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Programming of Hypertonicity in Neonatal Lambs: Resetting of the Threshold for Vasopressin Secretion

Perinatal Research Laboratories, Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California Los Angeles, Harbor/UCLA Medical Center, Torrance, California 90502

Address all correspondence and requests for reprints to: Mina Desai, Ph.D., Harbor/UCLA Medical Center, 1124 West Carson Street, RB-1 Building, Torrance, California 90502. E-mail: mdesai{at}obgyn.humc.edu.

	Abstract

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Lambs exposed in utero to maternal hypertonicity demonstrate plasma hypertonicity and arterial hypertension. To determine whether hypertonicity is due to an altered osmoregulatory set point, we examined arginine-vasopressin and cardiovascular responses to hypertonic saline infusion in these offspring. Study lambs [dehydrated (Dehy)] were exposed to maternal hypernatremia (8–10 mEq/liter increase; 110–150 d gestation) induced by water restriction. Control singleton and Control twins were born to ewes provided ad libitum water. We anticipated reduced birth weight due to maternal dehydration-induced anorexia and therefore included a Control group of twin gestations to approach a similar birth weight near term. After delivery, ewes from all three groups were provided ad libitum water, and their newborns were allowed ad libitum nursing. At 15 ± 2 d of age, lambs were prepared with bladder and vascular catheters. At 23 ± 2 d, after a 2-h basal period, neonatal lambs were iv infused with hypertonic 0.83 M NaCl (0.075 ml/kg·h) for 2 h, followed by a 2-h recovery. Neonatal mean arterial pressure and urine flow were continuously monitored, and blood samples were obtained before, during, and after infusion. During the basal period, Dehy neonates and Control twins demonstrated significantly increased plasma sodium levels and mean arterial pressure than Control singletons. In addition, the Dehy neonates had significantly increased plasma osmolality compared with Control singletons and twins. In response to hypertonic infusion, the Dehy offspring continued to exhibit hypertonicity and hypertension. Importantly, plasma tonicity and blood pressure were greatest in Dehy singletons, lowest in singleton controls, and intermediate in twin controls. Furthermore, the plasma osmolality threshold for AVP secretion was significantly higher in Dehy singletons (290 ± 2 mOsm/kg) than Control twins (285 ± 1 mOsm/kg) and Control singletons (280 ± 2 mOsm/kg), indicating in utero programming of an altered set point for systemic osmolality and blood pressure regulation. Because both twin gestation and dehydration-anorexia incur potential fetal nutritional stress, the results suggest that both in utero hypertonicity and nutrition reduction contribute to offspring programming. We postulate that the nutritional stress associated with twins (as well as dehydration-induced anorexia) contributes to increased plasma sodium levels, whereas the increased plasma osmolality is due to in utero hypertonicity.

	Introduction

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THE NEAR TERM ovine and likely human fetuses demonstrate intact arginine-vasopressin (AVP) secretory and dipsogenic responses after systemic and/or central hypertonicity. The neuropathways for the sensing of hypertonicity, as evidenced by select nuclei cFOS expression, fetal endocrine, and ingestive responses develop during the last third of gestation (1, 2, 3, 4). Despite the functionality of these responses, fetal sensitivity to increases in plasma tonicity is markedly reduced compared with the adult (4). Thus, the development of fetal osmoregulatory responses must undergo changes near term and perhaps post delivery. In utero, intact AVP secretory and dipsogenic responses may result in urinary antidiuresis and increased swallowing, respectively, to preserve fetal body water in response to maternal hypertonicity, potentially induced by maternal dehydration or exercise (5, 6, 7). Perhaps more importantly, exposure of the fetus to plasma hypertonicity may alter the developmental processes of osmoreceptor sensitivity and thus imprint/program offspring fluid homeostasis (8, 9). Programming is a process whereby a stimulus or insult, at a critical or sensitive period of development, has lasting or lifelong consequences (10).

