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

Todd J. Roberts, Anne Caston-Balderrama, Mark J. Nijland, and Michael G. Ross

Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of California Los Angeles (UCLA) School of Medicine, Harbor-UCLA Medical Center, Torrance, California 90502


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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.

renal function; fetal sheep; swallowing; thirst; behavioral state


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

FETAL SWALLOWING represents the development of a critical physiological function for food and fluid intake. During development, fetal fluid homeostasis is often reflected by changes in amniotic fluid (AF) volume, a result of alterations in fetal urine and/or lung fluid production, and fetal resorption of AF via swallowing (21). Moreover, fetal swallowing may represent the development of a critical physiological function for food and fluid intake. In sheep and perhaps human fetuses, dipsogen-mediated swallowing and antidiuretic responses develop during the last one-third of gestation. At birth, rat, ovine, and human fetuses have developed mechanisms to acquire water and food via suckling and swallowing, and taste mechanisms are functional (8, 13). Thus ingestive behavior systems must be functional before term delivery.

Fetal growth and development are influenced by numerous factors, including nutritional, environmental, genetic, and uteroplacental (21, 30). It is believed that appetite and perhaps satiety functions develop in utero in precocial species and that the neurotransmitters involved in this process are functional and may influence fetal/neonatal growth and development. Additionally, fetal swallowing of AF proteins and growth factors may alter fetal gastrointestinal growth and maturation, fetal somatic growth, and AF volume.

There are a host of appetite and satiety mediators with interactive control of energy homeostasis and growth. Neuropeptide Y (NPY) is a powerful appetite stimulant, produced primarily in the arcuate nucleus and acting at the level of the paraventricular nucleus (12, 16, 29, 32). Although NPY has been shown to facilitate food and water intake, NPY may also cause diuresis and natriuresis in the adult rat (2). Human studies have provided increasing evidence that the in vitro environment impacts on fetal development and alters adult regulatory mechanisms [i.e., Barker hypothesis (1)]. We hypothesize that appetite and satiety mechanisms develop in utero and that the related neurotransmitters involved in this process are functional and may influence fetal growth and development. Because appetite-mediated swallowing potentially develops in utero, we examined the effect of central NPY on fetal swallowing activity and urine production.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Animals and surgery. Six mixed-breed pregnant ewes with singleton fetuses (gestational age 130 ± 2 days, term 148 days) were studied. The care and use of the animals were approved by the Animal Research Committee of Harbor-UCLA Medical Center and were in accordance with guidelines of the American Association for Accreditation of Laboratory Animal Care and the National Institutes of Health. The sheep were housed indoors in individual steel study cages and acclimated to a 12:12-h light-dark period (lights on at 0600). Both feed (alfalfa pellets) and water were provided ad libitum, except for the last 24 h before surgery, when feed was withheld. Animals utilized in the current experiment had been previously used in a study of central fetal leptin (unpublished results). Studies were performed 36 h apart, and basal fetal swallowing activity was observed to be within normal ranges for nonstressed fetal sheep (24).

