Robertsonlab.human.cornell.edu

Blood pressure and heart rate in the ovine fetus:ontogenic changes and effects of fetal adrenalectomy NOBUYA UNNO,1,2 CHI H. WONG,1,3 SUSAN L. JENKINS,1 RICHARD A. WENTWORTH,1XIU-YING DING,1 CUN LI,1 STEVEN S. ROBERTSON,4 WILLIAM P. SMOTHERMAN,3AND PETER W. NATHANIELSZ11Laboratory for Pregnancy and Newborn Research, Department of Physiology, College of VeterinaryMedicine, and 4Department of Human Development, Cornell University,Ithaca, New York 14853-6401; 3Laboratory of Perinatal Neuroethology, Department of Psychology,Binghamton University, Binghamton, New York 13902; and 2Department of Obstetricsand Gynecology, Faculty of Medicine, University of Tokyo, 113 Tokyo, Japan Unno, Nobuya, Chi H. Wong, Susan L. Jenkins, Rich-
weeks of gestation as a result of both an increase in ard A. Wentworth, Xiu-Ying Ding, Cun Li, Steven S.
cardiac output and a rise in peripheral vascular resis- Robertson, William P. Smotherman, and Peter W.
tance (18), whereas the decrease in FHR has been Nathanielsz. Blood pressure and heart rate in the ovine
ascribed to a baroreflex response to the increased FABP fetus: ontogenic changes and effects of fetal adrenalectomy.
(19), resulting in increased parasympathetic influence Am. J. Physiol. 276 (Heart Circ. Physiol. 45): H248–H256,1999.—Ontogenic changes in baseline and 24-h rhythms of via the vagus on basal FHR (48). However, the exact fetal arterial blood pressure (FABP) and heart rate (FHR) and mechanisms responsible for these changes are un- their regulation by the fetal adrenal were studied in 18 fetal known, partly because ontogenic changes in FABP and sheep chronically instrumented at 109–114 days gestation FHR have not been fully characterized.
(GA). In the long-term study, FABP and FHR were continu- It has been shown that influences of ␤-sympathetic ously recorded from 120 days GA to spontaneous term labor and parasympathetic activity on baseline FHR increase (Ͼ145 days GA) in five animals. Peak times (PT) and ampli- with gestational age in the sheep fetus (47). In addition, tudes (Amp) of cosinor analysis were compared at 120–126, plasma concentrations of hormones that have stimula- 127–133, and 134–140 days GA. Consistent, significantlinear increases in FABP and linear decreases in FHR were tory effects on the fetal cardiovascular system increase observed in all fetuses. Significant 24-h rhythms in FABP and with gestational age (25, 34, 41). However, relative FHR were observed during all the time windows. In the roles of the fetal endocrine and autonomic nerve system adrenalectomy study, to test the hypothesis that fetal cortisol in the ontogenic changes in fetal cardiovascular system plays a key role in cardiovascular maturation, fetal adrenals have not been characterized. Because glucocorticoids were removed in eight animals (ADX); sham fetal adrenalec- have a pronounced stimulatory effect on blood pressure tomy was performed on five animals (Con). Cortisol (4 µg/ (BP) in adult (40) and fetal (11, 12, 45, 50) sheep, it is min) was infused intravenously in four ADX fetuses from day possible that the ontogenic changes in the fetal cardio- 7 postsurgery for 7 days (ADXϩF). No significant changes in vascular system are, at least in part, regulated by the PT and Amp in FABP and FHR were observed. Plasmacortisol levels remained low in Con and ADX fetuses (Ͻ4.9 fetal hypothalamic-pituitary-adrenal axis. In one previ- ng/ml). Cortisol infusion increased fetal plasma cortisol to ous study, bilateral adrenalectomy (ADX) in fetal sheep 22.3 Ϯ 3.2 ng/ml (mean Ϯ SE) on day 13 in ADXϩF fetuses.
at 119 to 133 days of gestation (GA) produced no FABP increased in control and ADXϩF but not ADX fetuses; significant changes in FHR and FABP compared with FHR decreased in control and ADX but rose in ADXϩF intact fetuses (35). In a second study, short-term (5 h) fetuses. These results suggest that, in chronically instru- intrafetal cortisol infusion at Ͼ132 days GA to intact mented fetal sheep at late gestation, 1) increases in FABP fetuses produced an increase in plasma cortisol concen- and decreases in FHR are maintained consistently from 120 tration to 6.3 Ϯ 0.7 ng/ml and caused a transient to 140 days GA, with distinct 24-h rhythms, the PT and Ampof which remain unchanged, and 2) the physiological increase increase in FABP and a decrease in FHR (50). Finally, in FABP is dependent on the fetal adrenal; bilateral removal continuous cortisol infusion at a rate of 4 µg/min to of the fetal adrenals does not prevent the ability of cortisol to intact fetuses induced a sustained increase in FABP for produce a sustained increase in FABP.
