Fetal Swallowing Activity Research Articles

Central Angiotensin I Increases Swallowing Activity and Oxytocin Release in the Near-Term Ovine Fetus

The brain renin-angiotensin system (RAS) plays an important role in hydromineral and neuroendocrine balance. Although previous studies showed that exogenous angiotensin (Ang) II increased dipsogenic and vasopressin responses in near-term fetuses, little is known about the functional development of fetal endogenous brain RAS in the regulation of body fluid homeostasis. To determine the functional development of the central angiotensin-converting enzyme (ACE) in utero, we investigated the electrocortical (ECoG) activity, swallowing activity, oxytocin (OT) release, and c-fos expression in response to intracerebroventricular Ang I administration in the near-term fetal lamb. Ang I did not change fetal low-voltage (LV) and high-voltage (HV) ECoG temporal distributions, but increased fetal swallowing activity during LV ECoG (1.0 ± 0.1 to 3.5 ± 0.4 swallows/min). Additionally, Ang I evoked an increase in c-fos-immunoreactivity in putative dipsogenic centers, including the supraoptic and paraventricular nuclei of the hypothalamus, accompanied by an increase in fetal plasma OT levels. The expression of c-fos was demonstrated in OT neurons in the hypothalamus. The Ang I-mediated increase in fetal swallowing and plasma OT was inhibited by captopril. These results demonstrate the functional development of the fetal brain ACE system in the last trimester of gestation, which plays an important role in the RAS-mediated dipsogenic response and OT release in the regulation of body fluid homeostasis.

N-Methyl-D-Aspartate Glutamate Receptor Mediates Spontaneous and Angiotensin II-Stimulated Ovine Fetal Swallowing

In adult rats, N-methyl-D-aspartate (NMDA) receptors have been implicated in the central control of body fluid homeostasis, as intracerebroventricular (ICV) injection of NMDA receptor antagonists suppresses stimulated drinking behavior. Fetal swallowing occurs at a significantly higher rate as compared to adult drinking, contributing to amniotic fluid volume regulation and fetal gastrointestinal development. The aim of present study was to determine the role of central NMDA receptors in the modulation of fetal swallowing activity. Eight time-dated pregnant ewes and fetuses were chronically prepared with fetal vascular and ICV catheters, electrocorticogram (ECoG), and esophageal electromyogram electrodes and studied at 130 +/- 1 days' gestation. Following an initial 2-hour baseline period (time 2 h), the NMDA receptor antagonist, dizocipline (1 mg), was injected ICV. At time 4 h, the dose of dizocipline was repeated, together with angiotensin II (AngII, 6.4 microg). Fetal swallowing was monitored for 2 hours after each injection. Four of these fetuses also received an identical control study (on an alternate day) in which dizocipline was replaced with artificial cerebrospinal fluid (aCSF). ICV dizocipline injection nearly abolished spontaneous fetal swallowing activities (0.6 +/- 0.1 to 0.2 +/- 0.1 swallows/min; P < .001). ICV AngII in the presence of dizocipline did not demonstrate a dipsogenic effect on fetal swallowing (0.1 +/- 0.1; P < .001). In the control study, ICV injection of aCSF did not change fetal swallowing activity (1.0 +/- 0.1 swallows/min), while ICV AngII resulted in a significant increase in fetal swallowing (2.0 +/- 0.1 swallows/min; P < .001). This study demonstrates that central NMDA-glutamate receptor-mediated activity contributes to the high rate of spontaneous and AngII-stimulated fetal swallowing. We speculate that reduced NMDA receptor expression within the forebrain dipsogenic neurons may account for observed differences in drinking activities between the fetus/neonate and the adult.

Persistent sucrose stimulation of ovine fetal ingestion: Lack of adaptation responses

Objective. Sweet taste responsiveness is reduced in adult rats and humans following continued oral sucrose. We have previously demonstrated that sublingual sucrose stimulates near term ovine fetal swallowing, suggesting intact taste responsiveness. We sought to determine if prolonged oral sucrose infusion to the near term ovine fetus will evoke adaptation, as manifested by reduced swallowing stimulation.Methods. Time-dated pregnant ewes and fetuses (n = 4) were chronically prepared with fetal vascular and sublingual catheters, and electrocorticogram and esophageal electromyogram electrodes and studied at 129 ± 1d gestation. Following an initial 2 h basal period, sucrose (2.5%) was infused sublingually (0.25 ml/min) to the fetus for 8 h. Fetal swallowing activity, blood pressure and heart rate were continuously recorded while maternal and fetal arterial blood samples were taken at timed intervals.Results. During the basal period, fetal swallowing averaged 0.9 ± 0.1 swallows/min. Fetal swallowing increased significantly following sublingual 2.5% sucrose infusion and remained significantly elevated at 2, 4, 6 and 8 h after initiation of sucrose infusion (1.3 ± 0.1, 1.2 ± 0.1, 1.3 ± 0.1, 1.3 ± 0.1 swallows/min; p < 0.001). There were no significant changes in fetal cardiovascular or arterial blood parameters.Conclusions. Although oral sucrose significantly stimulates near term ovine fetal ingestive behavior, sweet taste adaptation or habituation does not occur, in contrast to that observed in adult animals and human. The lack of taste adaptation in the fetus/newborn may facilitate increased neonatal food intake and accelerated growth.

