Fetal Arterial Blood Pressure Research Articles

Development of cardiovascular function in the horse fetus

In mammals, the mechanisms regulating an increase in fetal arterial blood pressure with advancing gestational age remain unidentified. In all species studied to date, the prepartum increase in fetal plasma cortisol has an important role in the maturation of physiological systems essential for neonatal survival. In the horse, the prepartum elevation in fetal cortisol and arterial blood pressure are delayed relative to other species. Hence, the mechanisms governing the ontogenic increase in arterial blood pressure in the horse fetus may mature much closer to term than in other fetal animals. In the chronically instrumented pony mare and fetus, this study investigated how changes in fetal peripheral vascular resistance, in plasma concentrations of noradrenaline, adrenaline and vasopressin, and in the maternal-to-fetal plasma concentration gradient of oxygen and glucose relate to the ontogenic changes in fetal arterial blood pressure and fetal plasma cortisol concentration as term approaches. The data show that, towards term in the horse fetus, the increase in arterial blood pressure occurs together with reductions in metatarsal vascular resistance, elevations in plasma concentrations of cortisol, vasopressin, adrenaline and noradrenaline, and falls in the fetal : maternal ratio of blood P(a,O(2)) and glucose concentration. Correlation analysis revealed that arterial blood pressure was positively related with plasma concentrations of vasopressin and noradrenaline, but not adrenaline in the fetus, and inversely related to the fetal : maternal ratio of blood P(a,O(2)), but not glucose, concentration. This suggests that increasing vasopressinergic and noradrenergic influences as well as changes in oxygen availability to the fetus and uteroplacental tissues may contribute to the ontogenic increase in fetal arterial blood pressure towards term in the horse.

Chronic alterations in ovine maternal corticosteroid levels influence uterine blood flow and placental and fetal growth.

Previous work from this laboratory demonstrated that the elevation of maternal plasma corticosteroid concentrations during pregnancy is important for the support of fetal development. Reducing ovine maternal plasma cortisol concentrations to nonpregnant levels stimulates homeostatic responses that defend fetal blood volume. The present study was designed to test the hypothesis that chronic decreases or increases in maternal plasma cortisol concentration alter uterine and placental blood flow and morphology. Three groups of pregnant ewes and their fetuses were chronically catheterized and studied: ewes infused with cortisol (1 mg.kg(-1).day(-1); high cortisol), ewes adrenalectomized and underreplaced with cortisol (0.5 mg.kg(-1).day(-1); low cortisol), and control ewes. The normal increment in uterine blood flow between 120 and 130 days was eliminated in the low-cortisol ewes; conversely, uterine blood flow was increased in the high-cortisol group compared with the control group. Fetal arterial blood pressure was increased in the high-cortisol group compared with controls, but there was no increase in fetal arterial pressure from 120 to 130 days of gestation in the low-cortisol group. The fetuses of both low-cortisol and high-cortisol groups had altered placental morphology, with increased proportions of type B placentomes, and overall reduced fetal placental blood flow. The rate of fetal somatic growth was impaired in both low-cortisol and high-cortisol groups compared with the fetuses in the intact group. The results of this study demonstrate that maternal plasma cortisol during pregnancy is an important contributor to the maternal environment supporting optimal conditions for fetal homeostasis and somatic growth.

Effects of dexamethasone on the uterine and umbilical vascular beds during basal and hypoxemic conditions in sheep