up to 48 h when administered at 103–120 days GA, but cardiovascular system; circadian rhythm; adrenal; cortisol had no effect at 130–137 days GA (12, 45). Thesestudies demonstrated that glucocorticoids can act toincrease FABP, although they are not required for themaintenance of basal FABP. In addition they showed IN THE SHEEP FETUS during late gestation, arterial blood that the effect of glucocorticoids on FABP is gestational pressure (FABP) increases steadily (6, 10, 22) and fetal age dependent. In adult sheep, extensive investigations heart rate (FHR) declines steadily (22). It has been have been conducted on the BP increases produced by postulated that the FABP increases during the last few both ACTH and cortisol. It has been shown that ACTHadministration induces an increase in cardiac outputwith a consequent rise in BP within 24 h unaccompa- The costs of publication of this article were defrayed in part by the nied by changes in peripheral vascular resistance (40).
payment of page charges. The article must therefore be hereby In adult sheep it has also been reported that the marked ‘ advertisement’ in accordance with 18 U.S.C. Section 1734solely to indicate this fact.
ACTH-induced BP increase is not abolished by treat- 0363-6135/99 $5.00 Copyright ௠ 1999 the American Physiological Society ment with ␣- and ␤-adrenergic blockade, angiotensin- converting enzyme inhibitors, or ganglion blockades Surgery was performed under halothane general anesthe- (43), suggesting that mechanisms in addition to the sia on five ewes between 113 and 114 days GA in the sympathoadrenomedullary and the renin-angiotensin long-term study and on 13 ewes between 109 and 113 days GA system may be involved in mediating the hypertensive in the ADX study using techniques that have been described in detail (30, 31, 36). Briefly, polyvinyl catheters were in- Short-term cortisol infusion in intact fetal sheep at serted into a maternal carotid artery and jugular vein and Ͼ132 days GA decreases plasma norepinephrine and advanced into the arch of the aorta and superior vena cava,epinephrine concentrations (50). This suppression of respectively. The uterus was then exposed through a midline the fetal sympathoadrenomedullary system suggests Long-term study. Hysterotomy was performed, and fetuses that catecholamines play a relatively unimportant role were instrumented with polyvinyl vascular catheters in- in the cortisol-induced BP increase. However, more serted via the carotid artery and jugular vein. Multistranded direct experiments to explore the roles of catechol- stainless steel wire (Cooner Sales, Chastsworth, CA, catalog amines in the maintenance of the elevated BP have not no. AS 632) electrodes were sewn to the myometrium.
been conducted. Inasmuch as a previous study demon- ADX study. Hysterotomy was performed. In eight fetal strated that cortisol stimulated epinephrine release sheep both fetal adrenal glands were exposed and isolated via from cultured fetal adrenal medulla cells (17), it is a retroperitoneal approach and removed. In five fetuses the possible that the adrenal medulla plays a role in the adrenals were exposed but not removed (Con; n ϭ 5) (30).
Fetuses were instrumented with polyvinyl catheters inserted maintenance of the cortisol-induced FABP increase.
via the femoral artery and tibial vein. An amniotic cavity Furthermore, no information is available that ad- dresses the effects of fetal ADX on the ontogenic After surgical preparation of the ewe and fetus, all fetal changes in FHR or the effects of prolonged elevation of catheters and leads were grouped to exit the lateral abdomi- plasma cortisol levels on basal FHR.
nal wall of the ewe at a single point. Surgical closure was Several studies have demonstrated the existence of accomplished in layers. The ewe returned to the laboratory.
24-h rhythms in FABP (7) and FHR in sheep (7, 9, 24).
During the four days after surgery, the ewe received 1 g/day iv However, no study to date has examined whether there ampicillin sodium. The ewes were fed daily, and water was are ontogenic changes in amplitudes and peak times of available ad libitum. All fetuses were allowed to recover for atleast 5 days after surgery before being studied.
the 24-h rhythms in these fetal cardiovascular vari- Maternal and fetal arterial blood samples (0.5 ml) were ables. It has been suggested that glucocorticoids play a taken daily after the surgery for measurements of blood gases significant role in the regulation of 24-h rhythms of and pH on a blood gas analyzer (ABL500, Radiometer, FHR in the human fetus (1); however, there is no Copenhagen, Denmark). Measurements were corrected to information on the changes in the 24-h rhythms of 39°C. A heparin solution (10 U/ml physiological saline) was FABP and FHR after fetal ADX or sustained premature continuously infused at a rate of 0.5 ml/h into each vascular increases in plasma cortisol concentrations in the sheep catheter to ensure that catheters remained open.
