Karen T. Ball

A Potential Role for Adenosine in the Inhibition of Nonshivering Thermogenesis in the Fetal Sheep

ABSTRACT: Adenosine is released by the placenta into the fetal circulation and has potent antilipolytic properties in vitro. Nonshivering thermogenesis cannot be demonstrated by cooling fetal sheep in utero but can be induced by supplemental oxygenation and umbilical cord occlusion; this suggests the presence of inhibitor(s) of placental origin. To test whether circulating adenosine could be such an inhibitor, a series of experiments was carried out in nine fetal sheep at 136–145 d gestation. Birth was simulated in utero by sequentially cooling the fetus 2.49 ± 0.23°C with no change in the low levels of plasma FFA or glycerol; ventilating with O2 via an exteriorized tracheostomy tube and umbilical cord occlusion. Thermogenic indices rose markedly, and plasma FFA and glycerol concentrations peaked at 725 ± 88 µEq/L (p < 0.01) and 771 ± 154 µmol/L, (p < 0.001), respectively, O2 consumption rose to 20 ± 2 mL/min/kg, and temperature increased 1.99 ± 0.35°C. The long-acting adenosine analog N6-(L-2-phenylisopropyl)-adenosine (PIA) was then infused (90 µg/kg bolus, then 300 µg/kg/h for 30 min); plasma FFA and glycerol decreased to 265 ± 56 µEq/L (p < 0.003) and 477 ± 102 µmol/L (p < 0.04), respectively; O2 consumption fell rapidly to 4.5 ± 0.3 mL/min/kg (p < 0.01); temperature decreased 1.89 ± 0.39°C (p < 0.001); and fetal arterial BP decreased to 38 ± 5 mm Hg (p < 0.004) in 30 min. A stepped dose-response study was performed in three fetal sheep. Birth was simulated in utero and then PIA was administered in escalating doses for five sequential 30-min periods with 60-min intervals in between, starting at 0.08 µg/kg bolus. The fetal arterial blood pressure was not affected by any of the relatively low doses of PIA used; however, all of the doses of PIA inhibited nonshivering thermogenesis in a dose-dependent manner. These results are consistent with adenosine suppression of brown adipose tissue thermogenesis in utero and suggest that adenosine may be an inhibitor of placental origin.

Reversible umbilical cord occlusion: effects on thermogenesis in utero.

ABSTRACT: The initiation of thermogenesis at birth is an important adaptation for survival. We examined the sequential effects of cooling, increased oxygenation, and repeated episodes of umbilical cord occlusion on nonshivering thermogenesis in six fetal sheep at 139 to 145 d of gestation. The fetal sheep were cooled by circulating cold water through a coil placed around the trunk for 4 h. The fetal core temperature fell 2.47 ± 0.24°C in the first 60 min of cooling with minimal changes in plasma FFA and glycerol levels. After fetal arterial O2 tension was increased above 6.65 kPa by ventilation, fetal temperature and thermogenic indices rose significantly in 60 min. After occlusion of the umbilical cord by a reversible occluder cuff, plasma FFA levels rapidly increased to 635 ± 69 μEq/L (p < 0.005) by 30 min, fetal temperature increased a further 0.96 ± 0.20°C (p < 0.001) and fetal O2 consumption peaked at 25.3 ± 4.9 mL·min-1·kg-1. Release of cord occlusion caused a rapid fall in FFA to 149 ± 23 μEq/L (p < 0.005) and a fall in fetal core temperature of 0.90 ± 0.13°C (p < 0.001) in 30 min. After irreversibly snaring the umbilical cord, the plasma FFA rose to 611 ± 83 μEq/L (p < 0.005) and the fetal temperature rose 0.78 ± 0.09°C (p < 0.02). The effects on thermogenesis of interrupting and reestablishing placental flow are rapid and reversible and suggest the presence of placental inhibitors of brown adipose tissue thermogenesis.

Changes in Selected Brain Neurotransmitters and Their Metabolites in the Lamb after Thyroidectomy during the Last Two Trimesters of Gestation or the Early Neonatal Period

ABSTRACT: To evaluate in a developmental context the effect of congenital hypothyroidism on concentrations of the neurotransmitters norepinephrine, dopamine, and serotonin (5HT) in selected brain areas of the ovine fetus, we studied the effect of thyroidectomy at three ages on the concentrations of these neurotransmitters and their major metabolites, homovanillic acid and 5-hydroxyindoleacetic acid. Fetuses underwent thyroidectomy at 90-95 or 105- 115 d gestation (term = 147-150 d) or 1-5 d after birth. Approximately 25 d after thyroidectomy, at d 120-125 or 130-135 of gestation or 25-30 d after birth, respectively, the ewes were killed and fetal brains removed. Neurotransmitters and their metabolites were measured by HPLC with electrochemical detection. Thyroidectomy in the 2nd trimester increased 5HT in five brain areas: anterior hypothalamus, dorsal medial hypothalamus, pons, medulla, and cerebellum. Thyroidectomy in the 3rd trimester increased 5HT in the pons and medulla, increased norepinephrine in the dorsal medial hypothalamus and pons, and increased homovanillic acid in the posterior hypothalamus. Thyroidectomy in the newborn period decreased NE in the anterior hypothalamus, ventral medial hypothalamus, and midbrain, decreased 5-hydroxyindoleactic acid in the posterior hypothalamus, lateral hypothalamus, dorsal medial hypothalamus, and ventral medial hypothalamus, and decreased homovanillic acid in the dorsal medial hypothalamus and ventral medial hypothalamus. From these data we conclude the following: 1) Hypothyroidism causes changes in neurotransmitter concentrations only in selected brain areas of the ovine fetus, rather than causing generalized and similar changes in all brain ares; and 2) 5HT 5- hydroxyindoleacetic acid concentrations are affected more often than the other neurotransmitters evaluated, perhaps because the 5HT neurotransmitter system is developing at these times.

The ontogeny of [3H]-5-hydroxytryptamine binding in the lamb : effects of in vivo thyroidectomy

The effects of congenital hypothyroidism in the late gestation ovine fetus include changes in serotonin concentrations in specific brain areas. To investigate possible ontogenic patterns of changes in 5‐HT receptor function, we studied the binding characteristics of [3H]5‐HT in the midbrain, hypothalamus and cerebral cortex in the late gestation ovine fetus and young lamb. We compared the binding characteristics of control fetuses to those of thyroidectomized fetuses, with or without thyroxine replacement therapy.

Presence of a diurnal rhythm in fetal prolactin secretion and influence of maternal nutrition

The possible effect of altered maternal nutrition on fetal prolactin (PRL) secretion and the possible presence of a diurnal rhythm in fetal PRL secretion has been investigated in 11 fetuses aged between 132 and 140 days of gestation. Fetal PRL levels in 4 of 5 ewes fed once a day were high (greater than 40 ng/ml) and exhibited a distinct diurnal rhythm in PRL secretion. Fetal PRL levels in those fetuses where ewes fed 4-hourly (n = 6) were all low (less than 10 ng/ml) and did not exhibit a diurnal rhythm. This study suggests that frequent maternal feeding results in low fetal PRL concentrations and that maternal undernutrition results in high fetal PRL levels that exhibit a distinct diurnal rhythm.