We have recently studied the effects of prolonged maternal hypertonicity on AVP gene expression and pituitary content in newborn sheep. Newborn lambs that have been subjected to in utero hypertonicity for the last 20% of gestation had increased plasma sodium and total pituitary content, but lower hypothalamic AVP mRNA levels than Control newborns (11). At 2 months of age, prenatally dehydrated (Dehy) lambs continue to demonstrate higher plasma sodium levels, although hypothalamic AVP mRNA levels and pituitary AVP content were similar to those of Control lambs (12, 13). An increased plasma sodium level in the presence of normal plasma AVP level suggests an alteration essentially of sodium/osmo receptor set points and/or renal AVP responsiveness. Thus, prolonged prenatal exposure to plasma hypertonicity may imprint the hypothalamic pituitary AVP regulatory system, a phenotype significantly different from maternal nutrient restriction.

In the present study, we sought to determine the effects of prolonged in utero plasma hypertonicity on offspring plasma osmolality thresholds for AVP secretion. The results suggest an imprinting of AVP/osmoregulatory mechanisms with potentially critical consequences for body composition homeostasis in adult life.

	Materials and Methods

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Animals and surgery
Time-dated pregnant, Western, mixed-breed sheep were obtained from a local source (Nebeker Ranch, Palmdale, CA). Study animals were housed indoors in individual steel study cages and acclimated to a 12-h light, 12-h dark cycle. Food (alfalfa pellets) was provided ad libitum, and water was provided as described below. The care and use of the animals were approved by the Animal Research Committee of Harbor/UCLA Medical Center and in accordance with the American Association for Accreditation of Laboratory Animal Care and National Institutes of Health guidelines.

Prenatal dehydration
The animal model for the preparation of chronic prenatal dehydration has been previously described (10). Briefly, at 105 ± 1 d gestation (term = 150 d), ewes (n = 6) with singleton pregnancy were surgically prepared with femoral vein catheters. Maternal blood samples were drawn daily to monitor plasma tonicity and electrolytes. After establishing the baseline plasma osmolality, water was removed from the ewes for 8 h followed by water-restriction of approximately 1 liter daily throughout the remainder of pregnancy. The water intake was titrated to achieve an 8- to 10-mEq increase in plasma sodium concentration from 110 d gestation until spontaneous delivery at term. A matched group of prenatal euhydrated newborns were born to ewes carrying either singleton (Control singleton; n = 6) or twin (Control twin; n = 6) gestations provided ad libitum water and food throughout gestation. (We anticipated reduced birth weight due to maternal dehydration-induced anorexia and therefore elected to use a Control group of twin gestations, to approach a similar birth weight near term). Control ewes were not prepared with vascular catheters and were allowed ad libitum food and water intakes throughout the pregnancy. In both Study and Control groups, ewes were allowed to deliver naturally. Immediately after delivery, ewes were provided ad libitum water and food, and newborns allowed ad libitum nursing.

Experimental protocol
At 15 ± 2 d of age, prenatally Dehy and Control lambs (both, singleton and twin) were surgically prepared with femoral arterial and venous catheters. All experiments were performed on conscious lambs maintained in a specially designed support sling. At 23 ± 2 d, a 2-h basal period (-2 to 0 h) was followed by a 4-h experimental period (0–4 h). During the subsequent 2-h basal period, arterial blood pressure and urine volume were continuously monitored. Lamb arterial blood samples (4 ml) were obtained at 30 min periods for determination of arterial pH, blood gases, plasma osmolality, electrolytes and hematocrit. Following the basal period, lambs received an iv infusion of hypertonic NaCl (0.83 M NaCl, 0.075 ml/kg·h) for 2 h and were subsequently monitored for an additional 2 h following infusion. Arterial blood pressure was continuously monitored and arterial blood samples obtained at timed intervals during and following the infusion. Before this study, neonatal responses to an intravenous infusion of hypotonic saline were examined (results reported separately). All lambs were allowed 48 h recovery before the present study.

