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DEVELOPMENT AND TISSUE PLASTICITY
Department of Physiology and Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, Australia 2052
Submitted 8 May 2003 ; accepted in final form 20 June 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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heart rate; behavior; electrocortical activity; fetal breathing movements
There is good evidence that although resting sympathoadrenal activity is normally low in the late-gestation fetal sheep, its activation and effects are essential for survival during hypoxia. These findings were described by Parer and cited by Jensen and Berger (8). In addition, drug-induced changes in fetal arterial pressure evoke reflex changes in fetal RSNA as well as heart rate (15). It is not known at what age RSNA first occurs, although it has been measured at 116 days (term = 150 days) of gestation (16).
Innervation of the developing kidney is essential for the surge in renin levels that occurs at birth (13). Preterm lambs that do not have the normal increase in RSNA at birth have lower arterial pressures compared with preterm lambs in which the increase in RSNA occurred as a result of pretreatment with dexamethasone (16).
In the latter part of gestation, the human fetus and the fetal sheep show variable electrocortical (electrocorticographic; ECoG) activities. These have been classified into a number of different behavioral states, the descriptions of which are different in the two species. Dawes et al. (4) first characterized the behaviors of late-gestation fetal sheep in both exteriorized and "in utero" preparations (3). In the sheep fetus, there are two types of ECoG, rapid eye movement (REM; low voltage) and non-rapid eye movement (NREM; high voltage; Ref. 14). REM can be classified further into REM plus fetal breathing movements (FBMs) and REM lacking FBMs. Classification of these various fetal behavioral states depends on defining not only the type of ECoG activity present but also the extent to which there are eye movements (electrooculogram; EOG activity), breathing movements, and forelimb and neck muscle electromyogram (EMG) activity. Normally, the fetus cycles regularly through these states.
In 1994, Segar et al. (17) suggested that the spontaneous and parallel changes in fetal mean arterial pressure (MAP), heart rate (HR), and RSNA observed in paralyzed fetal sheep within 24 h of surgery were due to centrally mediated changes in sympathetic tone. Therefore, we measured RSNA in late-gestation fetal sheep to find out whether the level of activity of the fetal sympathetic nervous system was affected by the fetal behavior. Because we needed to define the particular behaviors of the fetus and we wanted to study the effects of spontaneously generated FBMs on fetal RSNA, we carried out our studies in unanesthetized, nonparalyzed fetal sheep 1-3 days after surgery.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Surgical preparation. Ewes were fasted for 16 h and anesthetized
with 1.5 g (iv) sodium thiopental (Pentothal; Abbott, Macclesfield, Cheshire,
UK). Anesthesia was maintained with 2-3% halothane (Fluothane; Clifford Hallam
Pharmaceuticals, Riverwood, NSW, Australia) in oxygen. Under aseptic
conditions, the fetus was partially exteriorized, a left paravertebral
incision was made, and a renal sympathetic nerve was identified. The nerve was
threaded through the two spirals of a bipolar silver electrode (made of
insulated silver wire from which the insulation had been stripped; 0.25-mm
conducting diameter and insulated with 0.023-mm polyester; Goodfellow,
Cambridge, UK). The silver electrode was soldered to 
1 m of miniature
shielded cable. Silver-plated miniature connectors (2 mm, RS 444-472/501/517;
RS Components, Sydney, Australia) were soldered to the proximal ends of the
two signal leads and to the 7/0.2-mm tin and copper stranded conductor
insulated with 0.3-mm polyvinyl chloride tubing, overall diameter 1.2 mm
(364-051; RS Components, Sydney, Australia). The nerve and electrode were
embedded in silicone gel (Sil-Gel 604Aa and 604B; Wacker-Chemie, Munich,
Germany).
To record ECoG activity, a midline incision was made in the skin overlying
the sagittal suture of the skull, and holes were drilled in the bone on each
side of the skull, 0.8 cm from the midline. A Teflon screw, through which
a silver wire was threaded so that the distal end protruded from the end of
the screw and was formed into a small solid ball, was screwed into each hole.
