To evaluate contributions of catecholamines to inhibition of growth during chronic hypoxemia or severe undernutrition, epinephrine (Epi; 0.25–0.35 μg ⋅ kg−1 ⋅ min−1) or norepinephrine (NE; 0.5–0.7 μg ⋅ kg−1 ⋅ min−1) was administered to normoxemic fetuses in twin-pregnant ewes for 8–12 days, from 125 to 127 days of gestation. Both had similar effects and decreased fetal weight by ∼20% relative to control twins ( P < 0.01). Weight gain ceased during infusion of Epi or NE (−21 ± 14.8 or 14 ± 20.9 g/day), whereas controls gained 93 ± 13.2 g/day ( P < 0.01). Effects on tissues and organs varied, spleen and thymus being most retarded, whereas brain weight and skeletal measures were affected little. Selected muscles from infused fetuses weighed 72% of those in controls. Growth ceased during infusion ( P < 0.001). Weight gain of hindlimb bones was negligible, but length increased at 56% of control rates. Arterial blood CO2and plasma insulin were decreased ( P< 0.001), but plasma glucose, growth hormone, and blood oxygenation increased ( P < 0.001). Actions of Epi and NE could underlie asymmetrical growth retardation occurring in many adverse physiological situations during fetal development.

Increased epinephrine (Epi) and norepinephrine (NE) production plays an important role in fetal adaptation to reduced oxygen and/or nutrient availability, inhibiting insulin secretion and slowing growth to support more essential processes. To assess the importance of hypoinsulinemia for the efficacy of catecholamines, normoinsulinemia was restored by intravenous insulin infusion (0.18 mU. kg(-1). min(-1)) during prolonged infusion of either Epi (0.25-0. 35 microgram. kg(-1). min(-1) for 12 days, n = 7) or NE (0.5-0.7 microgram. kg(-1). min(-1) for 7 days, n = 6) into normoxemic fetuses in twin-pregnant ewes, from 125-127 days of gestation. Insulin infusion for 8 days during Epi infusion or for 4 days during NE infusion decreased arterial blood pressure, O(2) content, and plasma glucose, but increased heart rate significantly (all P <0.05), despite continuation of Epi or NE infusion. Cessation of insulin infusion reversed these changes. Estimated growth of fetuses infused with insulin during Epi or NE infusion (55 +/- 13.9 and 83 +/- 15.2 g/day) did not differ significantly from that of untreated controls (72 +/- 15.4 g/day, n = 6). Growth of selected muscles and hindlimb bones was not altered either. Restoration of normoinsulinemia evidently counteracts the redistribution of metabolic activity and decreased anabolism brought about by Epi or NE in the fetus. Inhibition of insulin secretion by Epi and NE, therefore, appears essential for the efficacy of catecholamine action in the fetus.

During winter (December to March), when late-pregnant ewes were maintained under an artificial long-day photoperiod (16 h light) for 3 weeks or more before insertion of fetal vascular cannulae between 118 and 120 days of gestation (full term, 147 days), plasma prolactin concentrations in their fetal lambs were significantly increased throughout the last 3 weeks of gestation in comparison with values in similar aged fetuses from ewes experiencing only the natural short-day (less than 9 h light) winter photoperiod. When additional lighting was given only after vascular cannulation, fetal plasma prolactin increased steadily from low values, characteristic of winter pregnancies, to high values, characteristic of long-day (16 h light:8 h darkness) pregnancies. Maternal plasma prolactin concentrations changed in a similar way. During summer pregnancies (greater than 16 h light), plasma prolactin in fetal lambs was significantly reduced within 48 h when ewes were given melatonin by i.v. infusion for 14 h each night to simulate the winter duration of the nocturnal increase in plasma melatonin. Maternal plasma prolactin concentrations also decreased significantly when melatonin was given for 3 weeks, but not in a shorter experiment. Increases in fetal plasma prolactin were proportional to the basal prolactin concentration in fetuses injected i.v. with TRH or a dopaminergic antagonist, metoclopramide, to assess how photoperiod influenced the responsiveness of prolactin secretion to acute stimulation. The results confirm that photoperiod, rather than developmental maturity, is the principal determinant of plasma prolactin in the fetal lamb during the last third of gestation, and provide evidence that photoperiodic information is transmitted to the fetus through the diurnal rhythm of melatonin in the ewe.