In the present study we studied the chronically instrumented sheep fetus to test the hypothesis that From the sixth day after the surgery, FABP, FHR, and fetal cortisol plays a key role in cardiovascular matura- myometrial electrical activities were recorded continuously tion in late gestation. We characterized 1) the ontogenic throughout the study with the use of a data acquisition changes in FABP and FHR and 2) the ontogenic system that collected data averaged every second (16). FABP changes in the amplitude and the peak time of 24-h and amniotic cavity pressure were measured continuously rhythms in these fetal cardiovascular variables by with the use of a calibrated pressure transducer (Cobe, measuring hourly FABP and FHR continuously be- Lakewood, CO) connected to the fetal artery and amnioticcavity catheters. Amniotic fluid pressure was taken as the tween 120 and 140 days GA. In addition we also zero pressure reference for FABP. FHR was calculated from investigated 1) the effects of fetal ADX on the ontogenic the BP systolic peak to peak intervals. In each fetus, averaged changes in FABP and FHR and 2) the effects of fetal values of FABP and FHR were calculated every 40 s and ADX on cortisol-induced increases in FABP between analyzed with an IBM compatible personal computer using Microsoft Excel. Inappropriate signals due to blood sam-plings, fetal movements, and catheter malfunctioning wereexcluded. Hourly and daily averaged values for FABP and MATERIALS AND METHODS
FHR were calculated beginning at 0000 (Eastern Standard Time) on 120 days GA in the long-term study and at 1600 onthe sixth day after surgery in the ADX study.
Eighteen Rambouillet-Columbia crossbred ewes bred on a single occasion only and carrying a fetus of known gestational age were used. All procedures were approved by the CornellUniversity Animal Care and Use Committee. All facilities Long-term study. After the onset of labor, confirmed by the were approved by the American Association for the Accredita- presence of irreversible contraction-type myometrial electri- tion of Laboratory Animal Care. From 7 days before surgery, cal activities, the ewe and the fetus were killed with an the ewe was housed in a metabolic stall with ad libitum overdose of pentobarbital sodium (Fatal-Plus, Vortech Phar- alfalfa cubes and water in a room with controlled light-dark maceuticals, Dearborn, MI) and the body weight was deter- cycles (lights on at 0700 and off at 2100).
ADX study. From six days after surgery, 5 ml of maternal ADX study. Fetal body and organ weights were compared and fetal blood were collected daily between 0900 and 1000, among the three treatment groups using one-way ANOVA.
and plasma was removed, frozen in liquid N2, and stored at Changes in daily values of fetal blood gases and pH were Ϫ20°C until assayed for ACTH and cortisol. ADX fetuses were analyzed among the three groups using one-way ANOVA and divided into two groups. Four adrenalectomized fetuses in each treatment group using one-way RM ANOVA. Data for (ADXϩF) were continuously infused with cortisol (Solu- fetal plasma ACTH and cortisol concentrations were com- Cortef, Upjohn, Kalamazoo, MI) via the fetal venous catheter pared among the three treatment groups by one-way ANOVA at a rate of 4 µg/min starting at 1600 on the seventh day after or by Kruskal-Wallis nonparametric ANOVA where appropri- surgery until necropsy. The four other adrenalectomized ate. Changes in daily FABP and FHR values were compared fetuses (ADX) received vehicle alone. Fetuses were delivered by one-way RM ANOVA in Con and ADX fetuses. In ADXϩF by cesarean section and killed by exsanguination while under fetuses, daily FABP and FHR were analyzed between the halothane general anesthesia at 123–125 days GA. Complete- values on the day before infusion (day Ϫ1), 1 day after the ness of ADX was confirmed in all ADX and ADXϩF fetuses by commencement of infusion (day 1), and the fifth day of careful inspection of the surgical sites. Tissues were collected infusion (day 5) with the use of one-way RM ANOVA. Post hoc analyses for multiple comparisons were performed with theSNK test. Cosinor analysis was carried out to determine the presence of 24-h rhythms and to evaluate any change pro- Plasma ACTH concentrations were measured with a com- duced by ADX and ADXϩF. Cosinor curves were fitted to the mercial RIA kit (INCStar, Stillwater, MN) validated for hourly FABP and FHR data averaged in each animal from hormone measurements in sheep plasma (46). Assay sensitiv- day 1 to day 6. Peak times and amplitudes were compared over three treatment groups by one-way ANOVA.