The incision was closed with an epoxy resin. The silver wires were soldered to
1 m of shielded cable. A ground was attached to the proximal end of the
shield, and 2-mm-range silver-plated miniature connectors were attached to all
three leads.
Electrodes for detecting eye movements (EOG) and muscle activity (EMG) were similar to those described above, except that the distal ends were fashioned into a small circle that was sutured into muscles above and below the orbit of the eye, or into the flexor and extensor muscles of the forearm. Grounds connected to the shields were sutured onto the adjacent fetal skin. To record FBMs by measuring fluctuations in intratracheal pressure (ITP), a polyvinyl catheter filled with saline [inner diameter (ID) 1.5 mm, outer diameter (OD) 2.7 mm] was inserted into the trachea, below the level of the larynx, and the top part of the trachea was ligated. Polyvinyl catheters (ID 1.0 mm, OD 1.5 mm, 150-cm length) filled with heparinized saline (100 U/ml; Baxter Health Care, NSW, Australia) were inserted into a fetal femoral artery and a tarsal vein. Another 1.5-mm ID x 2.7-mm OD catheter was placed in the amniotic cavity to measure intra-amniotic pressure (IAP), and 600 mg of procaine penicillin and 750 mg of dihydrostreptomycin sulfate (3 ml, Ilium Penstrep; Troy Laboratories, Smithfield, NSW, Australia) were injected into the amniotic cavity (9). Polyvinyl catheters (ID 1.5 mm, OD 2.7 mm) were inserted into a maternal femoral artery and vein. At the end of surgery, 600 mg of procaine penicillin and 750 mg of dihydrostreptomycin sulfate were given (im) to the ewe. For the next 2 days, these antibiotics were given to the fetus via the amniotic catheter. All arterial and venous catheters were flushed with heparinized saline (100-U/ml Heparin Injection BP; David Bull Laboratories, Mulgrave Victoria, Australia) daily. Ewes were housed in metabolic cages, and the ambient temperature was 18-23°C. They were given free access to water, lucerne chaff, and oats. Daily fluid and food intake and urine output were measured. Experiments were performed on the next 1-3 days after surgery.
Experimental protocol. On the day of an experiment, the ewe in her metabolic cage was wheeled into a small room, so that the cage could be shielded. The electrode around the renal nerve was connected to a high-impedance probe (model HIP5; Grass Instruments, Quincy, MA) connected to a Grass 7511L preamplifier and a Grass polygraph (model 7H). The incoming signal was amplified (up to 20,000 times) and filtered (band pass 30 Hz to 3 kHz). The output of the preamplifier was monitored using an oscilloscope and a speaker. It was rectified and integrated using an EM Leaky Integrator (Neomedix, NT124, NSW, Australia) with a 20-ms time constant. The raw nerve signal, the integrated signal, fetal MAP, and ECoG were also recorded onto a Vetter video recorder. ECoG, EOG, and EMG signals were amplified and filtered (sensitivities: 10 µV, 10 µV, and 15 µV/mm, respectively; bandwidths: 1 Hz to 3 kHz, 0.3 Hz to 0.3 kHz, and 1 Hz to 1 kHz, respectively) by use of a Grass 7511L preamplifier. MAP and IAP were recorded continuously using pressure transducers (Easyvent; Deadender Cap, Ohmeda, Sydney, Australia). All signals were sampled at 500 Hz with the use of an analog-to-digital data acquisition card (National Instruments, PCI-MIO-16E-4, Austin, Texas) and an IBM-compatible personal computer running Windows 95/98. Continuous chart records of MAP, IAP, ITP, ECoG, EOG, EMG, raw nerve, and integrated nerve signals were also obtained.