Surgical anesthesia was induced by an intramuscular injection of ketamine hydrochloride (20 mg/kg) plus atropine sulfate (50 µg/kg) and was subsequently maintained by maternal endotracheal ventilation with 1 l/min O2 and 1-2% isoflurane. The uterus was exposed by midline abdominal incision, and a small hysterotomy was performed to expose a fetal hindlimb. The fetal femoral vein and artery were catheterized (Tygon, ID = 1.0 mm, OD = 1.8 mm), and the femoral catheters were threaded to the inferior vena cava and abdominal aorta, respectively. The maternal femoral vein and artery were similarly catheterized with polyethylene 8-Fr catheters. The fetal bladder was catheterized (Tygon, ID = 1.3 mm, OD = 2.3 m) via cystotomy, and an intrauterine catheter (Corometrics Medical System, Wallingford, CT) was inserted to measure AF pressure. For determination of fetal swallowing, electromyogram (EMG) wires were placed in the fetal thyrohyoid muscle and upper and lower nuchal esophagus. Electrodes were implanted on the parietal dura for determination of fetal electrocortical (ECoG) activity. An 18-gauge needle connected to a polyethylene catheter (0.02 in. ID, 0.04 in. OD) was inserted into the lateral ventricle and was identified 20 mm above the lamboid suture, 5 mm lateral to the sagittal suture, and 18 mm below the surface of the skull. The lateral ventricle needle was immobilized with dental cement with the assistance of two stainless steel screws affixed in the fetal skull. AF lost during surgery was replaced with equivalent volumes of 0.15 M sodium chloride on completion of the operation. The uterus and maternal abdomen were closed in layers. All catheters were exteriorized to the maternal flank. At least 5 days of postoperative recovery were allowed before experimental studies. Antibiotics were administered intravenously twice daily to the ewe (1 g chloramphenicol, 967 mg oxacillin sodium, and 72 mg gentamicin sulfate) and to the fetus (33 mg oxacillin sulfate and 8 mg gentamicin sulfate) during the first 3 days postsurgery. Maternal and fetal catheters were flushed daily with heparinized saline (10 IU/ml) and subsequently filled with sodium heparin solution (10 IU/ml and 1,000 IU/ml, respectively) and sealed with sterile plastic caps.

Experimental protocol. All experiments were performed on conscious animals standing in their holding cages, with feed and water provided ad libitum. Fetal swallowing and ECoG activity were monitored during a 3-h basal period and for 8 h after a bolus of NPY. Similarly, blood pressure, heart rate, and urine flow (the fetal bladder was drained to gravity) were monitored during a 3-h basal period and for 6 h thereafter. At t = 3 h, ovine NPY (0.05 mg/kg; Sigma, St. Louis, MO) in artificial cerebral spinal fluid (aCSF) with 0.2% bovine serum albumin was administered into the left ventricle (500 µl over 10 min). A control study of central administration of aCSF vehicle alone was performed before NPY administration. Basal fetal swallowing rates were within normal ranges before the beginning of the NPY study (24).

Throughout the study period, 30-min samples of fetal urine were collected for sodium, potassium, chloride, osmolality, and flow rates. Maternal and fetal blood samples were obtained for arterial pH, hematocrit, plasma electrolyte composition, osmolality, arginine vasopressin (AVP), and angiotensin II (ANG II) concentrations at 30, 60, 120, 240, and 360 min. The total volume of fetal blood withdrawn was replaced after each sample with an equal volume of maternal blood that had been withdrawn before each experiment and filtered through a 20-µm filter.

Analytic methods. Maternal and fetal arterial blood pressure and AF pressure were monitored with a Beckman R-612 recorder (Beckman Instruments, Fullerton, CA) and Statham P23 pressure transducers (Garret, Oxnard, CA). All signals were digitized at 50 Hz and acquired on an IBM-compatible computer by use of WinDAQ acquisition software (DataQ Instruments, Akron, OH). Heart rate and systolic, diastolic, and mean arterial pressures were calculated from the pressure waveforms with Advanced CODAS software (DataQ Instruments,).

Plasma and urinary electrolyte concentrations were determined with a Nova 5 electrolyte analyzer (Nova Biomedical, Waltham, MA). Osmolality was measured by freezing point depression by use of a Fiske 2400 Multisample Osmometer (Fiske Associates, Norwood, MA). Blood pH values were measured at 39°C with a Nova Stat 3 blood gas analyzer (Nova Biomedical). Plasma AVP levels were assayed by RIA as previously described (27). The AVP assay is sensitive to 0.8 pg/ml plasma (0.16 pg/tube). The intra- and interassay coefficients of variation were 6 and 8%, respectively. The ANG II RIA procedure has been described elsewhere (23). The intra- and interassay coefficients of variation were 7 and 9%, respectively.

