The objective of this research is to investigate mechanisms of the responses of the immature kidney to hypoxemia and hemorrhage. Hypoxemia and hemorrhage are known complications of obstetric delivery and other conditions in the newborn period and may lead to renal failure. These responses will be studied in a chronic lamb experimental model which exhibits maturation of renal function similar to that seen in humans. The role of the adrenergic system in the renal response to hypoxemia during early postnatal maturation will be studied by examining the effects of intrarenal infusion of specific alpha-adrenergic inhibitor and denervation of the kidney on responses to hypoxemia. Renal blood flow will be measured by electromagnetic flow probe and renal function by standard clearance techniques. The responses and interactions of urinary prostaglandin (PGE, PGF, and 1-keto-PGF1Alpha) excretion rate, serum catecholamines, plasma renin activity, serum angiotensin-II concentration, serum cortisol and serum aldosterone concentration to these conditions will also be evaluated. The mechanism of organ tissue blood flow responses to acute hemorrhage will be studied (using radiolabelled microspheres) by examining the effects of systemic administration of adrenergic system (Alpha-blockade with phenoxybenzamine and Beta-blockade with propranolol), renin-angiotensin system (angiotensin-coverting enzyme inhibition with captopril and angiotensin-II blockade with [Sar1-ala8]-angiotensin-II) and prostaglandin system (indomethacin and meclofenamate)inhibitors on responses to non-hypotensive and hypotensive hemorrhage and reinfusion. The role of the adrenergic system in local renal effects of hemorrhage and reinfusion will be studied by measuring renal blood flow (by electromagnetic flow probe) and renal function responses to hypotensive and non-hypotensive hemorrhage during intra-renal Alpha-adrenergic blocked with phenoxybenzamine, renal denervation, and combined adrenergic blockade/denervation. The responses and interactions of urinary prostaglandin (PGE, PGF, and 1-keto-PGF1Alpha) excretion rate, serum catecholamines, plasma renin activity, serum angiotensin-II concentration, serum cortisol and serum aldosterone concentration to these conditions will also be evaluated. Insight into these events through these studies may improve clinical outcome in infants exposed to these adverse conditions.