Fetal arterial blood samples (1 ml) were taken at the start of the experimental period. Arterial blood gases, pH, and bicarbonate were measured at 37°C and corrected to 39°C with the use of a Radiometer ABL 700 series (Radiometer, Copenhagen, Denmark). To test the responsiveness of the nerve to the arterial baroreceptors, fetal MAP was raised by infusion of phenylephrine from 1.2 to 2.4 mg/h (Neosynephrine; Sanofi-Winthrop, Boston, MA) or lowered by 0.96-1.92 mg/h (iv) of sodium nitroprusside (Mulgrave; Faulding Pharmaceuticals, Victoria, Australia).
Before any experimental manipulation, such as the baroreceptor challenge described above, recordings of fetal ECoG, EOG, EMG, ITP, MAP, and IAP were obtained for variable periods of time (up to 2 h).
At the end of the experiment, the ewe and fetus were given an overdose (15 ml) of pentobarbital sodium (Lethabarb, 325 mg/ml; Virbac, Peakhurst, NSW, Australia), and the level of residual RSNA was recorded.
Analysis of data. Fetal HR was derived from the MAP record. Fetal MAP was corrected by subtracting IAP.
Only data obtained before or sometime after an experimental manipulation, such as testing the baroreflex, were used to determine the relationships between fetal behavioral state and RSNA. The integrity of the renal sympathetic nerve was determined from inspection of the oscilloscope trace and from the auditory signal. In addition, we determined whether RSNA increased when MAP was lowered by injection of sodium nitroprusside or decreased when MAP was raised by phenylephrine (iv). RSNA was analyzed using software designed by Drs. S. Malpas and M. Navakatikyan (Dept. of Physiology, Univ. of Auckland, New Zealand). All signals were averaged over 2-s intervals. RSNA was corrected for background by subtracting values recorded from the nerve after death and expressed as arbitrary units. The chart records obtained during the experiment were used to define fetal state and choose those parts of the record suitable for analysis. This was necessary for several reasons. First, it meant that no segments were used where there was any evidence of gross electrical interference (that is the appearance of an identical electrical perturbation occurring in all leads at exactly the same time). Second, it enabled us to describe five fetal behavioral states. When we could not decide which behavior the fetus was displaying, the section of data was excluded. Third, it enabled us to clearly identify FBMs. The five behavioral states were defined as follows: 1) high-voltage ECoG activity not associated with FBMs or with significant EOG activity (HV), 2) low-voltage (LV) ECoG activity not associated with FBMs but associated with increased EOG activity and EMG activity (LV0), 3) LV ECoG activity associated with FBMs and increased EOG and EMG activity (LVB), 4) periods during which the fetus moved from HV to LV (HV to LV), and 5) periods during which the fetus transitioned from LV to HV (LV to HV).
Statistical analysis. The only way in which we could determine fetal state was to use our eight-channel polygraph records. From these we used ECoG, EOG, ITP, and EMG to determine fetal behavioral state. MAP, IAP, and raw and integrated renal nerve activity were also on the charts but were not used to determine fetal state. As stated above, we only excluded data if we could not determine the fetal state or if it was a period of recording measured after experimental manipulation of the fetus. The mean length of our analyzed records ranged from 2.5 ± 0.1 (mean ± SE) to 6.0 ± 0.3 min. (Individual values for each animal in each state for each day are shown; see Table 2.) At the same time as we collected our chart recordings, we derived and stored 2-s averages of MAP, IAP, HR, and integrated RSNA. Having determined fetal state from the chart record, we then found the same segments in our stored data and obtained the mean value in each record for each of the four variables.