Objective The purpose of the study was to test the hypotheses that maternal treatment with dexamethasone leads to a reduction in basal umbilical blood flow and diminishes the fetal umbilical hemodynamic response to acute hypoxemic stress in sheep. Study design While under general anesthesia, 23 ewes and their fetuses were instrumented with vascular catheters and transonic blood flow probes around a uterine and umbilical artery at 117 days of gestation (term, approximately 145 days). At 124 days, the ewes were injected intramuscularly with 2 doses of either dexamethasone (12 mg) or saline solution at 24-hour intervals. All animals experienced 2 episodes of hypoxemia during treatment (125±1 days) and after treatment (128±1 days). Results Maternal dexamethasone treatment caused a sustained increase in fetal arterial blood pressure (from 41±3 mm Hg to 45±3 mm Hg) and a transient fall in umbilical vascular conductance (from 6.2±0.9 mL · min −1 · [mm Hg] −1 to 5.4±0.7 mL · min −1 · [mm Hg] −1). During both episodes of hypoxemia, there was a significant increase in umbilical blood flow in the controls, but not in the dexamethasone-treated animals. Conclusion Maternal dexamethasone treatment with doses used in human clinical practice significantly decreased basal umbilical vascular conductance and prevented the normal increase in umbilical blood flow that is induced by acute hypoxemia in fetal sheep.

Cardiovascular and endocrine responses to cutaneous electrical stimulation after fentanyl in the ovine fetus

Objective The purpose of this study was to determine whether physical stimulation is stressful to the ovine fetus, as judged from physiologic changes that are similar to those reported for other stressors (such as hypoxia); whether any stress response could be blocked by clinically used doses of fentanyl; and whether fentanyl alone had any potentially deleterious physiologic effects in the fetus. Study design We investigated the effect of fentanyl analgesia on the cardiovascular and endocrine response to cutaneous electrical stimulation in the late gestation (>125 days) ovine fetus (n = 7 fetuses). Chronically implanted catheters and blood flow probes were used to measure fetal arterial blood pressure, heart rate, carotid and femoral blood flow, pH, P o 2, P co 2, lactate, cortisol, and β-endorphin levels before, during, and for 1 hour after 5 minutes of cutaneous electrical stimulation to the lip, forelimb, and abdomen, in a crossover design. Clinically used 30 or 150 μg doses of fentanyl (which approximated 10 or 50 μg/kg estimated fetal weight) or saline solution were given intravenously to the fetus 2 minutes before stimulation. Results When compared with the control, stimulation caused a significant rise in fetal heart rate ( P = .003; mean maximal rise, 48.6±14.0 beats/min, 0-10 minutes after the start of stimulation) but caused no change in any other parameters studied. Neither dose of fentanyl attenuated the changes in heart rate that were observed in response to stimulation alone. Fentanyl alone significantly increased fetal heart rate, carotid blood flow, and lactate and cortisol levels and significantly decreased pH and P o 2. Conclusion Cutaneous electrical stimulation in the fetal sheep causes an increase in heart rate, which fentanyl does not block. Fentanyl itself has significant effects on the cardiovascular and endocrine system, which might adversely affect the fetus.

Different Responses of Myocardial and Cerebral Blood Flow to Cord Occlusion in Exteriorized Fetal Sheep

Type and duration of fetal asphyxial insult affect the distribution of blood flow to the heart and brain. The purpose of this study was to describe dynamic and quantitative changes in regional myocardial and cerebral blood flow (CBF) during fetal asphyxia induced by total occlusion of the umbilical cord. Eleven exteriorized fetal sheep were subjected to total umbilical cord occlusion and five fetal sheep served as sham controls. Regional blood flow (BF) to the brain and heart was quantified using radioactive microspheres before and after 5 min of occlusion and finally when fetal mean arterial blood pressure had decreased below 25 mm Hg, 9.8 (0.8) [mean (SD)] min after occlusion. Right coronary arterial (RCA) blood flow velocity and carotid BF were registered continuously. Mean values of arterial pH and oxygen content (mL O(2)/100 mL) were 7.08 (0.11) and 4.4 (2.9) before cord occlusion and decreased to 6.83 (0.05) and 1.4 (0.9) at 5 min after occlusion (p < 0.01, respectively). Carotid BF was significantly below preocclusion values by 2.5 min (p < 0.05), whereas RCA velocity time integral per minute remained above preocclusion values for 9 min. CBF decreased from 316 (24) before cord occlusion to 156 (30) mL/min/100 g at 5 min (p < 0.01), whereas right myocardial BF was maintained at 792 (125) and 751 (183) mL/min/100 g, respectively. CBF decreased rapidly after total cord occlusion whereas myocardial BF increased and was maintained until shortly before cardiac arrest, suggesting the myocardium to be better preserved during this type of insult in already partially asphyxiated fetuses.