coefficients of variation (CV) for quality control samples For all statistical tests, differences were considered to be containing 34.7 (pool of the assay kit), 10.9 (fetal pool), and 53.9 (maternal pool) pg/ml were 6.8 and 12.5%, 12.8 and 19.0%, and 6.5 and 10.7%, respectively. Plasma cortisolconcentrations were measured with a commercially available RIA kit (Diagnostic Products, Los Angeles, CA) validated formeasurements in sheep plasma (46). Intra-assay CV was Spontaneous labor was confirmed by the presence of 8.8% for a quality control sample containing 36.1 ng/ml (n ϭ contraction-type myometrial electrical activity at 20). Interassay CV was 2.3% for a quality control sample 146.7 Ϯ 0.5 days GA. At necropsy, fetal body weight was containing 29.9 ng/ml (n ϭ 20). Assay sensitivity (90% B/B0) Arterial blood gases and pH in ewes and fetuses.
Mean values for arterial blood gases and pHa in ewesand fetuses are presented in Table 1. There were no All data are presented as means Ϯ SE. Data were analyzed significant changes in pHa and arterial blood gases.
first by the summary of measures method (27) to focus the Overall changes in FABP and FHR. After we deleted unusable, corrupt, or unavailable periods of recording Long-term study. Daily average values for FABP and FHR signals, hourly values were obtained in 95 Ϯ 2% of total were determined in each fetus. Changes in FABP and FHRwith gestational age were analyzed with one-way repeated- period in each fetus. No cardiovascular data were measures (RM) ANOVA followed by the Student-Newman- analyzed within 2 days of labor. Daily average values Keuls (SNK) test for post hoc comparisons. Cosinor analysis for FABP and FHR from 120 to 143 days GA are was performed on hourly average values in each animal to presented in Fig. 1. FABP increased steadily with determine the presence of 24-h rhythms (33). Cosinor curves gestational age from 35.2 Ϯ 1.7 mmHg on 120 days GA were fitted to the hourly FABP and FHR data in each animal to 47.4 Ϯ 2.4 mmHg on 143 days GA, whereas FHR over 7-day periods (120–126, 127–133, and 134–140 days decreased with gestational age from 178 Ϯ 3 beats/min GA) after the subtraction of the linear component based on on 120 days GA to 143 Ϯ 2 beats/min on 140 days GA.
the results of the linear regression analysis. Among animals Between 140 and 143 days GA baseline FHR increased.
that revealed a significant 24-h rhythm, peak times and Ontogenic changes in 24-h rhythms in FABP and amplitudes were compared among three groups using one-way RM ANOVA. For the statistical analysis of arterial blood FHR. Hourly values in FABP and FHR beginning at gases and arterial pH (pHa), one-way RM ANOVA was 2400 on 120 days GA until 2300 on 143 days GA are applied on weekly average values, which was followed by the illustrated in Fig. 2. Cosinor analysis on 24-h rhythms of cardiovascular variables revealed significant 24-h Table 1. Arterial blood gases and pH in ewes and fetuses in the long-term study Data are presented as means Ϯ SE of 5 animals. Blood samples were taken at 0900–1000 every day beginning at 120 days gestation (GA).
Data were averaged in each animal to obtain representative values for each period. pHa, PaCO , Pa , arterial pH, PCO No significant differences were observed throughout the study period.
Table 2. Peak time amplitude of 24-h rhythms in FABPand FHR in the long-term study Values are means Ϯ SE of 5 fetuses, except in fetal arterial blood pressure (FABP) at 120–126 days GA and 127–133 days GA, wheren ϭ 4. FHR, fetal heart rate. No significant differences were observedthroughout the study period. Lights were on at 0700 and off at 2100.
Fig. 1. Daily fetal arterial blood pressure (FABP) and daily fetalheart rate (FHR) (n ϭ 5 ewes). Values were presented as means Ϯ SE.
pHa values in ADXϩF fetuses increased significantly FABP increased from 120 to 143 days gestation (GA), whereas FHR after cortisol infusion. Arterial partial pressure of O2 decreased steadily from 120 to 140 days GA. bpm, Beats/min.