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To control for variation between animals in MAP, HR, and RSNA, data were analyzed using ANOVA for repeated measures (23), and differences between means when the ANOVA was significant were detected by use of a Newman-Keuls test or Student's independent t-test. Values are expressed as means ± SE.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Table 1 shows the mean arterial PO2, PCO2, and pH on the 3 days after surgery. Three hundred twenty-two segments of the chart recordings were analyzed using software described in METHODS (see Fig. 1). There were significant differences in RSNA, MAP, and HR between different sheep. The fluctuations in ITP (FBMs) were highly variable in frequency (0-3 Hz), making it difficult to determine the respiratory rate. Occasionally, pressure fluctuations as great as 50 mmHg could be seen, but usually changes in ITP ranged from 5 to 25 mmHg in the one episode.
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Table 2 shows the number of recordings from each sheep on each day and the mean duration in each state on each day. There were no differences in the mean duration of recordings obtained over the 3 days. Six fetuses were studied on day 1, six were studied on day 2, and two sheep were studied on day 3. Table 2 also shows that the length of the periods of HV, LVB, and LV0 that were used were similar, but the lengths of the transitional periods (HV to LV and LV to HV) were less (P < 0.005). In total, 132 recordings were obtained on day 1, 131 on day 2, and 59 on day 3.
Figure 1 shows representative computer-generated records of 2-s averages of ECoG, IAP, RSNA, HR, and MAP from two fetuses in various behavioral states that were determined from the polygraph charts. Successful recordings of RSNA obtained for 3 days in two sheep from data were further analyzed to see whether any trends developed over the 3 days that RSNA was measured. RSNA was same on all 3 days in these two animals (2.6 ± 0.15, n = 35; 2.4 ± 0.14, n = 43; 2.79 ± 0.14 units, n = 59).
Table 3 shows that most records from the seven fetuses were obtained when they were in HV (26.4 ± 2.2%) or in LV and breathing (LVB: 33.6 ± 3.6%), but only a few records were obtained when fetuses were in LV and not breathing (LV0: 6.7 ± 1.7%); 15.4 ± 1.4 and 16.5 ± 0.5% of records of the transition states HV to LV and LV to HV were obtained. On the third day, a greater percentage of records of LVB and a lower percentage of records of LV0 were obtained (Table 4). Over the 3 days, there were four occasions when no LV0 records were obtained. On one day, no record of HV to LV was obtained (Table 2). Therefore, to obtain a sufficient number of records of LV0, data from all fetuses were used to study the effects of the five behaviors on RSNA, MAP, and HR.
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There were significant effects of fetal behavior on RSNA, MAP, and HR. RSNA was lowest in fetuses when they were in LV0 compared with all other states (Fig. 2; P < 0.001). In addition, RSNA was greater in LVB than in HV (P < 0.05). MAP was greater in HV and when the fetuses moved from LV to HV compared with both LV states (Fig. 3A; P < 0.001 to P < 0.03). HR was also higher in HV than in all other states (P < 0.001; Fig. 3B). In LVB, HR was also lower than when fetuses were going from HV to LV and from LV to HV (P < 0.01).
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In each behavioral state, we looked for relationships between RSNA, HR, and MAP. In three out of the five behavioral states, there was a significant inverse correlation between MAP and HR (Table 4). When fetuses were going from HV to LV or were in LV0, this relationship was not evident (Table 4). In LVB a direct correlation between RSNA and MAP was found (P = 0.004). Also, when fetuses were in the transitional state LV to HV, the correlation between RSNA and MAP was direct and almost significant (P = 0.08), and there was a significant inverse correlation between RSNA and HR (P = 0.02).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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250% at delivery as a result of exposure to a cold
environment (10). The increase
in fetal RSNA at birth depends on the late-gestation rise in cortisol. Thus
preterm lambs delivered at <120 days do not show a rise in renal RSNA at
birth unless treated with a synthetic glucocorticoid
(16). In addition, fetal
adrenalectomy is associated with failure of RSNA to increase at birth, an
effect reversed by intravenous infusion of hydrocortisone for 10 days.