Relationships among Doppler-derived umbilical artery absolute velocities, cardiac function, and placental volume blood flow and resistance in fetal sheep

We hypothesized that umbilical artery (UA) absolute blood flow velocities measured by Doppler ultrasonography reflect placental volume blood flow (Q(UA)) and placental vascular resistance (R(UA)) in a late gestation fetal sheep model. In addition, we examined the relationships between umbilical artery absolute blood flow velocities and parameters of fetal cardiac function. Twenty-six sheep fetuses were instrumented at 112-132 days of gestation. After a 5-day recovery period, experiments were performed under general anesthesia in 16 normal fetuses, in 5 fetuses after maternal administration of phenylephrine, and in 5 fetuses after placental embolization. The Q(UA) and arterial blood pressures were measured using a transit-time ultrasonic flow probe and a catheter placed into the descending aorta, respectively. UA peak systolic velocity (PSV), end-diastolic velocity (EDV), time-averaged maximum velocity (TAMXV), pulsatility index (PI), mean velocity (V(mean)), fetal cardiac output, ventricular ejection forces, and the proportion of isovolumetric relaxation time (IRT%) in the cardiac cycle were measured with the use of Doppler ultrasonography. Significant positive linear correlations were found between UA EDV, TAMXV, and V(mean) versus Q(UA), whereas UA PI had a significant negative correlation with Q(UA). Significant negative correlations were shown between UA EDV, TAMXV, and V(mean) versus R(UA). A significant positive correlation was present between UA PI and R(UA). Doppler-derived UA parameters did not correlate with fetal arterial blood pressures, cardiac output, ventricular ejection forces or IRT%. In fetal sheep, Doppler-derived UA PI and absolute velocities, except PSV, are closely related to directly measured Q(UA) and R(UA), validating the use of noninvasive Doppler velocimetry in the assessment of placental circulation.

The effect of intrafetal infusion of metyrapone on arterial blood pressure and on the arterial blood pressure response to angiotensin II in the sheep fetus during late gestation.

While the impact of exogenous glucocorticoids on the fetal cardiovascular system has been well defined, relatively few studies have characterised the role of endogenous fetal glucocorticoids in the regulation of arterial blood pressure (BP) during late gestation. We have therefore infused metyrapone, an inhibitor of cortisol biosynthesis, into fetal sheep from 125 days gestation (when fetal cortisol concentrations are low) and from 137 days gestation (when fetal cortisol concentrations are increasing) and measured fetal plasma cortisol, 11-desoxycortisol and ACTH, fetal systolic, diastolic and mean arterial BP, heart rate, and the fetal BP responses to increasing doses of angiotensin II (AII). At 125 days gestation, there was a significant increase in fetal plasma ACTH and 11-desoxycortisol by 24 h after (+24 h) the start of the metyrapone infusion, and plasma cortisol concentrations were not different at +24 h when compared with pre-infusion values. Whilst the initial fall in circulating cortisol concentrations may have been transient, systolic, diastolic and mean arterial BP were ~5-6 mmHg lower (P < 0.05) in metyrapone- than in vehicle-infused fetuses at 24-48 h after the start of the infusion. When metyrapone was infused from 137/138 days gestation, there was a significant decrease in plasma cortisol concentrations by +6 h, which was followed by an increase back to pre-infusion values. While cortisol concentrations decreased, there was no change in fetal mean arterial BP during the first 24 h after the start of metyrapone infusion. Mean fetal arterial BP values at 137-139 days gestation were not different in fetuses that had been infused with either vehicle or metyrapone from 125 days gestation or with metyrapone from 137/138 days gestation. At 137-139 days gestation, however, arterial BP responses to increasing doses of AII were significantly blunted in fetuses that had been infused with metyrapone from 125 days gestation, when compared with fetuses that had been infused with metyrapone from 137/138 days gestation or with vehicle from 125 days gestation. The dissociation of the gestational age increase in arterial BP and the effects of intrafetal AII on fetal arterial BP indicates that increase in fetal BP with gestational age is not entirely a result of an increased vascular responsiveness to endogenous AII. Furthermore there may be a critical window during late gestation when the actions of cortisol contribute to the development of vascular responsiveness to AII.

