Significant activation of the sympathoadrenal system (SAS) occurs during the transition from fetal to neonatal life. Increases in circulating catecholamines, derived predominantly from adrenal medullary secretion and also post-ganglionic sympathetic nerves, support major cardiovascular, pulmonary and metabolic adaptations to postnatal life. While activation of the sympathoadrenal system is vital to these alternation the duration of this dependence is unknown. The duration of elevated circulating catecholamines will be determined in newborn sheep. The effects of ablation of these responses through adrenalectomy will be determined in preterm sheep. Physiologic thresholds for the hemodynamic, metabolic and endocrine effects of circulating catecholamines in newborn and adult sheep will be compared with recent data from fetal animals. The contribution of individual organ systems to the catecholamine responses at birth and the physiologic significance of regional metabolism of catecholamines will be elucidated using regional organ kinetic studies. The pulmonary vascular bed normally metabolizes a large fraction of circulating vasoactive amines. The developmental basis for this phenomenon in vivo will be studied. Endocrine changes during fetal life, including antenatal increases in cortisol and thyroid hormones, may importantly condition the sympathoadrenal system responses at birth. These effects on the developing sympathoadrenal system will be studied. Intrauterine growth retardation and chronic hypoxia may alter development of sympathetic nerve function, adrenal catecholamine synthesis, release of catecholamines or adrenergic receptor maturation. Each of these components of the SAS will be studied in growth retarded fetal lambs or lambs subjected to chronic hypoxia. The clinical pharmacology of adrenergic agents in use in critically ill neonates will be studied with sensitive and specific hormone assays. It is believed these experiments will lead to important new strategies new strategies for the care of premature infants as well as the compromised term infant.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Human Embryology and Development Subcommittee 2 (HED)
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Los Angeles County Harbor-UCLA Medical Center
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Stein, H M; Martinez, A; Oyama, K et al. (1995) Effect of corticosteroids on free and sulfoconjugated catecholamines at birth in premature newborn sheep. Am J Physiol 268:E28-32
Stein, H M; Martinez, A; Blount, L et al. (1994) The effects of corticosteroids and thyrotropin-releasing hormone on newborn adaptation and sympathoadrenal mechanisms in preterm sheep. Am J Obstet Gynecol 171:17-24
Berg, R A; Donnerstein, R L; Padbury, J F (1993) Dobutamine infusions in stable, critically ill children: pharmacokinetics and hemodynamic actions. Crit Care Med 21:678-86
Stein, H; Oyama, K; Martinez, A et al. (1993) Plasma epinephrine appearance and clearance rates in fetal and newborn sheep. Am J Physiol 265:R756-60
Stein, H M; Oyama, K; Martinez, A et al. (1993) Effects of corticosteroids in preterm sheep on adaptation and sympathoadrenal mechanisms at birth. Am J Physiol 264:E763-9
Berg, R A; Padbury, J F; Donnerstein, R L et al. (1993) Dobutamine pharmacokinetics and pharmacodynamics in normal children and adolescents. J Pharmacol Exp Ther 265:1232-8
Oyama, K; Padbury, J; Chappell, B et al. (1992) Single umbilical artery ligation-induced fetal growth retardation: effect on postnatal adaptation. Am J Physiol 263:E575-83
Stein, H M; Oyama, K; Sapien, R et al. (1992) Prolonged beta-agonist infusion does not induce desensitization or down-regulation of beta-adrenergic receptors in newborn sheep. Pediatr Res 31:462-7
Oyama, K; Padbury, J; Martinez, A et al. (1992) Effects of fetal growth retardation on the development of central and peripheral catecholaminergic pathways in the sheep. J Dev Physiol 18:217-22
Martinez, A M; Padbury, J F; Thio, S (1992) Dobutamine pharmacokinetics and cardiovascular responses in critically ill neonates. Pediatrics 89:47-51

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