Digitization of all signals was performed at a rate of 75 Hz. ECoG and EMG signals were directed into a Grass physiological recorder and a WinDaq analog-digital system. An EMG-propagated swallow, representing a coordinated laryngeal-esophageal contraction, was defined by a time sequence of integrated EMG signals from the thyrohyoid muscle to the upper and lower nuchal esophagus.

Fetal ECoG was assessed by visual analysis and was divided into periods of low voltage (LV) and high voltage (HV). Periods of ECoG activity that did not clearly belong to either LV or HV activity (<5% of total ECoG) were considered intermediate ECoG activity. Total swallowing activity was calculated as defined above and expressed as swallows per minute. The percentage of swallows associated with each electrocortical state was then calculated. The number of swallows occurring in each state was divided by the amount of time spent in that state for each animal to normalize swallowing activity for the amount of each electrocortical state and was expressed as swallows per minute of LV and HV. Fetal swallowing activity occurs primarily during LV ECoG (17).

Calculations and statistics. All values are expressed as means ± SE. The basal values represent the means of measurements obtained at 0, 60, and 180 min of the basal period. Differences were analyzed with repeated-measures analysis of variance (SAS Generalized Linear Models) and with Dunnett's post hoc test. Statistical significance was accepted at P <=  0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Fetal and maternal blood pressures, pH, O2 and CO2 pressures, and plasma osmolality and electrolyte concentrations during the basal period were representative of values previously reported in our laboratory for unstressed animals and were unchanged during the experimental period (Table 1). Fetal heart rate and cardiovascular responses remained largely unchanged throughout the study, apart from a small (significant) decrease in fetal heart rate at hours 2 and 4 post-NPY administration (Table 2).

                              
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Table 1.   Effect of central NPY on fetal and maternal arterial blood values


                              
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Table 2.   Fetal and maternal cardiovascular and arterial blood values after central fetal NPY injection

Swallowing activity. During the basal period, fetuses demonstrated normal swallowing rates during LV and HV ECoG (Fig. 1, A and B). Fetal swallowing values (1.26 ± 0.15 swallows/min LV activity) were similar to those observed in previously reported data for near-term fetuses (24, 25). NPY increased fetal swallowing activity by as much as 89%. Specifically, swallowing activity during LV ECoG significantly increased 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) post-NPY administration (Fig. 1A). Swallowing activity during HV ECoG demonstrated a nonsignificant increase (Fig. 1B).


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Fig. 1.   A: effect of central neuropeptide Y (NPY) and artificial cerebral spinal fluid (aCSF) on fetal swallowing activity during a low-voltage (LV) electrocorticogram (ECoG). B: effect of central NPY and aCSF on fetal swallowing activity during high-voltage (HV) ECoG. * P <=  0.05, a significant difference from basal.

Electrocortical activity. The temporal distribution of the LV and HV states during the basal period was 51 ± 3 and 49 ± 3%, respectively (Table 3). Electrocortical states remained unaltered during the experimental period, apart from a nonsignificant decrease in time spent in LV at 2 h (Table 3). Swallowing distribution by ECoG state was similarly unaltered after NPY: 75% of the swallows occurred in LV, whereas 25% of the swallowing activity occurred in HV (Table 3).

                              
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Table 3.   Effect of central NPY and aCSF on fetal ECoG and swallowing distribution

Fetal renal responses. Urine flow rates were normal during the basal period, although fetuses demonstrated slightly elevated urine osmolality values. As shown in Fig. 2, urine flow rate numerically increased at 2 h (0.13 ± 0.02 to 0.19 ± 0.05 ml · kg-1 · min-1), with a significant increase noted at 4 h (0.21 ± 0.05 ml · kg-1 · min-1, P < 0.05) and 6 h (0.19 ± 0.04 ml · kg-1 · min-1, P < 0.05) post-NPY administration. The increase in fetal urine flow was associated with increased urine sodium, chloride, and potassium excretion and osmolar clearance (Table 4).