In utero development of fetal thirst and appetite: potential for programming.

Thirst and appetite-mediated ingestive behavior develop and are likely programmed in utero, thus preparing for newborn and adult ingestive behavior. Fetal swallowing activity is markedly different from that of the adult, as spontaneous fetal swallowing occurs at a markedly (six-fold) higher rate compared with spontaneous adult drinking activity. This high rate of fetal swallowing is critical for the regulation of amniotic fluid volume and the development of the fetal gastrointestinal tract. Disordered fetal swallowing has been associated with both a decrease (oligohydramnios) and increase (polyhydramnios) in amniotic fluid volume. Both conditions are associated with a significant increase in perinatal morbidity and mortality, and limited treatment modalities are currently available. The mechanisms underlying the high rate of human fetal swallowing are regulated, in part, by tonic activity of central angiotensin II, glutamate N-methyl-D-aspartate receptors, and neuronal nitric oxide synthase. Fetal hypertonicity-mediated dipsogenesis is likely programmed in utero, as offspring of water-restricted ewes demonstrate a programmed syndrome of plasma hypertonicity, with significant hematologic and cardiovascular alterations. Similar to dipsogenic mechanisms, peripheral and central fetal orexic mechanisms also develop in utero, as demonstrated by increased fetal swallowing after both oral sucrose infusion and central injection of neuropeptide Y. The role of leptin in regulating fetal ingestive behavior is interesting because, contrary to actions in adults, leptin does not suppress fetal ingestive behavior. Teleologically, this may be of value during the newborn period, as unopposed appetite stimulatory mechanisms may facilitate rapid fetal and newborn weight gain. An adverse intrauterine environment, with altered fetal orexic factors during the critical developmental period of fetal life, may alter the normal setpoints of appetitive behavior and potentially lead to programming of adulthood hyperphagia and obesity. Further research is needed to delineate the mechanistic relationship between the intrauterine environment and the development of the setpoints of adult appetite and thirst.

Effects of central angiotensin II receptor antagonism on fetal swallowing and cardiovascular activity

Objective: Fetal plasma angiotensin II levels are 10 times the levels found in adults. Despite these high levels, central injection of angiotensin II may stimulate fetal swallowing and increase fetal arterial blood pressure. We postulated that the high rate of spontaneous fetal swallowing and normal fetal pressor regulation may be dependent, in part, on central angiotensin II. In view of the potential dipsogenic role of both type 1 and type 2 angiotensin II receptors, we examined the central effect of the nonselective angiotensin II receptor antagonist saralasin on fetal swallowing and cardiovascular responses. Study Design: Six time-dated pregnant ewes and fetuses were chronically prepared with fetal vascular and intracerebroventricular catheters, electrocorticograms, and esophageal electromyogram electrodes and studied at 130 ± 1 days' gestation. After an initial 2-hour baseline period (0 to 2 hours), saralasin (1 mL, 64 μg) was injected intracerebroventricularly (2 to 4 hours). After 4 hours the dose of saralasin was repeated together with angiotensin II (1 mL, 6.4 μg), and the fetuses were monitored for a final 2 hours. Four fetuses also underwent an identical control study (on an alternate day) in which saralasin was replaced with artificial cerebrospinal fluid. Results: Blockade of central angiotensin II receptors by intracerebroventricular saralasin significantly reduced mean (± SEM) spontaneous fetal swallowing (1.3 ± 0.1 to 0.4 ± 0.1 swallows per minute; P <.001) but did not alter fetal mean blood pressure (50 ± 5 versus 56 ± 5 mm Hg). Intracerebroventricular angiotensin II, in the presence of saralasin, did not affect swallowing (0.6 ± 0.1 swallows per minute) or fetal blood pressure. In the control study, intracerebroventricular artificial cerebrospinal fluid did not change fetal swallowing (0.9 ± 0.1 versus 1.0 ± 0.1 swallows per minute), whereas intracerebroventricular angiotensin II significantly increased swallowing activity (1.0 ± 0.1 versus 2.0 ± 0.1 swallows per minute; P <.001) and fetal blood pressure (51 ± 2 to 59 ± 3 mm Hg; P =.003). Conclusions: Tonic activity of central angiotensin II receptor stimulation contributed to the high rate of basal ovine fetal swallowing but not fetal basal blood pressure. Angiotensin II–mediated fetal dipsogenic and pressor responses are a result of specific angiotensin II receptor binding in central brain regions. These results indicate that fetal exposure to angiotensin II antagonists or angiotensin-converting enzyme inhibitors may have adverse effects on fetal and amniotic fluid homeostasis. (Am J Obstet Gynecol 2001;185: 828-33.)

