Acute episodes of severe hypoxia are among the most common stressors in neonates. An understanding of the development of the physiological response to acute hypoxia will help improve clinical interventions. The present study measured ACTH and corticosterone responses to acute, severe hypoxia (8% inspired O(2) for 4 h) in neonatal rats at postnatal days (PD) 2, 5, and 8. Expression of specific hypothalamic, anterior pituitary, and adrenocortical mRNAs was assessed by real-time PCR, and expression of specific proteins in isolated adrenal mitochondria from adrenal zona fascisulata/reticularis was assessed by immunoblot analyses. Oxygen saturation, heart rate, and body temperature were also measured. Exposure to 8% O(2) for as little as 1 h elicited an increase in plasma corticosterone in all age groups studied, with PD2 pups showing the greatest response ( approximately 3 times greater than PD8 pups). Interestingly, the ACTH response to hypoxia was absent in PD2 pups, while plasma ACTH nearly tripled in PD8 pups. Analysis of adrenal mRNA expression revealed a hypoxia-induced increase in Ldlr mRNA at PD2, while both Ldlr and Star mRNA were increased at PD8. Acute hypoxia decreased arterial O(2) saturation (SPo(2)) to approximately 80% and also decreased body temperature by 5-6 degrees C. The hypoxic thermal response may contribute to the ACTH and corticosterone response to decreases in oxygen. The present data describe a developmentally regulated, differential corticosterone response to acute hypoxia, shifting from ACTH independence in early life (PD2) to ACTH dependence less than 1 wk later (PD8).

The purpose of the present study was to evaluate the effect of exposure to hypoxia from birth to 7 days of age on leptin, insulin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), glucose, corticosterone, body weight, and body composition in rats studied at 7 days of age and then after return to normoxia. Hypoxia for the first 7 days of life resulted in a significant decrease in plasma leptin, body weight, and an increase in corticosterone and insulin with no change in plasma glucose, GH or IGF-1. There was no significant effect of hypoxia on % lean body mass, but a small but significant increase in % body fat. Bone mineral density (BMD) was lower in 7-day-old hypoxic rats as compared to normoxic controls. All hormonal variables and BMD had normalized by 7 days after return to normoxia. However, body weight remained lower even 5 weeks after return to normoxia. We conclude that leptin is decreased during neonatal hypoxia despite no change in adiposity. Furthermore, insulin is increased probably to overcome the effects of increased counterregulatory hormones (such as corticosterone).

Hypoxia leads to a decrease in food intake and attenuated weight gain in rats. The purpose of this study was to measure plasma leptin and insulin in young rats exposed to hypoxia for 7 d as compared to a normoxic control group of the same age. One group was exposed from birth to 7 d of age; the other was exposed from 28 to 35 d of age (weaned at 21 d of age). As expected, body weight was significantly lower in rats of either age exposed to hypoxia for 7 d. Plasma leptin was significantly lower in hypoxic (2.0+/-0.2 ng/mL; n = 41) compared with normoxic (2.6+/-0.3 ng/mL; n = 30) 7-d-old rats. Plasma leptin was also significantly lower in hypoxic (1.1+/-0.1 ng/mL; n = 20) as compared to normoxic (1.5+/-0.1 ng/mL; n = 20) 35-d-old rats. Seven-day-old rats exposed to hypoxia demonstrated significant increases in plasma glucose and insulin whereas 35-d-old rats exhibited a decrease in both variables. We conclude that exposure to hypoxia for 7 d leads to a decrease in body weight and plasma leptin in infant and juvenile rats. The decrease in leptin may be an attempt to reverse hypoxia-induced anorexia.