(18). All these previous
studies were carried out in paralyzed fetuses and ewes (both were sedated with
diazepam). Even so, it was possible to show that there were periods in which
increases in RSNA, MAP, and HR occurred simultaneously
(17), although the reason for
these spontaneous fluctuations in RSNA, MAP, and HR was not determined. In the present study, we measured fetal RSNA in nonparalyzed fetuses while the ewe was standing quietly in a metabolic cage for the first time. Because we also measured fetal ECoG, EOG, and ITP, we could relate MAP, HR, and RSNA to fetal behavioral state. We have shown for the first time that fetal behavioral state and spontaneously generated breathing movements affect fetal RSNA as well as fetal MAP and HR.
It was also possible to collect records over several days. No recordings were obtained until 24 h after surgery. Like others, we were constrained by the viability of our nerve recordings to studying fetal RSNA <5 days after surgery. Because the fetuses were heavily instrumented to measure behavioral state, it was, we felt, an achievement to obtain recordings in two of the fetuses for up to 3 days and to demonstrate that there was no decline in nerve activity in these animals.
In preliminary studies, we found that RSNA was suppressed in the first 2 h after surgery, and for this reason we did not study the animals until 24 h had elapsed. This is in accordance with protocols established in studies of RSNA in fetuses carried by paralyzed, ventilated pregnant ewes (15, 17, 19). Thus it is unlikely that a high level of RSNA on the first day after surgery or a subsequent decline in RSNA in individual fetuses due to poor contact between nerve and electrode later in the experiment affected our findings. This conclusion is supported by the fact that we could not get a satisfactory record from fetus 4 until the second day after surgery (Table 2).
However, we accept that the variability in nerve activity in different fetuses could well be due to difference in contact between the nerve and the electrodes. For this reason and because both MAP and HR were also different between fetuses, we used repeated-measures ANOVA to analyze our results. Fetal sheep display two major states, REM and NREM (14). NREM is equivalent to HV. Two states of REM were detected. These were LV0 and LVB. About 30% of the time in REM is not associated with breathing activity (14). We did not set out to quantitate the total amount of time the fetuses spent in each behavioral state. To do this we would have had to have made continuous 24-h recordings, and we would not have been able to undertake any experimental manipulations such as testing the integrity of the nerve by raising and lowering MAP with pharmacological agents. However, the distribution of our records between the various fetal states agrees with previous reports (14), which probably accounts for the fact that we only had 24 records of LV0 compared with 103 records of LVB (Table 2). The incidence of periods of LVB were similar over the 3 days of the study (Table 3), which is surprising in that it has been reported previously that FBMs are suppressed within 24 h of surgery and anesthesia (4). We also looked at two transitional states (LV to HV and HV to LV) to see whether there were any marked fluctuations in MAP, HR, or RSNA at this time. There were no clearly marked alterations in MAP, HR, or RSNA, but we may have missed small or very transient fluctuations (see Fig. 1). Because we averaged data over these periods, we may have also obscured subtle differences in MAP, HR, and RSNA between HV and the two transitional states (Figs. 1, 2, 3).
It has been recognized that HR and MAP are higher in NREM or HV
(3,
14). We have also shown that
MAP and HR are higher at this time (Fig.
3). Although RSNA was also greater at this time than the activity
measured in LV0, it was not as great as nerve activity monitored
during LVB (Fig. 2).
Therefore, we have only partly substantiated the hypothesis of Segar et al.
(17) that synchronized changes
in MAP, HR, and RSNA represent a change in fetal behavioral state in that MAP,
HR, and RSNA were lowest in LV0 and higher in HV. However, MAP and
HR were also lower in LVB when RSNA was highest (cp. Figs.