Ovine fetal swallowing: expression of preterm neurobehavioral rhythms.

Fetal swallowing contributes importantly to amniotic fluid volume regulation and fetal gastrointestinal maturation. Near-term ovine fetal swallowing occurs in discrete bouts of activity (at approximately 30-min intervals) in association with fetal electrocortical voltage changes. Thus, swallowing rhythms have been hypothesized to be entrained to fetal neurobehavioral states. In the preterm ovine fetus, electrocortical activity does not demonstrate differentiation into high- and low-voltage periods until 120-130 days' gestation. We sought to quantify patterns of preterm (114 days, 0.75 gestation) ovine fetal swallowing activity and volume, and, in view of the lack of electrocortical pattern changes, to explore whether swallowing activity was regulated by an independent central pacemaker. Six singleton ovine pregnancies were chronically prepared with fetal and maternal femoral artery and vein catheters. Biparietal electrocortical electrodes were placed on the fetal skull. Following a minimum 5-day recovery period, fetuses were studied at 114 +/- 1 days. Patterns of fetal swallowing behavior were quantified by computer analysis of laryngeal-esophageal electromyography (EMG) and thoracic esophageal fluid flow during a 12-h period. Esophageal fluid flow was bidirectional, although antegrade flow predominated, leading to an average fluid acquisition rate of 13 +/- 3 ml/h (7.3 +/- 1.8 ml/h per kg) during the 12-h study (302 +/- 87 ml/day). Propagated esophageal EMG activity, representing coordinated 'swallows', averaged 56 +/- 6 swallows/h and correlated well with net esophageal fluid flow. 'Bouts' of swallowing activity (> or = 3 swallows/min) averaged 9 +/- 1 swallows/bout, lasted 1.8 +/- 1.4 min and accounted for 31 +/- 4% of the swallowed volume. Despite the absence of fetal electrocortical high-voltage/low-voltage transitions, there was a 26.1 +/- 3.9-min interval between periods of swallowing bout activity. Preterm (0.75 gestation) ovine fetal volume swallowed (302 ml/day) and volume swallowed for body weight (175 ml/day per kg) was significantly less than that previously noted at 0.85 gestation (831 ml/day, 274 ml/day per kg, respectively; p < 0.05) although the rates of swallowing activity were similar. The presence of swallowing bout activity at periodic intervals, in the absence of electrocortical differentiation, suggests an intrinsic central pacemaker regulating preterm fetal neurobehavior.

Central angiotensin induction of fetal brain c-fos expression and swallowing activity.

The present study examined physiological and cellular responses to central application of ANG II in ovine fetuses and determined the fetal central ANG-mediated dipsogenic sites in utero. Chronically prepared near-term ovine fetuses (130 +/- 2 days) received injection of ANG II (1.5 microg/kg icv). Fetuses were monitored for 3.5 h for swallowing activity, after which animals were killed and fetal brains were perfused for subsequent Fos staining. Intracerebroventricular ANG II significantly increased fetal swallowing in near-term ovine fetuses (1.1 +/- 0.2 to 4.5 +/- 1.0 swallows/min). The initiation of stimulated fetal swallowing activity was similar to the latency of thirst responses (drinking behavior) elicited by central ANG II in adult animals. ANG II evoked increased Fos staining in putative dipsogenic centers, including the subfornical organ, organum vasculosum of the lamina terminalis, and median preoptic nucleus. Intracerebroventricular injection of ANG II also caused c-fos expression in the fetal hindbrain. These results indicate that an ANG II-mediated central dipsogenic mechanism is intact before birth, acting at sites consistent with the dipsogenic neural network. Central ANG II mechanisms likely contribute to fetal body fluid and amniotic fluid regulation.

Plasma osmolality dipsogenic thresholds and c-fos expression in the near-term ovine fetus.

