The high renal vascular resistance and increased sodium avidity in the newborn is primarily due to increased alpha-adrenergic and decreased dopaminergic effects. Normal maturation is associated with decreasing alpha-adrenergic and increasing dopaminergic influence. HYPOTHESIS: In the rat, these phenomena are not due to changes in alpha1 or dopamine1 receptor affinity or density, but rather to maturation of post receptor mechanisms. Moreover, the increased adrenergic activity at the proximal tubular level enhances the effect of the high angiotensin II (AII) levels in the young and attenuates the effect of atrial natriuretic peptide (ANP) at the glomerulus and in the inner medullary collecting duct. These effects, in conjunction with the decreased activity of dopamine1 receptors at the cortical collecting duct, contribute to the increased avidity of the distal nephron to reabsorb sodium. In the spontaneously hypertensive rats (Okamoto-Aoki strain) and other forms of genetic hypertension, the orderly maturation of alpha- and dopaminergic activity is perturbed, allowing the high renal vascular resistance to persist. What prevents normal maturation from occurring is an abnormality of the renal dopaminergic system resulting in an increased activity of the renal nerves and the renin-angiotensin system and sodium retention.
The specific aims are: 1) to determine the effects of the intrarenal arterial infusion of selective adrenergic agonists and antagonists as well as ANP on renal hemodynamics and function at different time points during maturation. a) The role of renal nerves will be studied by unilateral renal surgical denervation. b) The role of AII will be evaluated by the use of an angiotensin converting enzyme inhibitor, and peptide and non-peptide AII antagonists. 2) to determine the effect of selective adrenergic agonists and antagonists as well as ANP at different time points during maturation on water and sodium transport in isolated nephron segments using in vitro microperfusion, amiloride sensitive 22Na uptake (Na+/H+ exchange activity in proximal tubule) and ouabain sensitive 86Rb uptake (Na+/K+ ATPase activity in isolated nephron segments). 3) to characterize the adrenoceptor in nephron segments, glomeruli and renal microvessels by radioligand binding and quantitative autoradiography, Northern blot analysis, and in situ hybridization. 4) to determine the second messengers linked to these receptors by measuring adenylate cyclase (in isolated nephron segments), phospholipase C and protein kinase C activities (in proximal and distal as well as medullary cell suspensions). These studies should provide insight on the role of the alpha-adrenergic receptors on renal function during development in normotensive and hypertensive animals. Information from these experiments in conjunction with data from experiments on dopamine receptors already funded by NIH should give an integrated picture of the role of catecholamines on regulation of renal function.
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