Catecholamines inhibit growth in fetal sheep in the absence of hypoxemia

Abstract

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.

Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep

“…The 55% increase in fetal plasma glucose concentrations is most likely due to reduced glucose oxidation in peripheral tissues of the NE fetus, which is further supported by the chronic hyperoxemia (3,39). Previous studies in fetal sheep have found that chronic hyperglycemia for 7-10 days results in impaired ␤-cell function and decreased insulin secretion (10).…”

“…During the 7-day infusion period, the dose of NE concentration was started at 1 g/min for the first 24 h, increased to 2 g/min for days 2-4, and finally increased to 4 g/min for days 5-7, as described previously (3). Control fetuses received an infusion of saline with 0.3% ascorbic acid.…”

“…In sheep fetuses, previous experiments have demonstrated that a 7-day infusion of NE slows growth and attenuates cardiovascular and metabolite effects (3). The objective of this study was to determine whether sustained exposure to elevated NE, independent of other intrauterine growth restriction-related deficiencies, acutely enhances secretagogue-stimulated insulin secretion after the exogenous administration of NE has been terminated for Ն3 h. In addition, we associated the compensatory enhancement in insulin secretion responsiveness in NE-infused fetuses with lower expression of AR and uncoupling protein 2 (UCP2) in pancreatic islets compared with vehicle-infused controls while also demonstrating that regulatory genes for insulin secretion or ␤-cell function were unaffected (2,11,19,42).…”

Third Pathophysiology of Prenatal Cocaine Exposure

“…Redistribution of blood flow during fetal stress is secondary to increased sympathoadrenal system activity and results in exaggerated elevations in plasma catecholamine levels [32,33] . This cascade of events is important in the pathophysiology of pregnancy disorders associated with placental dysfunction [34,35] , impaired placental blood flow and is a cause of intrauterine growth restriction [36][37][38] . This also explains the adverse effects on the fetus of uptake inhibitors, such as cocaine and amphetamines, which block catecholamine transport [6,39] .…”

Maternal Psychological Distress, Prenatal Cortisol, and Fetal Weight

“…Similarly, maternal sympathoadrenal dysregulation (i.e., elevated maternal norepinephrine levels) has been associated with low birthweight (4), and norepinephrine infusions induce uterine artery contractions and decrease uterine artery blood flow in humans (19,20). Furthermore, norepinephrine administered to pregnant ewes affects uterine artery and placental blood flow and decreases fetal insulin concentrations, increases fetal insulin-like growth factor binding protein 1 (IG-FBP-1) concentrations and results in fetal growth restriction (21,22). Although studies have been conducted to assess the effects of maternal HPA and sympathoadrenal function on fetal growth in animal models and birthweight and prematurity in humans, we are not aware of any studies that have assessed the effects of prenatal cortisol and norepinephrine on human fetal weight.…”