Nathash Kallichanda

Prolonged prenatal hypernatremia alters neuroendocrine and electrolyte homeostasis in neonatal sheep

Arginine vasopressin (AVP) is a neuroendocrine hormone synthesized in the hypothalamus, and is stored and secreted by the posterior pituitary gland in response to stimuli such as plasma hypertonicity and hypotension. The primary physiologic roles of AVP include plasma osmolality and blood pressure regulation. We have previously demonstrated that chronic prenatal plasma hypertonicity alters the AVP regulatory pathway in newborn lambs. The objectives of the present study were to evaluate prolonged effects of antenatal plasma hypertonicity on neonatal plasma osmoregulation. Pregnant ewes at 119 ± 3 days of gestation were water restricted to achieve and maintain hypertonicity until normal-term delivery. After delivery, ewes were provided food and water ad libitum and lambs were allowed maternal nursing. At the age of 28 days, blood samples were obtained for the analysis of plasma osmolality, electrolytes, and AVP levels from study (n = 5) and age-matched control (n = 6) lambs. Subsequently, lambs were euthanized, and the pituitary and hypothalamus were processed for the determination of pituitary AVP content by radioimmunoassay, and AVP gene expression by Northern analysis. In response to water restriction, maternal plasma osmolality significantly increased (306 ± 1.1 to 326 ±1.2 mOsm/kg, P < 0.001). At the age of 28 days, plasma sodium level was higher in study (prenatally dehydrated) than control lambs (144.6 ± 0.4 vs 142.6 ± 0.3, P < 0.05). Study lambs had higher plasma AVP concentrations than the control lambs (4.1 ± 0.4 vs 1.7 ± 0.4 pg/ml, P < 0.05). Similarly, total pituitary AVP content was higher in the in utero hypertonic lambs than in the control lambs (6.5 ± 1.0 vs 2.8 ± 1.2 μg, P < 0.05). However, there was no difference in hypothalamic AVP mRNA levels between the two groups. The present study demonstrates that chronic maternal and fetal plasma hypertonicity has prolonged effects on pituitary and plasma AVP, as well as plasma sodium in neonatal lambs, providing further evidence suggesting prenatal imprinting of osmoregulation through at least 1 month of age.

Gender Specificity of Programmed Plasma Hypertonicity and Hemoconcentration in Adult Offspring of Water-Restricted Rat Dams

Objective: We studied the impact of maternal water-restriction during rat pregnancy on newborn plasma composition, and determined the persistence of plasma composition alterations in adult offspring. Methods: Maternal dams were water-restricted from 10 days of pregnancy until term (21 days) and throughout lactation to increase plasma sodium levels by ∼6 mEq/L. At 21 days of age, offspring were weaned, and subsequently maintained on ad libitum food and water until 12 weeks of age. Daily water and food intake was monitored. Blood samples and organs were collected from 1-day- and 12-week-old offspring. Hematocrit, plasma osmolality, sodium, and arginine vasopressin (AVP) levels were analyzed. Because water-restriction led to concomitant reduction in mternal food intake (ie, dehydration anorexia), henceforth these dams and their offspring are referred to as “water-deprived/food-reduced” rats. Results: Water-deprived/food-reduced dams had significantly increased plasma sodium levels, reduced food intake, and lower body weight gain during pregnancy and lactation as compared to control dams. One-day-old newborns of water-deprived/food-reduced dams weighed 17% less and had increased plasma sodium levels, osmolality, and hematocrit. At 12 weeks of age, males exhibited 11% and females 19% reduction in body weight from controls. Notably, male offspring of water-deprived/food-reduced dams showed significantly elevated plasma sodium levels, osmolality, and hematocrit. Additionally, males demonstrated reduced adrenal growth and decreased water intake. Conversely, the female offspring had similar plasma osmolality with decreased sodium levels, though a persistently elevated hematocrit. No differences were evident in plasma AVP levels. Conclusions: Maternal water deprivation/food reduction is associated with increased newborn plasma osmolality and sodium levels and long-term physiologic changes in the offspring. The gender-specificity of programmed hypersmolality, though not hemoconcentration, implicates differing pathways/mechanisms for these phenotypic alterations. The contributions of pregnancy hypertonicity versus nutrient restriction in the mechanism for programmed offspring phenotype remain to be elucidated.