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Fig. 2.   Effect of central NPY on fetal urine flow. Solid bars represent numbers of hours after NPY delivery. * P <=  0.05, a significant difference from basal.


                              
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Table 4.   Fetal renal responses to central NPY

Control study. There were no changes in maternal or fetal arterial blood values, fetal swallowing activity, LV and HV ECoG activity, or urine flow and electrolyte excretion in response to aCSF (Tables 1-4).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Ingestive behavior and renal metabolism represent key systems for nutrition and body water homeostasis. In utero, fetal swallowing may play a role in the regulation of fetal growth and development, because swallowing of amniotic fluid proteins and growth factors contribute to fetal gastrointestinal growth and maturation and possibly fetal somatic growth (29). Moreover, fetal swallowing, which occurs primarily during LV ECoG (17), may represent the development of a critical physiological function for food and fluid intake. Thus alterations in key regulators of ingestive behavior, such as NPY, may ultimately contribute to fetal growth and development.

NPY, a putative regulator of ingestive behavior, increases food intake and alters glucocorticoid activity (8, 12, 13, 21, 29). In the present study, fetal sheep responded to central NPY with a marked increase in swallowing activity during LV ECoG. Swallowing activity during LV ECoG increased in response to NPY beginning 4 h after NPY administration and remained elevated throughout the remainder of the study. Although we noticed a proportionate increase in swallowing activity during HV ECoG, this change was not statistically significant. These results are consistent with NPY's effect on adult food and water intake. Several investigators (11, 12, 15, 22, 28) have observed (dose-dependent) increases in both food and water intake after NPY administration into the third, fourth, or lateral ventricle or directly into the paraventricular nucleus (PVN) of the rat. Increased water intake was shown to be irrespective of the presence or absence of food, and water intake increased less than food intake. These results are also consistent with studies in the adult sheep, in which lateral ventricular administration of NPY increased feeding and water intake in satiated sheep over a 6-h period (16). Similarly, the increase in water intake was shown to occur with or without food.

NPY also contributes to the regulation of ingestive behavior during development. Capuano et al. (4) demonstrated increases in milk and water intake in 2- and 15-day-old preweanling rats after PVN administration of NPY. Although there is no difference between milk and water intake responses until 8 days of age, the consumption of milk becomes greater at 15 days compared with water intake. Thus, in the rat, the response to NPY is present at birth and becomes more pronounced with age. Furthermore, NPY is present in the brain stem and diencephalon, including the PVN in rat embryos of 14 days postconception, and NPY concentration increases immediately after birth (4, 12). Taken together, these results demonstrate that NPY is present at birth and therefore must be intact before delivery to assist in the control and coordination of ingestive behavior.

Thirst- and appetite-mediated ingestive behavior are likely regulated via alternative mechanisms. Although we observed an increase in fetal swallowing, it is not possible to ascertain whether the stimulated fetal swallowing activity is of a dipsogenic or an appetite origin. We have previously shown a functional dipsogenic response in the near-term ovine fetus, with increased swallowing activity occurring in response to intracarotid or intravenous hypertonic saline infusion (24, 25). Additionally, the immediate-early gene product Fos was stimulated in putative central dipsogenic centers (5). Therefore, immunocytochemical localization of central Fos activation may provide insight into neuronal populations responding to central NPY.