(PaO ) in ADX fetuses was significantly lower than Con fetuses between the sixth and ninth day after surgery.
rhythms in FABP in four of the five fetuses between This difference in PaO was not observed during the rest 120–126 and 127–133 days GA and five fetuses during of the experimental period. A serial analysis revealed a 134–140 days GA; FHR showed significant 24-h significant increase of PaO in ADXϩF fetuses after rhythms in all of the five fetuses during all three gestational age windows. Peak times and amplitudes of Plasma ACTH and cortisol concentrations. In Con 24-h variations in FABP and FHR remained unchanged fetuses, fetal plasma ACTH levels remained stable throughout the study period (Table 2).
throughout the observed period (22.2 Ϯ 3.3, 20.6 Ϯ 2.4,and 22.2 Ϯ 3.3 pg/ml on day Ϫ1, day 3, and day 6, respectively). Plasma ACTH concentrations in ADX Fetal body and organ weights. At necropsy ADX fetuses were significantly greater compared with those fetuses and ADXϩF fetuses did not show any signifi- in Con fetuses (113 Ϯ 36, 107 Ϯ 31, and 128 Ϯ 37 pg/ml cant difference in body weight or in the weight of the on day Ϫ1, day 3, and day 6, respectively). In the fetal heart, lungs, kidneys, liver, spleen, or thymus ADXϩF group, the plasma ACTH concentration on day compared with Con fetuses (Table 3).
Ϫ1 was 120 Ϯ 93 pg/ml. After cortisol infusion, plasma Fetal blood gases and pH. pHa and arterial partial ACTH concentrations decreased and reached a level of 14.6 Ϯ 2.5 pg/ml on day 3. Fetal plasma ACTH re- out the experimental period, although pHa values in mained low (15.1 Ϯ 1.8 pg/ml on day 6) during the rest ADX fetuses were significantly lower than those in Con fetuses on the eighth and tenth day after surgery and There was no significant difference in maternal plasma cortisol concentration among the three groups,except on day 1, when the ADXϩF mothers showedsignificantly higher cortisol concentrations comparedwith Con and ADX mothers. No consistent interrelation-ship was found between maternal and fetal plasmacortisol concentrations. In Con and ADX fetuses, plasma Table 3. Fetal body and organ weights Fig. 2. Hourly FABP (A) and hourly FHR (B; n ϭ 5) beginning at Values are means Ϯ SE in grams; n ϭ 4 ewes each group. Con, 0000 on 120 days GA until 2300 on 143 days GA. Values are presented control; ADX, adrenalectomized; ADX ϩ F, ADX and cortisol-infused Table 4. Arterial blood gases and pH for fetuses of Con, Baselines of FABP and FHR. Daily baseline FABP ADX, and ADX ϩ F in the ADX study and FHR values on the sixth day after surgery were39.6 Ϯ 1.4 and 190 Ϯ 2, 39.4 Ϯ 1.6 and 185 Ϯ 1, and 44.9 Ϯ 1.9 mmHg and 187 Ϯ 3 beats/min in Con, ADX, and ADXϩF fetuses, respectively. There were no differ- ences among these groups. Hourly FABP and FHR values are shown for Con, ADX, and ADXϩF fetuses in Changes in FABP and FHR in Con and ADX. During the study period there was a significant increase in FABP associated with a significant decrease in FHR in Con fetuses. In contrast there was no significant change in FABP in ADX fetuses, whereas the decrease in FHR was similar to those in Con fetuses.
ADXϩF fetuses increased significantly on the first dayof cortisol infusion compared with values of the preced- ing day (Fig. 4C). This increase was sustained through- out the study period. FHR also increased after cortisol infusion (Fig. 4F). This increase was gradual compared with the FABP increase and remained sustained throughout the infusion period, which reached a signifi- cant level on the fifth day after the commencement of Changes in 24-h rhythms of FABP and FHR in ADX and ADXϩF. Cosinor analysis revealed a significant 24-h rhythm in FHR in three of four Con fetuses, four of four ADX fetuses, and four of four ADXϩF fetuses. No Values given are means Ϯ SE; numbers in parentheses are number difference was found in the peak time or amplitude of fetuses. Significant differences: * ADX vs. Con; † ADX or Con vs.
among the three treatment groups. The peak time and ADX ϩ F (1-way ANOVA, P Ͻ 0.05).
amplitude of each treatment group were not signifi-cantly different from those of the fetuses in the long- cortisol concentrations remained below the assay sensi- term study. Cosinor analysis was also applied to FABP, tivity level for the volume of plasma extracted (4.9 and a significant 24-h rhythm was found in two of four ng/ml) throughout the observation period. In ADXϩF Con fetuses, four of four ADX fetuses, and three of four fetuses, plasma cortisol concentrations increased signifi- cantly after the commencement of cortisol infusion andremained ϳ23 ng/ml (Fig. 3).