ABSTRACT. During prolonged administration of @-agonists such as ritodrine directly to chronically cannulated fetal lambs, the cardiovascular, metabolic, and endocrine changes observed during the 1st day of administration, lessen and return to normal within 3-4 d despite continuing drug administration. In our investigation, heart rate, plasma FFA, lactate, glucose, and insulin concentrations all increased significantly during the 1st day of ritodrine infusion (10 wg/min), whereas blood Poz and base excess were significantly decreased. After 3 d, despite continued drug infusion, all these changes had ameliorated. To examine the hypothesis that this tachyphylaxis to ritodrine also results in decreased sensitivity to endogenous catecholamines, epinephrine (1 pg/min i.v. for 60 min, then 2 pg/min i.v. for a further 60 min) was infused into fetal lambs (124-130 d gestation) 1 d before, then 5 f 1 d after, and again 10 f 1 d after beginning ritodrine infusion. Before ritodrine administration, epinephrine significantly increased plasma FFA, lactate, glucose, and glucagon concentrations and decreased insulin. However, after ritodrine treatment for either 5 +. 1 or 10 f 1 d, epinephrine resulted in no significant increases in FFA or glucagon, and those in lactate and glucose were significantly reduced. Decreases in insulin during epinephrine administration were unchanged by ritodrine. Initial responses of mean arterial pressure and heart rate to epinephrine were significantly greater during prolonged ritodrine treatment. Fetal responses to epinephrine mediated through @-adrenergic receDtor mechanisms were clearlv decreased when administration of @-agonists was prolonged beyond 24 h. (Pediatr Res 28: 388-393,1990) typical of prolonged stimulation of P-adrenergic receptor mechanisms. Hyperglycemia, hyperlactacidemia, and hyperinsulinemia occur and acid-base balance is severely taxed during the 1st 48-72 h of infusion. Further, Warburton et al. (7) have observed that the hyperglycemia is associated with substantial depletion of hepatic glycogen reserves after 24 h administration. Also, both we (6) and Warburton et al. (8) have shown that administration of ritodrine for 24 h or longer results in the development of marked hypoxemia at least as severe as that seen in fetal lambs during prolonged hyperglycemia and/or hyperinsulinemia (9, 10). After administration of the drug for more than 48 h, these changes moderate (6). It appears that it is only the development of tachyphylaxis to the drug that permits the restoration of homeostasis during more prolonged administration. Indeed, Warburton et al. (1 1, 12) have shown that there is already a very marked reduction in the P-adrenergic receptor population of fetal lung tissue after 24 h of ritodrine administration. More widespread changes in sensitivity of P-adrenergic receptor mechanisms have not been investigated.Although this reduction in sensitivity may permit fetal survival in the face of prolonged ritodrine treatment, we questioned whether it might have other less desira...

The immunotoxicity of TCDD in the mouse has been well documented. To date, the most sensitive endpoint to TCDD-induced toxicity in mice is that reported by Clark et al. (Clark, D. A., Gauldie, J., Szewczuk M. R. and Sweeney, G. (1981) Proc. Soc. Exper. Biol. Med. 168, 290.) who found that TCDD suppressed the murine cytotoxic T lymphocyte (CTL) response following four weekly doses of 4 ng TCDD/kg/week. However, these results have never been corroborated, as other laboratories have been unable to detect immunosuppression by TCDD at such low levels. In this study, we evaluated the effect of TCDD on the in vivo- and in vitro-generated CTL response to P815 mastocytoma cells in adult C57BL/6J female mice via a 51Cr release assay. Mice were given weekly intraperitoneal injections of TCDD or vehicle for 4 weeks at dosages ranging from 0.01 to 3.00 micrograms/kg/week. No statistically significant suppression of the in vivo- or in vitro-generated CTL response was detected at any dosage. As expected, significant increases in liver weights and decreases in thymus weights were observed at TCDD dosages of 1.0 and 3.0 micrograms/kg/week. Likewise, suppression of the antibody plaque-forming cell response to sheep erythrocytes was observed at dosages of 1.0 and 3.0 micrograms TCDD/kg/week. Although expected humoral immunosuppression and organ effects were observed, our data do not support suppression of murine CTL responses at the TCDD doses employed in this study.