In ovine and human pregnancy, fetal swallowing contributes importantly to amniotic fluid homeostasis. Fetal dipsogenic responsiveness to short-term plasma hyperosmolality develops in late gestation, although fetal swallowing is not stimulated in response to long-term plasma osmolality increases (2 to 3%), which typically stimulate adult drinking behavior. To explore the near-term fetal plasma osmolality threshold for swallowing stimulation, we examined the effects of i.v. hypertonic saline-induced subacute increases in plasma hypertonicity on fetal swallowing behavior. Central sites of activation were examined by c-fos expression in putative dipsogenic nuclei. The results demonstrate that subacute 2 to 3% plasma osmolality increases do not stimulate near-term ovine fetal swallowing. However, fetal swallowing activity significantly increased (3 times) after plasma osmolality increased >6% above basal values. Consistent with a specific dipsogenic response, i.v. hypertonic saline induced c-fos expression in the anterior third ventricle region, a putative dipsogenic center, as well as in the fetal hindbrain. The stimulation of fetal swallowing under conditions of higher osmotic stimulation and the correlation with forebrain c-fos expression indicates that near-term fetal osmoregulation mechanisms are functional, although not completely mature. Reduced fetal dipsogenic responsiveness may result from altered osmoreceptor sensitivity, downstream neuronal or synaptic immaturity, or potentially inhibitory actions of stimulated hindbrain nuclei.

Central leptin stimulates ingestive behavior and urine flow in the near term ovine fetus.

Leptin inhibits ingestive behavior and induces diuresis and natriuresis. To examine whether leptin influences fetal physiologic functions, we investigated the effect of central leptin on ovine fetal swallowing activity and urine flow. Six pregnant ewes with singleton fetuses (130 +/- 2 d gestation) were prepared with maternal and fetal arterial and venous catheters, fetal lateral intra-ventricle cannula, fetal bladder and amniotic fluid catheters. Electromyogram wires were placed in the fetal thyrohyoid muscle and upper and lower nuchal esophagus and electrodes were implanted on the parietal dura. Five days after surgery, recombinant human leptin was infused into the lateral ventricle and the fetus monitored for 8 h. Central leptin increased fetal swallowing activity during low-voltage electrocortical activity from basal values (0.96 +/- 0.08 swallows/min) at 2 h (1.41 +/- 0.24 swallows/min), 4 h (2.81 +/- 0.57 swallows/min), 6 h (2.53 +/- 0.59 swallows/min) and 8 h (2.08 +/- 0.39 swallows/min, p < 0.05). In comparison to basal values, low voltage electrocortical activity decreased (57 +/- 5% to 42 +/- 4%) and high voltage electrocortical increased (43 +/- 5% to 61 +/- 4%). In response to leptin, fetal urine flow initially decreased from basal values at 2 h (0.12 +/- 0.03 to 0.08 +/- 0.02 ml/kg/min, p < 0.05) then subsequently increased at 4 h and 6 h (0.20 +/- 0.04; 0.21 +/- 0.04 ml/kg/min, respectively, p < 0.05). Central leptin significantly increases near term ovine fetal swallowing activity and urine output, suggesting that leptin contributes to in utero development of ingestive behavior.

Ovine fetal swallowing: expression of preterm neurobehavioral rhythms

Objective: Fetal swallowing contributes importantly to amniotic fluid volume regulation and fetal gastrointestinal maturation. Near-term ovine fetal swallowing occurs in discrete bouts of activity (at approximately 30-min intervals) in association with fetal electrocortical voltage changes. Thus, swallowing rhythms have been hypothesized to be entrained to fetal neurobehavioral states. In the preterm ovine fetus, electrocortical activity does not demonstrate differentiation into high- and low-voltage periods until 120-130 days' gestation. We sought to quantify patterns of preterm (114 days, 0.75 gestation) ovine fetal swallowing activity and volume, and, in view of the lack of electrocortical pattern changes, to explore whether swallowing activity was regulated by an independent central pacemaker. Methods: Six singleton ovine pregnancies were chronically prepared with fetal and maternal femoral artery and vein catheters. Biparietal electrocortical electrodes were placed on the fetal skull. Following a minimum 5-day recovery period, fetuses were studied at 114 &#45 1 days. Patterns of fetal swallowing behavior were quantified by computer analysis of laryngeal-esophageal electromyography (EMG) and thoracic esophageal fluid flow during a 12-h period. Results: Esophageal fluid flow was bidirectional, although antegrade flow predominated, leading to an average fluid acquisition rate of 13 &#45 3 ml/h (7.3 &#45 1.8 ml/h per kg) during the 12-h study (302 &#45 87 ml/day). Propagated esophageal EMG activity, representing coordinated 'swallows', averaged 56 &#45 6 swallows/h and correlated well with net esophageal fluid flow. 'Bouts' of swallowing activity ( &#83 3 swallows/min) averaged 9 &#45 1 swallows/bout, lasted 1.8 &#45 1.4 min and accounted for 31 &#45 4% of the swallowed volume. Despite the absence of fetal electrocortical high-voltage/ low-voltage transitions, there was a 26.1 &#45 3.9-min interval between periods of swallowing bout activity. Conclusions: Preterm (0.75 gestation) ovine fetal volume swallowed (302 ml/day) and volume swallowed for body weight (175 ml/day per kg) was significantly less than that previously noted at 0.85 gestation (831 ml/day, 274 ml/day per kg, respectively; p < 0.05) although the rates of swallowing activity were similar. The presence of swallowing bout activity at periodic intervals, in the absence of electrocortical differentiation, suggests an intrinsic central pacemaker regulating preterm fetal neurobehavior.

