Imprint Osmoregulation/Maternally-Dehydrated Offspring

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DESCRIPTION (provided by candidate): Pregnancy evokes marked physiologic adaptations in the composition and volume of fluid compartments. During human and rat pregnancy, maternal blood volume increases and plasma osmolality decreases. Failure to adequately "reset" maternal plasma osmolality or exposure to maternal plasma hypertonicity, as a result of hyperemesis, exercise or dehydration, results in increased fetal plasma osmolality, which stimulates fetal arginine vasopressin (AVP) secretion, causing reduced amniotic fluid (AF) volume. Conversely, induced maternal plasma hypotonicity reduces fetal plasma osmolality, increases fetal urine flow, reduces fetal swallowing and increases AF volume in sheep and humans. More importantly, chronic in utero plasma tonicity alterations imprint newborn rat and human osmoregulation and renal responses including AVP synthesis and secretion, and possibly blood pressure. The imprinting of osmoregulation may increase the susceptibility of the newborn and/or adult to water/electrolyte imbalance, hypertension and coronary heart disease. It is also possible that the imprinted osmoregulation may have intergenerational effects such that the female offspring may not appropriately reset their plasma osmolality and adequately expand their plasma volume during their subsequent pregnancies. Our preliminary studies of rats indicate that maternal dehydration during pregnancy results in hypernatremia and hypertonicity in the newborn. We hypothesize that maternal dehydration alters basal plasma tonicity in newborn and adult offspring, as a result of: (1) an elevated osmoregulatory set-point of the central osmoreceptor nuclei, and altered cellular volume regulation or (2) reduced basal AVP mRNA and synthesis, and AVP secretion in response to osmotic stimuli, and/or (3) reduced AVP-induced renal antidiuresis. We propose to examine central and peripheral mechanisms for the imprinting of the AVP-osmoregulatory system. We will determine the molecular and cellular mechanism(s) and peripheral renal AVP receptor changes. Finally, we will delineate the critical period during which imprinting of the AVP/osmoregulatory pathway occurs.