This proposal is a revised application which will examine the mechanisms whereby renal adrenergic effector mechanisms influence glomerular hemodynamics and tubular functions and determine the extent to which adrenergic influences are mediated by interaction with other intrarenal hormones, angiotensin II and other relevant hormones. Recent studies from this laboratory have demonstrated a strong renal interaction between adrenergic activity and angiotensin II. These studies will utilize 1) renal micropuncture evaluation of glomerular hemodynamics and tubular reabsorption, 2) analysis of glomerular and tubular angiotensin II and adrenergic subtype receptors, 3) analysis of adrenergic activity in the kidney by evaluation of catecholamine output and chromagranin A, a neurovesicle protein and 4) in vitro assessment of mesangial cell contraction responses to hormones and receptors in cells in culture. These studies will examine several issues: 1) We will define the mechanisms whereby adrenergic activity and individual adrenergic receptor subtypes alter glomerular hemodynamics and tubular function, using agonist infusion and adrenergic antagonists during renal nerve stimulation. 2) We will also determine to what extent the glomerular and tubular effects of adrenergic stimulation, defined above, are independent influences or require interaction with intrarenal angtiotensin II. 3) We will also determine mechanisms whereby increased renal adrenergic activity produces increased intrarenal angiotensin, i.e. adrenergic receptor stimulation and/or prostaglandin mediators. Studies will also define adrenergic:angiotensin II synergism at the effector cell, the mesangial cell. 4) We will determine the mechanisms whereby increased angiotensin II activity compensates for the acute and subacute removal of renal adrenergic activity with renal denervation. Finally, we will integrate these studies by determining whether the volume status of the animal conditions the glomerular hemodynamic response to renal nerve stimulation, and the mechanism whereby this modulation occurs.
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