DISCUSSION
Long-term study. This study is the first to report measurement of FABP and FHR continuously over thecritical period of development from 120 days GA todelivery in the sheep fetus. This approach enableddetailed analysis on ontogenic changes in baselineFABP and FHR and in their 24-h rhythms. Kitanaka etal. (22) reported a steady increase in FABP and asimultaneous decrease in FHR from 110 to 120 days GAover 21 days in the sheep fetus. Because they measuredFABP and FHR for only 1 h every day, it was difficult todetect small differences in the trajectory of developmen-tal changes in these parameters. Brace and Moore (7)found that both FABP and FHR have 24-h rhythms inthe late gestation sheep fetus, although they did notspecify the gestational ages at which the study was Fig. 3. Fetal plasma cortisol concentrations in adrenalectomized,cortisol-infused (ADXϩF) fetuses. Values are means Ϯ SE (n ϭ 4).
conducted. In the present study, we used well-accli- Dotted line indicates sensitivity of the assay. * On the sixth and mated sheep and computer-based data acquisition us- seventh day after surgery, all values were below the sensitivity of the ing carefully calibrated transducers and amplifiers to assay. Cortisol infusion to fetuses at a rate of 4 µg/min was com- achieve longitudinal continuous recording of FABP and menced after the blood sampling on the seventh day after surgery FHR for 24 days. We demonstrated clear and consistent and continued until necropsy. Values in control and ADX fetuses werebelow the sensitivity of the assay throughout.
ontogenic changes in FABP and FHR from 120 to 143 Fig. 4. Hourly FABP and hourly FHR. Values aremeans Ϯ SE beginning on the sixth day (i.e., 24-hbefore the beginning of cortisol and/or vehicleinfusion) in control (Con), ADX, and ADXϩFfetuses. Each day starts at 1600. A: hourly FABPin Con fetuses (n ϭ 5). B: hourly FABP in ADXfetuses (n ϭ 4). C: hourly FABP in ADXϩFfetuses (n ϭ 4); D: hourly FHR in Con fetuses(n ϭ 4); E: hourly FHR in ADX fetuses (n ϭ 3); F:hourly FHR in ADXϩF fetuses (n ϭ 3). Barindicates period of cortisol infusion in C and F.
* First day of significant sustained increase fromday Ϫ1.
days GA with distinct 24-h rhythms. These findings decrease in PaO is related to the FABP profile in ADX strengthen previous studies and provide important fetuses, because the FABP profile did not change after information to understand the mechanisms of the the recovery of PaO during the latter one-half of the ontogeny of the fetal cardiovascular system.
experiment. Further studies are required to evaluate ADX study. To examine the possible roles of the fetal the precise causal mechanism and overall physiological adrenals in the changes in FABP and FHR that have relevance of the effect of ADX on the rise in FABP that been characterized in the long-term study, we investi- occurs at this stage of gestation. Cortisol infusion to gated the effects of fetal ADX on the normal gestational ADX fetuses beginning at 117 days GA resulted in a age-related changes in FABP and FHR and on the significant increase in FABP that was similar to previ- previously described increase in FABP produced by ous findings in intact fetal sheep (12, 45). This increase infusion of glucocorticoids to the fetus (12, 45, 50). A in FABP was sustained for Ͼ6 days throughout the recent study reported a significant reduction in fetal cortisol infusion period. These results clearly indicate body weight 4 wk after fetal ADX at 111–114 days GA that the fetal adrenal medulla does not play an indis- (49). It is possible that long-term changes in fetal pensable role in mediating cortisol-induced FABP in- conditions after fetal ADX affect not only fetal growth creases in late gestation fetal sheep. A previous study but also ontogenic changes in the fetal cardiovascular on adult sheep reported that total autonomic blockade system. Therefore, in the present study we evaluated does not attenuate ACTH-induced increases in FABP the effect of ADX for 2 wk after fetal ADX at the criticalperiod of adrenal development. At necropsy, no differ- (43), supporting our conclusion that the adrenal me- ences were observed in fetal body and organ weights dulla is not critically involved. However, these observa- among Con, ADX, and ADXϩF fetuses, which supports tions do not exclude the possibility of interaction of the concept that overall fetal condition was substan- glucocorticoids at either the receptor or postreceptor tially unchanged in all animals during the study pe- level with locally released catecholamines. The sus- riod. In a previous study we demonstrated that the tained effects of cortisol on FABP for up to 6 days in the average fetal plasma cortisol over the 5 days before present study support and extend the results of a spontaneous vaginal delivery in control fetuses was previous study of the effects of 48-h cortisol infusion to 59 Ϯ 10 ng/ml (28). Thus the levels of replacement we intact fetuses in which the FABP increase after cortisol achieved (Ϫ23 ng/ml) were within the physiological infusion was evaluated for 48 h (12). Our findings also range the fetus reaches in late gestation.