Analytical methods
Throughout the measurement periods, neonatal arterial blood pressure was monitored continuously by means of a Beckman R-612 recorder (Beckman Instruments, Fullerton, CA) and Statham P23 pressure transducers (Garret Inc., Oxnard, CA). All signals were digitized at 50 Hz and acquired on an IBM-compatible computer. Heart rate and systolic, diastolic, and mean arterial pressures (MAPs) were calculated from the pressure tracings.

Plasma electrolyte levels were determined with a Nova 5 electrolyte analyzer (Nova Biomedical, Waltham, MA). Osmolality was measured by freezing point depression on an Advanced Digimatic Osmometer (Model MO, Advanced Instruments, Needham Heights, MA). Blood pH, arterial CO₂ tension (pCO₂), and arterial oxygen tension (pO₂) values were measured at 39 C with a Radiometer BM 33 MK2-PHM 72 MKS acid-base analyzer system (Radiometer, Copenhagen, Denmark). Plasma AVP were extracted and measured by RIA (14, 15).

Statistics
All values are expressed as mean ± SEM. Basal values represent the mean of measurements obtained during the basal period from -2 to 0 h, with SEM representing the variance between animals. Differences over time were assessed with repeated measures ANOVA with Dunnett’s post hoc test. To determine the osmolality thresholds for AVP secretion, plasma AVP concentrations were regressed against plasma osmolality. Linear regression equations were calculated for all data sets of the two groups and solved for the threshold value using the zero intercept. Statistical significance was accepted at P 0.05.

	Results

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Maternal dehydration
In response to water deprivation for 2 d, maternal plasma osmolality increased significantly from 313 ± 2 to 325 ± 3 mOsm/kg (P < 0.01), in accordance with significant increases in plasma sodium (149 ± 1 to 155 ± 1 mEq/liter; P < 0.001) and chloride (114 ± 1 to 117 ± 1 mEq/liter; P < 0.01) concentrations. With water intake restriction adjusted to approximately 1 liter/d, plasma osmolality and sodium levels of the ewes were maintained at significantly elevated levels throughout the remaining gestation. There were no significant changes in maternal plasma potassium (4.4 ± 0.3 to 4.9 ± 0.1 mEq/liter) or hematocrit (31.6 ± 1.7 to 37.3 ± 2.8%) in response to water restriction.

Neonatal studies
At birth, Control singletons had higher body weights compared with Control twin (P < 0.001) and Dehy singletons (P < 0.05), with no differences evident among Dehy singletons and Control twins. At 23 d of age, Control singletons maintained their higher body weights compared with Control twins (P < 0.001) but showed no differences from Dehy lambs. Furthermore, Dehy lambs now weighed significantly more than Control twin lambs (P < 0.001) (Table 1).

View larger version (36K): [in this window] [in a new window]   FIG. 1. Plasma osmolality and sodium levels, hematocrit, and hemoglobin in Control singleton (black circles), Control twins (gray circles), and Dehy (triangles) neonates during hypernatremia. 0 h represents basal period before infusion, followed by iv infusion of hypertonic NaCl (0.83 M NaCl, 0.075 ml/kg·h) over a 2-h period and subsequent recovery period over the next 2 h. Values are mean ± SE of n = 6 at each time point. Significant effect of hypertonic infusion on plasma osmolality, sodium levels, hematocrit, and hemoglobin. Significantly different between the groups; s, Control singleton; t, Control twin.

View larger version (30K): [in this window] [in a new window]   FIG. 2. Systolic, diastolic, and mean arterial blood pressures in Control singleton (black circles), Control twins (gray circles), and Dehy (triangles) neonates during hypernatremia. 0 h represents basal period before infusion, followed by iv infusion of hypertonic NaCl (0.83 M NaCl, 0.075 ml/kg·h) over a 2-h period and subsequent recovery period over the next 2 h. Values are mean ± SE of n = 6 at each time point. No effect of hypertonic infusion. Significantly different between the groups; s, Control singleton; t, Control twin.

The arterial blood pressures from the three groups followed a trend similar to the plasma tonicity, with the Dehy offspring maintaining elevated systolic, diastolic, and MAP, the Control twin exhibiting intermediary arterial pressure values, and the Control singleton showing the lowest values (Fig. 2).