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Cardiovascular regulation and expressions of NO synthase-tyrosine hydroxylase in nucleus tractus solitarius of ovine fetus.

The purpose of this study was to examine cardiovascular responses to fourth cerebral ventricle (4V) administration of nitroglycerin (NTG) or an inhibitor of nitric oxide (NO) synthase (NOS) in the near-term ovine and to determine whether, during birth, neuronal NOS (nNOS) is induced in noradrenergic A1 neurons in the medial nucleus tractus solitarius (mNTS). In chronically instrumented fetal sheep, 4V injection of NTG (1.2 nmol), an NO donor, produced an arterial blood depressor and a moderate decrease in heart rate. Arterial blood pressure is increased by 4V administration of NG-nitro-L-arginine methyl ester (10 nmnol), an inhibitor of NOS, in fetuses. Sections of the medulla from fetuses and newborn lambs were examined by using immunolabeling with tyrosine hydroxylase (TH) antibody combined with NADPH diaphorase (NADPHd) histochemistry, a marker of nNOS activity. The NADPHd-positive cells and TH-positive cells containing NADPHd reactivity were significantly increased in the mNTS of newborns compared with the fetuses. The results suggest that during birth, there is upregulation of NADPHd/nNOS in the noradrenergic neurons of mNTS resulting in a centrally mediated reduction of fetal arterial blood pressure.

The role of neuropeptide Y in the ovine fetal cardiovascular response to reduced oxygenation.

This study investigated the role of neuropeptide Y (NPY) in mediating cardiovascular responses to reduced oxygenation in the late gestation ovine fetus by: (1) comparing the effects on the cardiovascular system of an exogenous infusion of NPY with those elicited by moderate or severe reductions in fetal oxygenation; and (2) determining the effect of fetal I.V. treatment with a selective NPY-Y(1) receptor antagonist on the fetal cardiovascular responses to acute moderate hypoxaemia. Under general anaesthesia, 14 sheep fetuses (0.8-0.9 of gestation) were surgically prepared with vascular and amniotic catheters. In 5 of these fetuses, a Transonic flow probe was also implanted around a femoral artery. Following at least 5 days of recovery, one group of fetuses (n = 9) was subjected to a 30 min treatment period with exogenous NPY (17 microg kg(-1) bolus plus 0.85 microg kg(-1) min(-1) infusion). In this group, fetal blood pressure and heart rate were monitored continuously and the distribution of the fetal combined ventricular output was assessed via injection of radiolabelled microspheres before and during treatment. The second group of fetuses instrumented with the femoral flow probe (n = 5) were subjected to a 3 h experiment consisting of 1 h of normoxia, 1 h of hypoxaemia, and 1 h of recovery during a slow I.V. infusion of vehicle. One or two days later, the acute hypoxaemia protocol was repeated during fetal I.V. treatment with a selective NPY-Y(1) receptor antagonist (50 microg kg(-1) bolus + 1.5 microg kg(-1) min(-1) infusion). In these fetuses, fetal arterial blood pressure, heart rate and femoral vascular resistance were recorded continuously. The results show that fetal treatment with exogenous NPY mimics the fetal cardiovascular responses to asphyxia, and that treatment of the sheep fetus with a selective NPY-Y(1) receptor antagonist does not affect the fetal cardiovascular response to acute moderate hypoxaemia. These results support a greater role for NPY in mediating the fetal cardiovascular responses to acute asphyxia than to acute moderate hypoxaemia.