Central neuropeptide Y stimulates ingestive behavior and increases urine output in the ovine fetus.

We hypothesized that central neuropeptide Y (NPY) increases swallowing activity and alters renal function in the near-term ovine fetus. Six ewes with singleton fetuses (130 +/- 2 days of gestation; 148 days = term) were chronically prepared with arterial and venous catheters, a fetal lateral cerebroventricular cannula, and fetal bladder and amniotic fluid catheters. For determination of fetal swallowing, electromyogram wires were placed in the fetal thyrohyoid muscle and the upper and lower nuchal esophagus. Electrodes were implanted on the parietal dura for determination of fetal electrocorticogram (ECoG). After 5 days of recovery, fetal swallowing, ECoG, blood pressure, and heart rate were monitored during a 3-h basal period. At t = 3 h, ovine NPY (0.05 mg/kg) was administered into the lateral ventricle, and fetuses were monitored for an additional 8 h. A control study of central administration of artificial cerebral spinal fluid was performed on an alternate day. Central NPY significantly increased swallowing activity during low-voltage ECoG from basal activity (1.26 +/- 0.15 swallows/min) at 4 h (1.93 +/- 0.37 swallows/min), 6 h (1.69 +/- 0.27 swallows/min), and 8 h (2.38 +/- 0.31 swallows/min). NPY significantly increased fetal urine flow (basal: 0.13 +/- 0.02; 4 h: 0.21 +/- 0.04; 6 h: 0. 19 +/- 0.03 ml.kg(-1).min(-1)). These results demonstrate that central NPY stimulates fetal swallowing activity and increases urine output, which may contribute to the in utero development of ingestive behavior.

Nitric oxide modulates spontaneous swallowing behavior in near-term ovine fetus.

Human and ovine fetuses demonstrate an enhanced rate of swallowing, an activity critical for amniotic fluid regulation. Fetal swallowing may be modulated by both systemic and central factors. Nitric oxide (NO) is a central neuromodulator that has been localized to brain regions regulating thirst and swallowing. We sought to determine if NO contributes to the regulation of spontaneous ovine fetal swallowing. Six time-dated pregnant ewes with singleton fetuses (129 +/- 1 day) were chronically prepared with fetal vascular and lateral ventricle catheters and electrocorticogram (ECoG) and esophageal electromyogram electrodes. After a 2-h control period, fetuses were given lateral ventricle injection of NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME) and monitored for 2 h. NO precursor L-arginine was then injected into the lateral ventricle, and fetuses were monitored for a final 2 h. All fetuses received an additional control study of fetal swallowing before and after lateral ventricle injection of artificial cerebrospinal fluid (aCSF). Data were analyzed with repeated-measures ANOVA and paired t-test (P < 0.05). Suppression of a central NO with central L-NAME significantly reduced mean (+/-SE) spontaneous fetal swallowing (1.2 +/- 0.1-0.6 +/- 0.1 swallows/min low-voltage ECoG; P < 0.01). Restoration of central NO by L-arginine significantly increased fetal swallowing to pre-L-NAME levels (1.2 +/- 0.1 swallows/min low voltage). There were no changes in fetal swallowing during the control study of aCSF. Fetal ECoG activity and blood pressure did not change during the study or control aCSF injection. We conclude that NO is an important neuromodulator of fetal swallowing activity. Central NO synthase activity may contribute to the heightened level of spontaneous fetal swallowing and thus amniotic fluid regulation.

