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Met-enkephalin immunoreactivity (MET-ENKi), total enkephalin immunoreactivity (TOTAL MET-ENKi) and catecholamines were measured in adrenal and extra-adrenal tissue of fetal, newborn and adult rabbits. Met-enkephalin peptides were detected in adrenal and extra-adrenal tissue by 29 days of gestation. There were progressive increases in TOTAL MET-ENKi in both the adrenal and extra-adrenal tissue during development. In 29-day-old fetuses, MET-ENKi represented 43 and 50% of the peptide content in adrenal and extra-adrenal tissues respectively. By 3 days after birth, MET-ENKi represented only 15 and 7% of the peptide content in the same tissues. In the adult adrenals, 10% of enkephalin peptides were found as MET-ENKi. There were progressive increases in adrenal and extra-adrenal catecholamine content in the fetal and newborn rabbits throughout development. The changes in the ratio of MET-ENKi to TOTAL MET-ENKi peptides suggest differences in posttranslational processing of proenkephalin peptide during maturation. We speculate that enkephalin peptides derived from proenkephalin A are important during fetal and early newborn life and that extra-adrenal tissue may be an important source of these peptides during development.

The lungs play an important role in the metabolism of vasoactive substances including endogenous amines. The role of pulmonary clearance of circulating norepinephrine has not been well defined in the young lamb (7-8 d of age). Using radiolabeled tracer norepinephrine in acutely instrumented lambs, we determined the in vivo pulmonary clearance and spillover rate of norepinephrine under baseline and hypoxic conditions. The fractional extraction of norepinephrine, the percent removed on a single pass through the pulmonary circulation, was 23 +/- 2%. The corresponding pulmonary clearance rate was 61 +/- 10 mL/kg/min and the net pulmonary norepinephrine removal rate was 0.41 +/- 0.14 nmol/kg/min. This clearance represented over 70% of whole body norepinephrine clearance. The spillover of synaptic norepinephrine was 0.22 +/- 0.13 nmol/kg/min. During hypoxia, animals showed significant increases in pulmonary artery pressure and resistance. Fractional extraction and norepinephrine decreased to 16 +/- 3%, p less than 0.005. Pulmonary clearance decreased to 31 +/- 7 mL/kg/min, and net pulmonary norepinephrine removal rate decreased to 0.27 +/- 0.07 nmol/kg/min. These results demonstrate that pulmonary clearance plays a significant role in norepinephrine clearance in 1-wk-old lambs. Alteration of norepinephrine clearance during physiologic states such as hypoxia may be important in the pathophysiology of altered pulmonary vascular resistance in newborn animals.

The present studies were designed to determine the fetal catecholamine and metabolic responses to insulin-induced maternal hypoglycemia. Maternal hypoglycemia was induced by a primed constant infusion of insulin and glucose administered to pregnant ewes to maintain maternal glucose at 20-25 mg/dl. Maternal and fetal samples for measurement of catecholamine, glucose, and free fatty acid levels and arterial blood gas analysis were collected before insulin infusion and at intervals thereafter for 6 h. Maternal and fetal plasma catecholamine levels increased significantly in response to hypoglycemia (analysis of variance, P less than 0.01). Fetal insulin and glucagon levels did not change despite a 50% reduction in fetal whole blood glucose concentration. Fetal free fatty acid levels increased significantly during hypoglycemia (P less than 0.05). There were no significant changes in maternal or fetal heart rate, blood pressure, or arterial blood gases during hypoglycemia. These results suggest that the fetus is capable of responding to hypoglycemia with an increase in catecholamine and free fatty acid levels. These results are consistent with the interpretation that the fetus is able to mobilize alternative energy substrates in response to maternal insulin-induced hypoglycemia.

The effect of hypoxia on plasma met-enkephalin and catecholamine levels was studied in chronically catheterized fetal sheep. Maternal and fetal hypoxia was maintained for 20 min. We found hypoxia significantly increased the plasma levels of large mol wt met-enkephalin containing peptides from 1755 +/- 229 pg/mL during baseline to 4408 +/- 1426 pg/mL by 15 minutes of hypoxia. The levels of the met-enkephalin pentapeptide were unchanged during hypoxia from a baseline value of 168 +/- 56 pg/mL. Norepinephrine and epinephrine levels increased 5- and 10-fold, respectively, by 15 min of hypoxia. These observations suggest cosecretion of the large mol wt met-enkephalin peptides with catecholamines during stress in developing animals.

Plasma catecholamines circulate either in conjugated or unconjugated forms. In adult humans, sulfoconjugated catecholamines predominate; however, there is considerable variation between species. In a variety of pathophysiological states catecholamine conjugation is believed to represent an important mechanism of inactivation of high circulating catecholamine levels. To date, there have been few data in developing animals or humans on catecholamine sulfoconjugation. We studied the differences in free and sulfoconjugated catecholamines in full term (141 +/- 1 days) and preterm (123 +/- 1 days) chronically catheterized fetal sheep and determined the changes in free and sulfoconjugated catecholamines in response to hypoxia. The results demonstrate that term and preterm animals have a comparable percentage of basal circulating sulfoconjugated catecholamines (free-to-total ratio 50-60%). In response to hypoxia, both free and sulfoconjugated catecholamines were promptly elevated with significant increases in each by 5 min of hypoxia. This was true for both term and pretern animals. The proportion of free and total catecholamines remained relatively constant during hypoxia despite a 5- to 10-fold increase in circulating levels of each. These data demonstrate that fetal sheep, as early as 80% gestation, have a well developed mechanism for sulfoconjugation and subsequent inactivation of the high circulating levels of catecholamines seen during fetal and newborn life.