Hemodynamic changes during complete umbilical cord occlusion in fetal sheep related to hippocampal neuronal damage

Objectives: The purpose of our study was to examine the physiologic changes caused by 10 minutes of umbilical cord occlusion in fetal sheep and to determine the correlation between fetal acidemia or cerebral ischemia and hippocampal neuronal damage. Study design: Thirteen fetal sheep were instrumented and catheterized. Carotid artery blood flow (CaF), fetal mean arterial blood pressure (FMABP), pH, PCO2, base excess, oxygen saturation (SatO2), and PO2 were monitored throughout the occlusion study. Brain sections were examined for the hippocampal neuronal damage. Results: Our data showed severe ischemia (CaF: 10 ± 7 mL/min; FMABP: 29 ± 8 mm Hg) and acidemia (pH: 7.0 ± 0.05; base excess: −9.9 ± 2.4 mEq/L) at the end of occlusion. The neuronal damage score had significant correlations with ischemia and also with reperfusion, but not with the acidemic or hypoxic parameters. Conclusion: We demonstrated that the degree of hippocampal damage was correlated with the degree of ischemia and reperfusion. (Am J Obstet Gynecol 2003;188:413-8.)

Effects of low dose dexamethasone treatment on basal cardiovascular and endocrine function in fetal sheep during late gestation.

This study investigated the effects on ovine fetal basal cardiovascular and endocrine functions of fetal intravenous dexamethasone treatment, resulting in circulating concentrations that were one-fifth of the values measured clinically in human infants following maternal antenatal glucocorticoid therapy. Between 117-120 days gestation (dGA; term: ca 145 dGA), 26 Welsh Mountain sheep fetuses were surgically prepared under general anaesthesia with vascular catheters and a Transonic flow probe positioned around a femoral artery. At 125 +/- 1 dGA, fetuses were infused with dexamethasone (2.06 +/- 0.13 microg kg(-1) h(-1) i.v.; n = 13) or saline (n = 13) for 48 h. Daily fetal arterial blood samples were taken and cardiovascular data were recorded continuously (data acquisition system). Pressor, vasoconstrictor and chronotropic responses to exogenously administered doses of phenylephrine, angiotensin II and arginine vasopressin (AVP) were determined at 124 +/- 1 (pre-infusion), 126 +/- 1 (during infusion) and 128 +/- 1 (post-infusion) dGA. Fetal cardiac baroreflex curves were constructed using peak pressor and heart rate responses to phenylephrine. Dexamethasone treatment elevated fetal mean arterial blood pressure by 8.1 +/- 1.0 mmHg (P < 0.05), increased femoral vascular resistance by 0.65 +/- 0.12 mmHg (ml min(-1))(-1) (P < 0.05), depressed plasma noradrenaline concentrations and produced a shift in set-point, but not sensitivity, of the cardiac baroreflex (P < 0.05). Elevations in fetal arterial blood pressure, but not femoral vascular resistance and the shift in baroreflex set-point, persisted at 48 h following dexamethasone treatment. By 48 h following dexamethasone infusion, basal plasma noradrenaline concentration was restored, whilst plasma adrenaline and neuropeptide Y (NPY) concentrations were enhanced, compared with controls (P < 0.05). Fetal dexamethasone treatment did not alter the fetal pressor or femoral vasoconstrictor responses to adrenergic, vasopressinergic or angiotensinergic agonists. These data show that fetal treatment with low concentrations of dexamethasone modifies fetal basal cardiovascular and endocrine functions. Depending on the variable measured, these changes may reverse, persist or become enhanced by 48 h following the cessation of treatment.

