The overall objective of this proposal is to study, during normal and pathological conditions, the role of the sympathetic system in modulating renal hemodynamics and renal function during development using chronically catheterized and conscious fetal, newborn and adult sheep. I) The first major objective of this proposal will be to test the hypothesis that the renal hemodynamic and functional responses to Alpha, Beta, and dopamine receptor stimulation differ between fetal, newborn and adult animals. More specifically, this proposal is designed to investigate the ability of renal Alpha, Beta, and dopaminergic receptors to (a) modulate renal vascular tone, and (b) glomerular filtration rate, sodium and water metabolism, and renin release during development. Intrarenal infusion of different Alpha, Beta and dopamine agonists and antagonists will be used. Moreover, (c) results from these in vivo experiments will be correlated to in vitro characterization of renal Alpha, Beta and dopaminergic receptors in fetal, newborn and adult sheep. II) The second major objective of this proposal is to determine the role of circulating catecholamines and sympathetic nervous system in the fetal renal response to hypoxemia. We are speculating that there is a hierarchy in the mechanisms controlling renal hemodynamics and function during fetal hypoxemia, renal nerve activation modulating acute changes and circulating catecholamines modulating long-term effects of hypoxemia. Moreover, we are suggesting that these mechanisms may have different developmental patterns. More specifically, we are proposing to study in young (less than 115 days gestation) and near-term (greater than 135 days gestation; term 145 days) fetal lambs (a) the role of renal nerves, and (b) the contribution of circulating catecholamines in modulating the renal hemodynamic and functional responses to severe (pO2 about 8 mmHg) and moderate (pO2 about 14 mmHg) hypoxemia. Moreover, (c) the role of renal prostaglandins in attenuating the effects of sympathetically mediated renal vasoconstriction during severe and moderate hypoxemia will be studied. In summary, understanding of the fetal and neonatal renal responsiveness to sympathetic stimulation a) may have immediate clinical relevance since adrenergic agents are presently used in neonatal intensive care situations, and b) is essential for the development of new concepts regarding intrauterine therapy and management of the fetus during high-risk pregnancies and of severely sick premature infants.
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