Maternal plasma hypo-osmolality: Effects on spontaneous and stimulated ovine fetal swallowing

Fetal swallowing is a major route of amniotic fluid resorption, and thus swallowing activity may alter amniotic fluid volume. Near-term ovine fetal swallowing increases in response to plasma and/or cerebrospinal fluid hypertonicity. As maternal hydration status alters amniotic fluid volume, we hypothesized that maternal plasma hypotonicity may alter fetal swallowing activity. Pregnant ewes (130 +/- 1 d; n = 6) were chronically prepared with maternal and fetal vascular catheters, a fetal esophageal flow probe, and fetal thyrohyoid and nuchal and thoracic esophagus electromyogram electrodes. Spontaneous fetal swallowing and hypertonic saline thresholds for stimulated swallowing were determined prior to and following maternal hypotonicity induced with water loading and intravenous DDAVP (arginine vasopressin V2 agonist). Fetal swallowing thresholds were determined with intracarotid injections (0.15 ml/kg) of increasing sodium chloride concentrations (0.15-1.2 M) at 2-min intervals. Maternal DDAVP infusion significantly decreased mean (+/-SEM) maternal and fetal plasma osmolalities (298 +/- 2-284 +/- 3; 295 +/- 2-278 +/- 3 mOsm/kg, respectively) and sodium concentrations (147.3 +/- 0.4-137.5 +/- 0.9; 142.7 +/- 0.8-133.5 +/- 1.0 mEq/l, respectively), suppressed spontaneous swallowing activity and volume (1.1 +/- 0.2-0.6 +/- 0.1 swallows/min; 0.7 +/- 0.2-0.5 +/- 0.1 ml/min, respectively) and significantly increased the osmotic threshold for swallowing stimulation (0.77 +/- 0.08-1.03 +/- 0.09 M NaCl). We conclude that: (1) maternal, and thus fetal, plasma hypotonicity results in suppression of spontaneous fetal swallowing activity and a decrease in volume swallowed, suggesting that spontaneous fetal ingestive behavior results, in part, from tonic dipsogenic stimulation, and (2) under hypotonic conditions, the intracarotid NaCl injection concentration for swallowing stimulation increases. These results suggest that the reset (lower) maternal plasma osmolality during human pregnancy may serve to minimize fetal ingestive and perhaps arginine vasopressin-mediated antidiuretic responses to acute maternal hypertonicity.

Development of ingestive behavior

Swallowing represents a primary physiological function that provides for the ingestion of food and fluid. In precocial species, swallowing activity likely develops in utero to provide for a functional system during the neonatal period. The chronically instrumented ovine fetal preparation has provided the opportunity for recent advances in understanding the regulation of in utero swallowing activity. The near-term ovine fetus swallows fluid volumes (100-300 ml/kg) that are markedly greater, per body weight, than that of the adult (40-60 ml/kg). Spontaneous in utero swallowing and ingestive behavior contribute importantly to the regulation of amniotic fluid volume and composition, the acquisition and potential recirculation of solutes from the fetal environment, and the maturation of the fetal gastrointestinal tract. Fetal swallowing activity is influenced by fetal maturation, neurobehavioral state alterations, and the volume of amniotic fluid. Furthermore, intact dipsogenic mechanisms (osmolality, angiotensin II) have been demonstrated in the near-term ovine fetus. It remains unknown to what degree, if any, fetal swallowing may be influenced by nutrient appetite, salt appetite, or taste. Nevertheless, the development of dipsogenic and additional regulatory mechanisms for ingestive behavior occurs during fetal life and may be susceptible to changes in the pregnancy environment. This review describes what is currently known regarding the in utero development of ingestive behavior and the importance of this activity for fetal and perhaps ultimately adult fluid homeostasis.

Anticholinergic suppression of ovine fetal swallowing activity

Objective: Fetal swallowing contributes importantly to amniotic fluid volume regulation as the primary route of fluid resorption, reaching 500 to 1000 ml/day near term. Near-term ovine fetal swallowing activity occurs predominantly during low-voltage electrocortical activity. In view of the potential to pharmacologically alter electrocortical activity, we hypothesized that fetal administration of a centrally acting cholinergic antagonist may be used to modulate fetal swallowing activity. To explore cholinergic modulation of swallowing activity, we examined fetal swallowing and electrocortical activity in response to central and peripheral cholinergic suppression by atropine sulfate. Study Design: Singleton ovine fetuses ( n = 6) were chronically prepared with vascular catheters and thyrohyoid, nuchal, and thoracic esophageal electromyogram and biparietal electrocortical electrodes. Swallowing and electrocortical activity were monitored for 2 hours before and after intravenous injection (1 ml of 0.15 mol/L sodium chloride) of atropine sulfate (1 mg/kg). On a subsequent day an identical study was performed with use off atropine methyl nitrate (3 mg/kg), an atropine analog that does not cross the blood-brain barrier. Results: Atropine sulfate decreased low-voltage electrocortical activity (56% ± 5% to 14% ± 4%), increased high-voltage electrocortical activity (40% ± 5% to 81% ± 5%), and did not change intermediate electrocortical activity (4% ± 1% to 5% ± 1%). Fetal swallowing activity decreased from 46 ± 12 to 12 ± 2 swallows per hour after atropine sulfate administration. Atropine methyl nitrate had no discernible effect on either fetal electrocortical or swallowing activity. Fetal arterial pressure, plasma osmolality, pH, Pco 2, and Po 2 did not change. Conclusions: Central cholinergic antagonism suppresses low-voltage fetal electrocortical and swallowing activity in the ovine fetus. Studies exploring spontaneous or induced fetal swallowing should consider the behavioral state of the fetus when conclusions are drawn about changes in the swallowing activity.