Fetal swallowing activity occurs in association with electrocortical activity (17), with 75% of swallowing activity occurring primarily during LV ECoG. Although central NPY may produce sedation (i.e., suppression of locomotor activity, synchronizing effect on the electroencephalogram) in normal rats (7, 9, 10, 13, 14, 33), we demonstrated no change in fetal ECoG activity in the present study. Similarly, the distribution of fetal swallowing by ECoG state was unaffected by NPY. Interestingly, NPY has been shown to upregulate alpha 2-adrenergic receptors, which have been postulated to regulate the sleep-wakefulness cycle as well as cardiovascular parameters (20, 31). In the current study, cardiovascular parameters remained largely unaffected. Therefore, it is conceivable that this neuronal pathway may be incompletely developed in the near-term fetal sheep. Nevertheless, the lack of change in fetal ECoG activity suggests a direct effect of NPY on fetal ingestive behavior.

The current study demonstrates that NPY increases fetal urine production and alters sodium, potassium, and chloride excretion. Fetal urine flow significantly increased at 4 h after NPY and remained elevated for the remainder of the experiment. A concomitant rise in osmolar, sodium, chloride, and potassium excretion is a result of increased urine production in the presence of unchanged urine composition. Systemic NPY has previously been shown to cause diuresis and natriuresis (2, 19). In the adult rat, systemic infusion of NPY enhanced urine formation and sodium excretion. However, intrarenal infusion of NPY (0.3 or 1 µg · kg-1 · min-1) resulted in a smaller increase, and at times a decrease, in urine and sodium excretion (2). Similarly, in the primate, intrarenal NPY decreases urine flow, sodium excretion, and renal blood flow (6). The anti-diuresis observed upon intrarenal infusion of NPY is most probably related to renal vasoconstriction. Although NPY is a potent vasoconstrictor typically co-released with norepinephrine, systemic infusion of NPY may act in part by a pressure natriuresis system. Furthermore, unlike the adult animal, which increases fluid intake in response to a primary urinary diuresis, fetal fluid balance is rapidly maintained by placental fluid transport. Therefore, the increase in urine flow is unlikely a result of an increase in AF swallowing.

In the present study, except for a small decrease in fetal heart rate at 2 and 4 h, central NPY was without effect on cardiovascular parameters. The NPY-induced diuresis and natriuresis observed in the current study may involve a mechanism independent of the suggested pressure natriuresis system. The effects of central NPY on renal dynamics may be mediated via altering the hypothalamic-pituitary-adrenal (HPA)-axis. NPY has been shown to stimulate corticosterone, corticotropin-releasing factor (CRF), and adrenocorticotropic hormone (3, 18, 22, 26) in fetal sheep and adult sheep and dogs. NPY action at the HPA axis may be mediated by CRF, because a CRF antagonist attenuates HPA responses, and NPY and CRF-containing neurons are in close anatomic association within the PVN. Hence, central NPY administration may lead to an increase in HPA regulators, which have been shown to increase urine output and alter sodium excretion (2, 19).

In summary, central NPY stimulated fetal swallowing and induced diuresis in the near-term ovine fetus. The stimulation of fetal swallowing by NPY indicates that the fetal ingestive system is active in the near-term ovine fetus, although it may require additional functional maturation. NPY's actions on fetal swallowing activity are thought to be of an appetite origin; however, this does not rule out dipsogenic involvement. Further studies are needed to explore the site of action of NPY-mediated ingestive behavior and to what extent a potential imprinting mechanism is functional in utero.


    ACKNOWLEDGEMENTS

We acknowledge James Humme, Linda Day, and Glenda Calvario for technical assistance.


    FOOTNOTES

This study was supported by the March of Dimes Birth Defects Foundation and National Institutes of Health Grants DK-43311 and HL-40899 (both to M. G. Ross).

Current address of M. J. Nijland: Department of Veterinary Physiology, Cornell University, Ithaca, NY 14853.

Address for reprint requests and other correspondence: T. J. Roberts, Harbor-UCLA Medical Center, 1124 West Carson St., RB-1, Torrance, CA 90502 (E-mail: TJRoberts{at}prl.humc.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Received 9 December 1999; accepted in final form 6 April 2000.


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ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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Am J Physiol Endocrinol Metab 279(3):E494-E500
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