2 and
3). Inspection of
Fig. 1 shows that in
LVB, there appeared to be greater variability in RSNA as though it
was affected/enhanced by FBMs. When fetuses were breathing vigorously, the
rate of respiration was 1.5-3 Hz, and the fluctuations in ITP were highly
variable. These rates are similar to those described by others
(2). Thus it was not possible
to determine the relationship, if any, between the individual fluctuations in
ITP and fluctuations in MAP, HR, and RSNA. At this time, we can only conclude
that integrated RSNA was highest in LVB. It is unlikely that this
increase in RSNA in LVB was due to an artifact generated by fetal
respiratory movement, as we have used a bipolar electrode and all our leads
were fully shielded. Furthermore, no artifacts were seen in other leads (e.g.,
ECoG, EOG, and EMG) when fetuses were breathing.
We occluded the trachea to obtain evidence of fetal breathing by measuring pressure changes within the fetal thorax. Because our studies were carried out on the first 3 days after surgery, it is unlikely that there would have been major changes in lung size over this time. It is also unlikely that the higher intrathoracic pressure due to tracheal occlusion had any significant effect on the activity of pulmonary afferents. A previous study from our laboratory showed that injections of very large volumes of 0.15 M saline did not affect pulmonary afferent nerve activity as measured by reflex HR response (12).
In terms of integrated control of HR and RSNA, a paradoxical relationship during LVB (i.e., lower HR and MAP in the presence of a higher level of RSNA) would not be surprising. Respiratory modulation of HR (through effects on cardiac efferent vagal tone) is well described in adult animals, and there is also respiratory modulation of RSNA in the adult (1) and of sympathetic nerve activity in the neonate (6). Inspiratory stimulation of cardiac sympathetic tone is unlikely in fetal sheep, as we have not been able to show that there is tonic sympathetic control of fetal HR or that the fetal cardiac sympathetics act as effector pathways for baroreceptor-induced changes in fetal HR (21). In addition, Gootman et al. (5) showed that efferent cardiac sympathetic control of HR did not mature fully in the pig until 1 mo after birth.
Segar et al. (17) suggested that the parallel changes in fetal HR and MAP that occurred in association with changes in RSNA represented fluctuations in sympathetic control of the fetal cardiovascular system. They showed that ganglion blockade abolished these spontaneous fluctuations. As stated above, we have found that there is little/no evidence of tonic control of fetal HR by the cardiac sympathetic nerves (except under extreme conditions, such as infusion of cold saline across the fetal skin; Ref. 22). If increased levels of RSNA reflect a general increase in sympathetic tone, this increase in sympathetic tone to fetal vascular beds combined with withdrawal of vagal tone might cause the parallel increases in HR, MAP, and RSNA observed by Segar et al. (17) and seen in HV NREM states in the present study (Figs. 2 and 3)
Our data do not show as clearly the coupling of RSNA, MAP, and HR observed by Segar et al. (17). This could be due to the fact that there are two clearly identified REM behaviors in our study, one associated with lack of breathing (LV0) and one associated with FBMs that varied in intensity and duration (LVB). RSNA has only been studied previously in paralyzed fetal sheep, in which FBMs would be abolished. Because the lowest level of RSNA, MAP, and HR occurred in LV0 and dissociation among MAP, HR, and RSNA occurred in LVB, the loss of this state in paralyzed fetuses would mean that the fetus only transitioned between LV0 and HV (NREM), resulting in a clearer delineation of the differences in the levels of RSNA, MAP, and HR in the two behaviors.
Stimulation of RSNA in LVB could be due to central interactions
with the generation of respiratory activity or to the effects of vagal
efferent discharge from activation of pulmonary stretch receptors. The
introduction of very small volumes of air into the fluid-filled fetal lung
were sufficient to cause a profound brady-cardia
(12), and artificial
ventilation of the fetal lung with air caused an 50% increase in fetal
RSNA (10). However, the
introduction of even large volumes of isotonic saline did not elicit this
reflex (12). FBMs, although
associated with measurable but variable changes in ITP, do not elicit marked
changes in lung volume, so it is difficult to see how they would activate
pulmonary stretch receptors, in that there is only limited flow of fluid in
the trachea when FBMs occur
(2). However, compression of
venous return associated with FBMs might elicit reflex changes in HR and RSNA.