The linear regression of plasma AVP vs. plasma osmolality demonstrated a significantly higher threshold for AVP secretion in Dehy compared with Control twin and Control singleton neonates (290 ± 2 vs. 285 ± 1 and 280 ± 2 mOsm/kg; P < 0.001). The slopes of these regression lines (which represent the sensitivity of the hormonal response to an osmotic stimulus) suggested that the increment in AVP levels per unit of osmotic stimulus was unaltered (Fig. 3). Furthermore, when the thresholds for AVP secretion were determined separately for each lamb and then analyzed as a group, they still showed significant differences between the groups (Dehy, 292.0 ± 3.7 mOsm/kg; Control twin, 286.2 ± 3.0 mOsm/kg; and Control singletons, 279.9 ± 3.4 mOsm/kg; P < 0.01).

View larger version (21K): [in this window] [in a new window]   FIG. 3. Linear regression relation between plasma osmolality and plasma AVP levels in Control singleton (black circles), Control twins (gray circles), and Dehy (triangles) neonates. Linear regression equations were calculated for all data sets of the three groups and solved for the threshold value using the zero intercept. The threshold for AVP secretion: Dehy [PAVP = 0.27 (POsm, -290) r = 0.79; P < 0.001], Control twins [PAVP = 0.23 (POsm, -285), r = 0.73; P < 0.001), and Control singleton [PAVP = 0.13 (POsm, -280) r = 0.80; P < 0.001]. No significant difference in slope.

	Discussion

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In the present study, maternal plasma osmolality was increased by approximately 20 mOsm and maintained by titrated water restriction. Perhaps as a result of maternal dehydration-induced anorexia, the birth weight of Dehy singletons was less than that normally occurring with singleton term newborns. In anticipation, we elected to use a Control group of twin gestations, to approach a similar birth weight near term. Despite identical newborn treatment, the Dehy singletons had similar body weights as those of Control singletons and weighed significantly more than the Control twin lambs at 23 d of age. An increased weight gain in Dehy offspring, evidencing catch-up growth to Control singletons, is likely a result of increased food intake. Recent studies in rats and sheep suggest that hypothalamic control of appetite is subject to programming during fetal life, with reduced maternal food intake during pregnancy resulting in up-regulation of appetite in the offspring. For example, rats whose dams were 50% food restricted during the first 2 wk of pregnancy and returned to ad libitum feeding until 24 d of age had increased food intake as adults (16). Similarly, offspring of mothers whose food intake was restricted to 30% of Control rats were hyperphagic as adults (17). Ovine fetuses of pregnant ewes that were 50% food restricted during the last quarter of gestation had increased hypothalamic neuropeptide Y mRNA levels (18), consistent with the programming of orexic mechanisms in utero. Although we did not specifically examine relative orexic mechanisms in the Dehy and Control offspring, we speculate that maternal dehydration-induced anorexia resulted in a similar augmentation of offspring appetite with hyperphagia-induced growth discrepancy demonstrated by 23 d of age.

At the time of the study, there were significant basal differences between offspring of Dehy, Control twin, and Control singleton. Most importantly, Dehy offspring demonstrated hypertonicity, hypernatremia, and hypertension compared with Control singletons. These offspring had been previously studied 48 h earlier for their responses to a hypotonic iv infusion (19). During the basal period of the prior study, Dehy lambs also demonstrated increased plasma osmolality, sodium concentration, and arterial blood pressures.

In response to the infusion of 0.83 M saline, both Dehy and Control offspring demonstrated significant increases in plasma osmolality and sodium and AVP concentrations. This is likely a result of AVP-induced antidiuresis. All neonatal groups demonstrated decreases in hematocrit and hemoglobin, reflecting increased plasma volume in response to hypertonicity.