suggest that the cortisol-induced increase in FABP is BLOOD PRESSURE. After ADX, the FABP increase that not transient but may involve a fundamental change in normally occurs with gestation was attenuated, suggest- the regulation of the fetal cardiovascular system.
ing a significant contribution of the fetal adrenals to the The chronic hypertensive effect of glucocorticoids gestational age-related BP increase in fetal sheep.
during development we and others have demonstrated Although PaO values in ADX fetuses were significantly may play a role in the more long-term effects on BP that lower than Con fetuses during the first one-half of the follow prenatal glucocorticoid exposure demonstrated experimental period, it is not likely that this temporary in rats (3). Because growth retardation has been linked with development of high BP later in life (2) and an FHR decrease, such as baroreflexes, before circulating increase in fetal plasma cortisol concentrations in cortisol starts to increase exponentially at ϳ140 cordocentesis samples obtained from growth-retarded human fetuses has been reported (13), this stimulatory Twenty-four-hour rhythms in fetal cardiovascular action of cortisol on the fetal cardiovascular system system. Synchronized diurnal variations in BP and could be involved in the mechanism of adult hyperten- heart rate exist in the adult in many species, including sion and/or cardiovascular diseases of fetal origin. In rats (42), rabbits (14, 38), marmosets (39), monkeys addition, our findings of maintained effects on BP over (15), and humans (26), peak times of which correspond 6 days also have relevance to possible consequences of to the active period for respective species. In the sheep repeated antenatal glucocorticoid therapy adminis- fetus, similar diurnal rhythms in FABP and FHR have tered to women in threatened premature delivery over been described (7). However, ontogenic changes in the cardiovascular diurnal rhythms during fetal life have FETAL HEART RATE. Because the gestational age- not been characterized. Results of the present study related FHR changes are unaffected by ADX, our support previous findings and further indicate the findings suggest an insignificant role of fetal adrenal absence of ontogenic changes in the 24-h rhythms in maturation in this aspect of cardiac function. Changes FABP and FHR between 120 and 140 days GA in the in FHR in ADXϩF fetuses indicate a stimulatory effect sheep fetus. The mechanisms responsible for the 24-h of sustained elevation of plasma cortisol on basal FHR rhythms in the cardiovascular system have not been despite the concurrent increase in FABP. Because fully identified. It has been shown that the suprachias- baroreflexes are present and functional in the late matic nucleus, which is known as a ‘‘biological clock’’ in gestation sheep fetus (5), this stimulatory effect could mammals (23), plays a role in this phenomenon (20, be a result of alteration of the setting of the baroreflex 37). There is substantial evidence that suggests that responses. However, this is unlikely because changes in diurnal rhythms in BP and heart rate are under FHR in ADXϩF fetuses were completely opposite to sympathetic control (4, 21). A previous study in the FHR changes in Con and ADX fetuses. Alternatively, in human fetus reported that the 24-h FHR rhythm rats, it has been demonstrated that glucocorticoids disappears after maternal and fetal adrenal gland increase postsynaptic sensitivity of the cardiovascular suppression with triamcinolone (1), suggesting the system to norepinephrine (8). It has been also reported adrenocortical regulation of fetal 24-h rhythms. The that glucocorticoids enhance the sensitivity of the lack of changes in amplitudes of the 24-h rhythm in pacemaker ␤-adrenergic receptors to catecholamines FHR observed in the present study may suggest that (29). In adult sheep, Spence et al. (43) reported that the 24-h rhythm in the fetal cardiovascular system is acute ganglion blockade increased FHR to a greater regulated by an independent factor from fetal develop- level in ACTH hypertensive sheep than in normoten- ment, such as maternal endocrine environment, and/or sive controls and suggested that ACTH treatment may that the fetal mechanisms for this phenomenon are have a direct chronotropic action on the heart. Glucocor- already established at 120 days GA. Furthermore, the ticoids have also been suggested to play a key role in lack