Chintamaneni K, Bruder ED, Raff H. Effects of age on ACTH, corticosterone, glucose, insulin, and mRNA levels during intermittent hypoxia in the neonatal rat. Am J Physiol Regul Integr Comp Physiol 304: R782-R789, 2013. First published March 13, 2013 doi:10.1152/ajpregu.00073.2013.-Apnea, the temporary cessation of respiratory airflow, is a common cause of intermittent hypoxia (IH) in premature infants. We hypothesized that IH elicits a stress response and alters glucose homeostasis in the neonatal rat. Rat pups were studied on postnatal day (PD) 2, 8, 10, 12, and 14. Pups were exposed to normoxia (control) or six cycles consisting of 30-s exposures to hypoxia (FIO 2 ϭ 3%) over a 60-min period. Blood samples were obtained at baseline, after the third cycle (ϳ30 min), and after the sixth cycle (ϳ60 min). Tissue samples were collected following the sixth cycle. Plasma ACTH, corticosterone, glucose, and insulin were analyzed at all ages. Hypothalamic, pituitary, and adrenal mRNA expression was evaluated by quantitative PCR in PD2, PD8, and PD12 pups. Exposure to IH elicited significant increases in plasma ACTH and corticosterone at all ages studied. The largest increase in corticosterone occurred in PD2 pups, despite only a very small increase in plasma ACTH. This ACTH-independent increase in corticosterone in PD2 pups was associated with increases in adrenal Ldlr and Star mRNA expression. Additionally, IH caused hyperglycemia and hyperinsulinemia at all ages. We conclude that IH elicits a significant pituitary-adrenal response and significantly alters glucose homeostasis. Furthermore, the quantitative and qualitative characteristics of these responses depend on developmental age.hypothalamic-pituitary-adrenal axis; newborn; anoxia; apnea; adrenal cortex APNEA, the cessation of respiratory airflow, causes hypoxemia and bradycardia in the neonate (27). Apnea is the most common cause of hypoxia in neonates, particularly with prematurity, and is usually due to immature respiratory control systems (20). Incomplete respiratory maturation may involve deficits in neural respiratory control, central and peripheral chemoreceptors, or coordination of the upper airway muscles (20). It has previously been shown that about half of babies born prematurely (30 -31 wk of gestational age) may experience bouts of apnea (27).We have shown that acute, continuous hypoxia in the neonatal rat, a model of cardiopulmonary disease of prematurity, is a metabolic challenge that elicits a stress response from the hypothalamic-pituitary-adrenal (HPA) axis (3). This experimental model also results in bradycardia, alterations in glucose homeostasis, and a dramatic decrease in body temperature (3, 4, 11).The current study used intermittent hypoxia (IH) as an established model of apnea-induced hypoxia (21). IH mimics spontaneous, short duration episodes of hypoxia that occur during apnea in the neonate. A widely used definition of apnea specifies a 15-to 20-s cessation of breathing, a decrease in oxygen saturation to Ͻ80%, and a refractory period ...

The corticosterone response to acute hypoxia in neonatal rats develops in the 1st wk of life, with a shift from ACTH independence to ACTH dependence. Acute hypoxia also leads to hypothermia, which may be protective. There is little information about the endocrine effects of body temperature maintenance during periods of neonatal hypoxia. We hypothesized that prevention of hypothermia during neonatal hypoxia would augment the adrenocortical stress response. Rat pups separated from their dams were studied at postnatal days 2 and 8 (PD2 and PD8). In one group of pups, body temperature was allowed to spontaneously decrease during a 30-min prehypoxia period. Pups were then exposed to 8% O(2) for 3 h and allowed to become spontaneously hypothermic or externally warmed (via servo-controlled heat) to maintain isothermia. In another group, external warming was used to maintain isothermia during the prehypoxia period, and then hypoxia with or without isothermia was applied. Plasma ACTH and corticosterone and mRNA expression of genes for upstream proteins involved in the steroidogenic pathway were measured. Maintenance of isothermia during the prehypoxia period increased baseline plasma ACTH at both ages. Hypothermic hypoxia caused an increase in plasma corticosterone; this response was augmented by isothermia at PD2, when the response was ACTH-independent, and at PD8, when the response was ACTH-dependent. In PD8 rats, isothermia also augmented the plasma ACTH response to hypoxia. We conclude that maintenance of isothermia augments the adrenocortical response to acute hypoxia in the neonate. Prevention of hypothermia may increase the stress response during neonatal hypoxia, becoming more pronounced with increased age.