Metsala et al. (11) measured
HR variability in fetal sheep and showed that it was increased when FBMs were
present. They speculated that this was due to reflex changes in HR mediated in
response to alterations in venous return resulting from FBMs. Inspection of
the 2-s averages of HR and MAP suggests that variability in both may have been
influenced by FBMs (Fig.
1).
One of the questions that arose was whether there was evidence of baroreflex-mediated regulation of fetal HR and whether it was influenced by behavioral state. In three states (HV, LVB, and LV to HV), an inverse relationship between MAP and HR was found. This suggests that the arterial baroreceptors were functioning over the normal range of fetal MAP. The two states in which there were no inverse relationships between MAP and HR, LV0 and HV to LV, have one factor in common. In both there was no fetal breathing. LV0 was that REM state in which RSNA, MAP, and HR were at their lowest levels (Figs. 1, 2, 3). Thus there may be "disorganization or disassociation" of integrated neural control of the fetal cardiovascular system in LV0. If this hypothesis is correct, then it is possible that during transition from LV to HV, there could be reengagement of integrated neural control of the fetal cardiovascular system. In addition, in LVB there may be central effects of fetal respiratory activity that enhance sympathetic control of the fetal cardiovascular system. In both LVB and LV to HV, where, according to the above hypothesis, there may be a greater degree of integrated control of the fetal cardiovascular system, there were not only negative relationships between MAP and HR but also positive (or near positive) relationships between RSNA and MAP and in LV to HV a negative relationship between RSNA and HR (Table 4). In HV, however, the only relationship found that suggested that the fetal baroreflexes are operating in this state was an inverse relationship between HR and MAP.
It is not surprising that a relationship between resting MAP and RSNA was only found in one fetal behavioral state. Fetal MAP depends on the combined fetal cardiac output (i.e., the output of both right and left ventricles, with right ventricular output being dominant) and systemic vascular resistance (i.e., resistance within the fetal body, which is under neural control; Ref. 8) as well as extracorporeal (placental) vascular resistance. About 58% of the combined cardiac output is distributed to the placenta, which has no neural innervation. Thus any relationship between resting MAP and fetal RSNA would be weak, as RSNA is low compared with postnatal levels. If RSNA reflects sympathetic tone throughout the fetal cardiovascular system, there may only be low-level sympathetically mediated fluctuations in systemic vascular resistance, and the low resistance of the placental circuit could buffer these. In support of this hypothesis is the fact that a positive relationship between MAP and RSNA occurred in LVB when RSNA was greatest (Fig. 2, Table 4).
The direct association between fetal RSNA and MAP might seem at odds with the well-described indirect relationship between MAP and RSNA that is induced when MAP is raised or lowered by mechanical or pharmacological means. Vasoactive agents such as phenylephrine and sodium nitroprusside cause changes in both systemic and placental vascular beds, resulting in more abrupt, greater, and more generalized changes in vascular resistance and hence greater stimulation of baroreceptors. This is very different from the parallel fluctuations in RSNA and MAP measured by us and by Segar et al. (17).
The physiological significance of the low levels of RSNA measured in fetal
life are unknown, and it is not clear whether changes in the level of RSNA
associated with changes in fetal behavioral state mediate any effects on the
developing kidney. However, renal renin levels are high in the late-gestation
fetal sheep (24) and play a
role in growth and development of the fetal kidney
(20). Denervation of the fetal
kidney results in failure of the surge in renin release at birth
(13), and renal denervation
for 6-8 days in late gestation leads to failure of isolated renin-secreting
cells to secrete renin in response to 
-adrenoceptor agonists
(7). Thus low-grade tonic RSNA
and its variability in different behavioral states may influence normal
development of the fetal renin-angiotensin system, which is essential for
normal renal development in late gestation
(20).
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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. Section 1734 solely to indicate this fact.
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