Fetal Swallowing: Relation to Amniotic Fluid Regulation

In summary, fetal swallowing activity contributes importantly to fetal and amniotic fluid homeostasis, and fetal somatic and gastrointestinal development. Human and ovine fetal swallowing increases throughout gestational with fetal swallowed volumes markedly greater (relative to body weight) than adults. Although the regulation of swallowing activity in early gestation is unknown, intact central and systemic dipsogenic mechanisms have been shown during the last third of ovine gestation. Recent studies suggest that swallowing behavior may be modulated in accordance with neurobehavioral state changes and influenced by hypoxia, hypotension and plasma osmolality changes. Whether fetal swallowing also is regulated by the development of "hunger" sensation, salt appetite, or the development of taste is uncertain. Nevertheless, it is likely that, for species in which swallowing behavior develops in utero, there are potentially dramatic influences of the maternal-fetal pregnancy environment on the imprinting of regulatory mechanisms controlling ingestive behavior. Ultimately, the regulation of fetal swallowing may aid in the prevention and/or therapy of human amniotic fluid disorders.

1-Deamino-[8-d-arginine] vasopressin - induced maternal plasma hypoosmolality increases ovine amniotic fluid volume

OBJECTIVE: Maternal 1-deamino-[8-d-arginine] vasopressin (a selective antidiuretic agonist) and oral water loading decrease maternal and fetal plasma osmolality and markedly increase fetal urine flow in sheep over 24 hours. We hypothesized that a sustained reduction in plasma osmolality would increase the amniotic fluid volume. STUDY DESIGN: Pregnant sheep (130 ± 1 days, n = 6) were given oral water loading (2000 ml) and intravenous 1-deamino-[8-d-arginine] vasopressin (20 μg injection followed by 4 μg/hr) to induce maternal urinary antidiuresis and to maintain a maternal plasma osmolality decrease of approximately 20 mOsm/kg for 48 hours. Fetal plasma osmolality, electrolytes, atrial natriuretic factor, and arginine vasopressin levels, fetal swallowing activity, and fetal urine flow and composition were measured each study day, and amniotic fluid volume was measured by tracer dilution before and at 48 hours of plasma hypoosmolality. RESULTS: In response to 1-deamino-[8-d-arginine] vasopressin and water loading, maternal plasma osmolality decreased (298 ± 1 to 275 ± 3 mOsm/kg), mirrored by fetal plasma hypoosmolality (293 ± 1 to 271 ± 3 mOsm/kg). Fetal urine osmolality (155 ± 16 to 117 ± 10 mOsm/kg) and amniotic fluid osmolality significantly decreased (281 ± 3 to 269 ± 5 mOsm/kg). Fetal urine flow rate significantly increased (0.33 ± 0.06 to 0.51 ± 0.04 ml/min), whereas fetal swallowing activity decreased (56 ± 7 to 33 ± 5 swallows per hour). In response to alterations in fetal fluid dynamics, amniotic fluid volume significantly increased from 493 ± 80 to 839 ± 160 ml. CONCLUSION: Chronic maternal 1-deamino-[8-d-arginine] vasopressin - induced plasma hypoosmolality induces a sustained reduction in fetal swallowing activity and an increase in fetal urine production, which results in a marked increase in amniotic fluid volume. Use of maternal 1-deamino-[8-d-arginine] vasopressin and oral fluid loading has the potential for manipulation of amniotic fluid volume homeostasis and may prove useful in the treatment of oligohydramnios. (A M J O BSTET G YNECOL 1996;174:1118-27.)