The Normal Increase in Adrenal Secretion During Pregnancy Contributes to Maternal Volume Expansion and Fetal Homeostasis

This study was designed to test the hypothesis that the increase in maternal cortisol and aldosterone in pregnancy is critical to maternal and fetal homeostasis. Pregnant ewes were adrenalectomized (at approximately 112 days), and aldosterone and cortisol were given to either normal pregnant level (1 mg/kg per day cortisol and 3 microg/kg per day aldosterone) or nonpregnant level (half the dose of either cortisol or aldosterone). Blood samples for measurement of fetal and maternal plasma electrolytes, cortisol, and adrenocorticotropic hormone (ACTH) were collected at days 120, 125, and 130; fetal and maternal blood pressure and heart rate and maternal plasma volume were measured at days 120 and 130. Reduction of maternal cortisol or aldosterone decreased maternal plasma volume at 130 days. In the fetuses in the low cortisol group, cortisol concentrations were lower and ACTH concentrations were higher; however, there was no increase in fetal cortisol with age in the low cortisol or low aldosterone groups. Fetal arterial pressure was decreased in all groups of adrenalectomized ewes at 120 days and decreased in the low cortisol group at 130 days. Fetal arterial pressure was significantly related to maternal plasma volume at 130 days. Fetal arterial oxygen tension at 120 days was decreased in fetuses of low aldosterone ewes and was correlated with plasma volume. Overall fetal arterial oxygen tension correlated with fetal cortisol. Fetal ACTH concentrations correlated positively with fetal cortisol but negatively with fetal blood pressure. Maternal adrenal secretion maintains the normal increase in maternal plasma volume and fetal cortisol and indirectly supports fetal arterial oxygen tension, blood pressure, and adrenal secretion.

Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep.

It has been proposed that fetal adaptations to intrauterine nutrient deprivation permanently reprogram the cardiovascular system. We investigated the impact of restricted periconceptional nutrition and/or restricted gestational nutrition on fetal arterial blood pressure (BP), heart rate, rate pressure product, and the fetal BP responses to ANG II and the angiotensin-converting enzyme inhibitor captopril during late gestation. Restricted periconceptional nutrition resulted in an increase in fetal mean arterial BP between 115 and 125 days gestation (restricted 41.5 +/- 2.8 mmHg, n = 12; control 38.5 +/- 1.5 mmHg, n = 13) and between 135 and 147 days gestation (restricted 50.5 +/- 2.2 mmHg, n = 8; control 42.5 +/- 1.9 mmHg, n = 10) as well as an increase in the rate pressure product in twin, but not singleton, fetuses between 115 and 147 days gestation. Mean BP and fetal plasma ACTH were also positively correlated in twin, but not singleton, fetuses. This is the first demonstration that maternal undernutrition during the periconceptional period results in an increase in fetal arterial BP. This increase occurs concomitantly with an increase in fetal ACTH but is not dependent on activation of the fetal renin-angiotensin system.

Baseline function of placental vascular KATP -channels in healthy and in diabetic women

During pregnancy an optimal vascular function in the placenta is essential for normal fetal development and growth. Endothelial dysfunction in the fetal placental vascular bed in diabetes type 1 (DM) may contribute to the elevated perinatal morbidity and mortality in DM. The placental vascular bed is unique because it lacks autonomic innervation. Regulation of the placental circulation depends completely on locally produced vasoactive mediators. DM has been associated with endothelial dysfunction, in particular concerning the release of endothelium derived relaxing factors. One such factor is endothelium-derived hyperpolarising factor (EDHF) of which the identity remains unknown. EDHF relaxes smooth muscle cells at least partly by opening of ATP-dependent K+-channels (KATP-channels). We investigated whether the potassium efflux through KATP-channels contributes to the baseline vascular tone in the fetal placental vascular bed in diabetic patients as compared with healthy controls. We collected 11 placentas: four from diabetic patients and seven from healthy controls. Within 20 min of delivery a suitable cotyledon was selected for ex vivo dual perfusion. Fetal and maternal inflow were kept constant, perfusion fluid was oxygenated with 95% O2/5% CO2, temperature was 37° C and pH 7.4. A continuous measurement of fetal arterial blood pressure was performed. Because the perfusion flow was set at a constant level, the pressure in the circulation was considered to be a measure of the vascular resistance. By adding increasing concentrations of the KATP-channel blocker glibenclamide the KATP-channel dependent component of the baseline vascular tone in the fetal placental circulation was quantified. Concentration-response curves to glibenclamide were fitted by the sigmoid Emax model (GraphPad Prism), and the calculated Emax and EC50 were compared by two-tailed unpaired Student's t-tests (SPSS). The results as mean±s.e. mean. Baseline fetal arterial pressure was comparable in DM and controls (22.8 ± 2.8 vs 19.8 ± 0.4 mmHg). In controls, glibenclamide increased fetal arterial pressure concentration-dependently up to 56.3 ± 5.7 mmHg. In diabetes, a maximum pressure of 37.6 ± 4.2 mmHg was reached. The net glibenclamide-induced increase in pressure was attenuated in diabetes as compared with controls (14.7 ± 5.6 vs 36.5 ± 5.8 mmHg, P = 0.03) (Figure 1). The log EC50 did not differ between groups. Figure 1 The net glibenclamide-induced fetal arterial pressure in DM (n = 4, □) vs controls (n = 7, ▪). Glibenclamide induces vasoconstriction, pointing towards a functional role of KATP-channels in the regulation of baseline vascular tone in the placenta. In diabetes, this vasodilator mechanism appears to be impaired.

