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After the infusion of a bolus of 225 mEq NaCl (HS) to maternal ewes, we studied fetal plasma sodium, osmolality, total serum solids, plasma arginine vasopressin (AVP) and plasma renin activity (PRA) responses in 16 chronically catheterized, 112–139 days of gestation fetal lambs.To examine the degree to which this might have represented transplacental passage of AVP, we infused a large amount of synthetic AVP into the fetal circulation (protocol 3) and detected no change in maternal plasma AVP. The protocol was designed to allow multiple, frequent blood sampling not possible by infusing the synthetic AVP into the maternal circulation.In order to compare the fetal AVP response elicited by HS in the maternal ewe and that after direct HS into the newborn lamb and fetus, we calculated stimulus response ratio (SRR) as:Log (AVP)1 - Log (AVP)2, divided by Δosmolality.The SRR of lamb fetuses after maternal HS was significantly greater (0.16 ± 0.02) than that after direct fetal HS (0.04 ± 0.01). In comparison, the newborn lamb has a SRR of 0.02 ± 0.01, and the ewe has a SRR of 0.02 ± 0.01 after HS. These data suggest that after maternal HS infusion, both a volume and, to a lesser extent, an osmolar stimulus for AVP secretion occurs after an induced water flux from the fetal to maternal compartments. Maternal plasma sodium concentration rose promptly from a base line of 146 ± 2.2 (mean ± SEM) to 157 ± 2.8 mEq/liter by 1–20 min where it remained throughout the hour observation period. Fetal plasma sodium concentration rose more slowly from base line of 143 ± 1.8 to 149 ± 1.8 mEq/liter by 1 hr. When 85 mCi22Na was additionally infused with the HS, fetal 22Na constituted only 10% of maternal 22Na counts by the end of 1 hr.During the same period fetal PRA rose from a base line of 12.9 ± 3.8 to 32.0 ± 3.6 ng/ml/hr, while maternal renin remained unchanged. Maternal AVP rose modestly, 11 min after the HS, but promptly returned to base line. There was a rapid and sustained rise by fetal AVP from a base line of 0.7 μU/ml to a peak of 8.2 μU/ml by 22 min post HS.A fetal SRR, Log (AVP)1-Log (AVP)2/Δosmolality after maternal HS was greater than that after direct fetal HS or HS to the ewe or newborn lamb. In an additional experiment, using five chronically catheterized fetuses, 10 million μU AVP injected in the fetal circulation failed to produce an increase in maternal AVP.These results demonstrate that: 1) AVP does not cross the placenta; 2) the fetal sheep neurohypophysis is autonomous and responsive to both direct and indirect (maternal) osmolar stimulation; and 3) the relatively slow rate of maternal to fetal sodium transfer, the augmented SRR after maternal HS, and the elevated fetal PRA and AVP concentration suggest that there is a rapid fetal to maternal flow of water after maternal HS and a combined volume and osmolar stimulus to the fetus.Infusions of hypertonic saline in pregnant ewes resulted in rapid increases of fetal plasma sodium due to transfer of water from fetus to mother. A marked rise in fetal renin activity and AVP was also observed. The increase in AVP exceeded that seen in the mother and that produced by infusing hypertonic saline in the fetus. Fetal secretion of AVP is stimulated by hyperosmolality and volume contraction. Elevated AVP may help the fetal kidney retain water and, thereby, minimize hypotonic urine formation and volume depletion.