More importantly, there were marked differences between Dehy, Control singleton, and Control twin responses to the hypertonic infusion. The plasma tonicity and blood pressure were greatest in Dehy singletons, lowest in singleton controls, and intermediate in twin controls. Because both twin gestation and dehydration-anorexia incur potential fetal nutritional stress, the results suggest that both in utero hypertonicity and nutrition reduction contribute to offspring programming.

The higher hematocrit suggests less intravascular volume expansion occurring in Dehy offspring, despite relatively increased plasma osmolality and electrolyte levels. Thus, the increased offspring blood pressure in Dehy lambs is unlikely associated with augmented intravascular volume, because the hematocrit and hemoglobin changes suggest reduced rather than increased volume. Although the mechanism of hypertension is unclear, the present results indicate that hypertonic saline infusion unmasks basal hypertensive trends with significant hypertension.

Plasma osmolality thresholds for AVP secretion were determined by the zero intercept of the regression of plasma AVP and plasma osmolality. Dehy offspring demonstrated a significantly increased plasma osmolality threshold for AVP secretion, indicating a reset level of osmolality after in utero dehydration. The 10- and 5-mOsm/kg difference in plasma osmolality set points, compared with Control singletons and twins, respectively, is of physiological significance. Notably, plasma osmolality is generally maintained within relatively tight constraints (1–2%) by AVP-induced antidiuresis and dipsogenic responses. The nearly 2% alteration in thresholds in the present study is of potential clinical relevance, because these offspring may be more susceptible to hypertonicity-induced physiological effects (20) after exercise or water restriction. Furthermore, should these plasma tonicity changes persist through adulthood, female offspring may maintain pregnancies under basal conditions of relative plasma hypertonicity. Thus, generational effects of in utero hypertonicity may occur.

The results of the present study suggest that exposure to altered osmotic environments during the last third of ovine gestation may impact on the function and set point of osmoregulatory/AVP pathways among offspring, and potentially adults. Recent human studies as well as experimental rat studies provide increasing evidence of programming on subsequent adult regulatory mechanisms (10, 21, 22). Changes in osmoregulation have been well demonstrated in fetal and neonatal rats. For example, chronic tonicity alterations in utero alter AVP synthesis and secretion in neonatal rats (23). Perinatal sodium depletion of rats alters offspring plasma and urinary sodium concentration and hematocrit. As adults, these offspring demonstrated elevated fluid turnover and high sodium intake (24, 25). Similarly, extracellular dehydration in rats during pregnancy increased the salt appetite and blood pressure in the offspring (26, 27). Renal responsiveness to AVP also may be programmed as neonatal rat exposure to AVP results in a permanent decrease in renal AVP responsiveness due to a reduction in AVP binding sites in the adult kidney (23, 28). Studies in young rats suggest that induction of hyponatremia may have long-term effects on AVP transcription and translation in the maturing rat (29). Similarly, our studies in prenatally Dehy lambs demonstrate alteration in basal plasma tonicity as well as hypothalamic AVP mRNA and pituitary AVP content (10, 11, 12).

In summary, the present results demonstrate that prenatally Dehy lambs have an increased basal plasma osmolality and sodium levels, resulting in whole or part from programming of the plasma osmolality threshold for AVP secretion. Thus, offspring of water-restricted ewes may demonstrate a programmed syndrome of hypertonicity, hypernatremia, and hypertension with clinically significant hematological and cardiovascular alterations. If persistent through adulthood, these abnormalities may have adverse clinical effects and potentially impact the offspring physiological adaptation to their own subsequent pregnancy. We speculate that nutrition stress associated with twins (as well as dehydration induced anorexia) contributes to the increased plasma sodium levels, whereas the increased plasma osmolality is due to in utero hypertonicity.

	Acknowledgments

 
We acknowledge Linda Day and Glenda Calvario for technical assistance.

	Footnotes

 
This work was supported by the NIH (Grants R01 HL 40899 and R01 40899-S) and by the March of Dimes Birth Defects Foundation.

Abbreviations: AVP, Arginine-vasopressin; Dehy, dehydrated; MAP, mean arterial pressure.

Received February 12, 2003.

Accepted for publication July 1, 2003.

	References

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