of an effect of fetal ADX with or without subse- the developmental changes in the function of cardiac quent continuous cortisol supplementation on the 24-h ␤-adrenergic receptors in the rat (32). In the sheep rhythm of FHR suggests the lack of involvement of bothfetus, a recent study (44) demonstrated that intrafetal fetal adrenal cortical and medullary effects on the fetal cortisol infusion at a rate of 0.5 mg · kgϪ1 · hϪ1 for 60 h to 24-h rhythm. Both the human and sheep data would be fetal sheep at 128 days GA produced no changes in compatible with a role for the maternal but not the fetal myocardial ␤-adrenergic receptor density and affinity; adrenal in regulating these rhythms. Further studies however a significant increase in adenylate cyclase are required to elucidate the mechanisms regulating activity in myocardial tissue was observed. Therefore it is likely that the increase in FHR after cortisol infusion In summary, we have demonstrated in fetal sheep to ADX fetuses results from a stimulatory effect of that 1) there is a consistent increase in FABP baseline cortisol directly on the fetal heart. It is also likely that and a decrease in FHR baseline at 120–140 days GA; 2) postreceptor events are involved in the changes in FHR the normal gestational age-dependent increase in FABP after cortisol infusion. Additionally, the baroreceptors that occurs in late gestation is attenuated by ADX at probably play a role in this cortisol-induced increase in 110 days GA in fetal sheep; 3) cortisol infusion begin- FHR because FHR in ADXϩF fetuses began to increase ning at 117 days GA to adrenalectomized fetal sheep on the second day of cortisol infusion, contrasting with produces a sustained increase in FABP and FHR, which the FABP increase that occurred immediately on the is maintained up to 6 days; 4) 24-h rhythms in FABP first day (Fig. 4, C and F). Thus the early rise in FABP and FHR exist from 120 to 140 days GA, and their peak may dampen the mechanisms that lead to the increase times and amplitudes do not change throughout the in FHR. In the long-term study, we observed a steady study period; and 5) the 24-h rhythm in FHR remained decrease in baseline FHR from 120 to 140 days GA and unaffected by fetal ADX with or without subsequent an increase between 140 and 143 days GA (Fig. 1). It is cortisol supplementation. Taken together, these find- possible that, in physiological conditions in sheep partu- ings obtained in the present study indicate that gluco- rition, the chronotropic effect of cortisol is not strong corticoids of fetal adrenal origin play an important role enough to override mechanisms that cause a baseline in regulating ontogenic changes in baseline FABP during late gestation in the sheep fetus, whereas their 16. Figueroa, J. P., S. Mahan, E. R. Poore, and P. W. Nathanielsz.
role in baseline FHR regulation does not appear to be Characteristics and analysis of uterine electromyographic activ-ity in the pregnant sheep. Am. J. Obstet. Gynecol. 151: 524–531, prominent until 140 days GA, and that the 24-h rhythms in FHR that exist during the last 3 wk of 17. Graham, D. M., L. D. Longo, and C. Y. Cheung. Catechol-
gestation are not regulated by the fetal adrenal.
amine secretion from the adrenal medulla of the fetus: regulationby hormones. J. Dev. Physiol. (Eynsham) 8: 227–236, 1986.
The authors thank Dr. Norio Shinozuka for data transfer and 18. Hanson, M. A. The control of heart rate and blood pressure in
analysis and Karen Moore for assistance in preparing this paper.
the fetus: theoretical considerations. In: Fetus and Neonate, This study was supported by National Institute of Child Health Physiology and Clinical Applications. Cambridge, UK: Cam- and Human Development Grants HD-28014 and HD-21350.
bridge University Press, 1995, vol. 2, p. 1–22.
Address for reprint requests: P. W. Nathanielsz, Laboratory for 19. Itskovitz, J., E. F. LaGamma, and A. M. Rudolph. Baroreflex
Pregnancy and Newborn Research, Dept. of Physiology, College of control of the circulation in chronically instrumented fetal lambs.
Veterinary Medicine, Cornell Univ., Ithaca, NY 14853-6401.
Circ. Res. 52: 589–596, 1983.
20. Janssen, B. J., C. M. Tyssen, H. Duindam, and W. J.
Received 2 March 1998; accepted in final form 29 September 1998.
Rietveld. Suprachiasmatic lesions eliminate 24-h blood pres-
sure variability in rats. Physiol. Behav. 55: 307–311, 1994.
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