal sodium reabsorption in hypertension. We will evaluate the contribution of an elevation in renal sympathetic tone, a deficiency in the kallikrein-kinin system, and/or alterations in renal arachidonic acid metabolism to the resetting of tubular and vascular function. The effects of renal denervation, pharmacologic manipulation of the kallikrein-kinin system (using kininase inhibitors and a kinin antagonist) and alterations in renal eicosanoid production (using inhibitors of cyclooxgenase, thromboxanesynthetase and cytochrome P450 metabolism of arachidonic acid) on the pressure-natriuretic response, renal cortical and medullary hemodynamics and sodium reabsorption in superficial and deep nephrons will be compared in normotensive and hypertensive rats. Renal hemodynamics will be studied using laser- Doppler spectoroscopy and videomicroscopy. Tubular function will be evaluated using micropuncture. The urinary excretion of eicosanoids and the renal metabolism of arachidonic acid will be studied using radiochemical and radioimmunoassay techniques. Kallikrein and kinin excretion will be determined using radioimmunoassay. These studies will provide important new information on the role of the renal nerves, the kallikrein-kinin and renal eicosanoid systems in the regulation of vasa recta hemodynamics, renal interstitial pressure and tubular function, and the participation of these systems in the development of hypertension.
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