Development of concentration thresholds for fetal swallowing and arginine vasopressin stimulation in the preterm ovine fetus

We previously demonstrated that fetal swallowing was stimulated by intracarotid saline injections in the near term (130 ± 1 days gestation) ovine fetus. In order to examine the ontogeny of the regulation of thirst-mediated swallowing behavior and arginine vasopressin (AVP) secretion, the present study examined fetal swallowing and AVP secretory responses to hypertonic NaCl and sucrose in preterm (115 days gestation) ovine fetuses. Five fetuses were chronically prepared with thyrohyoid, nuchal and thoracic esophagus, and diaphragm electromyogram (EMG) electrodes, an esophageal flow probe, and vascular catheters. Fetuses received intracarotid injections (0.15 ml/kg) of increasing concentrations of NaCl (0.15–2.55 M), administered at 2-min intervals. The threshold saline concentration for swallowing was defined as the minimum NaCl dose eliciting swallow responses (within 20 s) following 4 of 5 injections at each dose. In 2 fetuses, the threshold dose was 0.75 M (confirmed by 4 of 5 injections resulting in swallows at the next higher dose). In the other 3 animals, no swallowing threshold was observed (i.e., no dose through 2.55 M elicited swallows to 4 of 5 injections). There were no significant increases in AVP secretion. On a subsequent day, equimolar sucrose injections did not affect fetal swallowing activity or AVP secretion. Together with previous reports, these studies indicate that plasma osmolality dipsogenic mechanisms become functional in some ovine fetuses by 115 days gestation, while all fetuses exhibit intact osmotic dipsogenic responses at 130 days gestation. These results further suggest an acute process of development of dipsogenic responsiveness, rather than by gradually increasing sensitivity to osmotic stimuli. © 1996 Wiley-Liss, Inc.

Development of concentration thresholds for fetal swallowing and arginine vasopressin stimulation in the preterm ovine fetus

We previously demonstrated that fetal swallowing was stimulated by intracarotid saline injections in the near term (130 +/- 1 days gestation) ovine fetus. In order to examine the ontogeny of the regulation of thirst-mediated swallowing behavior and arginine vasopressin (AVP) secretion, the present study examined fetal swallowing and AVP secretory responses to hypertonic NaCl and sucrose in preterm (115 days gestation) ovine fetuses. Five fetuses were chronically prepared with thyrohyoid, nuchal and thoracic esophagus, and diaphragm electromyogram (EMG) electrodes, an esophageal flow probe, and vascular catheters. Fetuses received intracarotid injections (0.15 ml/kg) of increasing concentrations of NaCl (0.15-2.55 M), administered at 2-min intervals. The threshold saline concentration for swallowing was defined as the minimum NaCl dose eliciting swallow responses (within 20 s) following 4 of 5 injections at each dose. In 2 fetuses, the threshold dose was 0.75 M (confirmed by 4 of 5 injections resulting in swallows at the next higher dose). In the other 3 animals, no swallowing threshold was observed (i.e., no dose through 2.55 M elicited swallows to 4 of 5 injections). There were no significant increases in AVP secretion. On a subsequent day, equimolar sucrose injections did not affect fetal swallowing activity or AVP secretion. Together with previous reports, these studies indicate that plasma osmolality dipsogenic mechanisms become functional in some ovine fetuses by 115 days gestation, while all fetuses exhibit intact osmotic dipsogenic responses at 130 days gestation. These results further suggest an acute process of development of dipsogenic responsiveness, rather than by gradually increasing sensitivity to osmotic stimuli.

Cocaine stimulation of ovine fetal swallowing

Cocaine acts to block reuptake of neurotransmitters, resulting in elevated intra-synaptic norepinephrine levels. As monoaminergic systems may contribute to central regulation of swallowing motor activity as well as dipsogenic responses, and cocaine is known to alter fetal behavior, we examined the effect of intravenous cocaine on fetal swallowing. Six ovine fetuses (130 ± 1 days) were chronically prepared with esophageal electrodes and an esophageal flow probe. Following a 1-h control period, fetuses received an intravenous injection of 1.0 mg/kg cocaine over 30 s. Fetal blood samples were withdrawn at timed intervals and fetal swallowing activity was monitored for 180 min after the cocaine bolus. Basal fetal swallowing activity during the control period was 0.6 ± 0.1 swallows/min, with esophageal flow of 0.3 ± 0.1 ml/min. At 10 min following cocaine, fetal swallowing rate increased to 1.4 ± 0.4 swallows/min though esophageal flow did not change significantly (0.4 ± 0.2 ml/min). Swallowing rate then returned to basal levels. Fetal heart rate increased in response to cocaine injection (149 ± 14 to 174 ± 24 bts/min at 180 min) though there was no change in fetal mean blood pressure. These results demonstrate acute stimulation of fetal swallowing activity in response to intravenous cocaine injection. Together with previous reports, these data further illustrate the diversity of fetal behavioral effects in response to in utero cocaine exposure.