Prenatal undernutrition, glucocorticoids and the programming of adult hypertension.

1. A range of epidemiological studies has shown that poor intra-uterine growth is associated with an increased prevalence of cardiovascular disease, non-insulin-dependent diabetes mellitus and the Metabolic syndrome in adult life. 2. Because these associations are independent of adult lifestyle or current size, it has been postulated that a reduced intra- uterine nutrient supply perturbs fetal growth and, concomitantly, alters or programmes the structure and function of developing systems. 3. A reduced fetal nutrient supply may be a consequence of poor placental function or inadequate maternal nutrient intake. 4. It has been proposed that one outcome of either a suboptimal placental or maternal nutrient supply is exposure of the fetus to excess glucocorticoids, which act to restrict fetal growth and to programme permanent changes in the cardiovascular, endocrine and metabolic systems. 5. While a range of studies in the rat has investigated the impact of maternal undernutrition on arterial blood pressure in the offspring, there have been relatively few studies in species, such as the sheep, in which the responses of the cardiovascular and neuroendocrine systems to intra-uterine undernutrition can be measured before birth. 6. The present review summarizes recent evidence that poor placental function or inadequate maternal nutrition each results in an increased exposure of fetal sheep tissues to glucocorticoids and, in specific, changes in the regulation of fetal arterial blood pressure. 7. These studies are important in determining how the timing, type and duration of fetal nutrient restriction are each important in determining the nature of the fetal neuroendocrine and cardiovascular adaptive responses and their pathophysiological sequelae in later life.

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

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

Maternal undernutrition increases arterial blood pressure in the sheep fetus during late gestation.

1. We have investigated the effect of a 50 % reduction in maternal nutrient intake during the last 30 days of pregnancy on arterial blood pressure and on arterial blood pressure responses to angiotensin II (AII) and the angiotensin converting enzyme (ACE) inhibitor captopril in the sheep fetus at 115-125 and at 135-145 days gestation (term = 147 +/- 3 days gestation). 2. Fetal plasma glucose concentrations were lower in the undernourished (UN) group compared to the control animals. There was no difference, however, in fetal plasma cortisol or adrenocorticotrophic hormone (ACTH) concentrations between the UN and control groups between 115 and 145 days gestation. 3. During the first 10 days of undernutrition, maternal plasma concentrations of cortisol were increased in the UN group compared to controls. At 115-125 days gestation, fetal arterial blood pressure was also higher in the UN group compared with controls and there was an inverse relationship (r = -0.62, P < 0.05) between mean arterial pressure and the fetal plasma concentrations of ACTH in the UN group. Fetal blood pressure responses to increasing doses of angiotensin II were also higher (P < 0.05) in UN compared to control animals at 115-125 days gestation. 4. Between 135 and 145 days gestation, fetal arterial blood pressure was increased in UN fetal sheep and mean arterial blood pressure was correlated with fetal plasma concentrations of cortisol. 5. Increased arterial blood pressure and responsiveness to AII measured in the fetuses of nutrient-restricted ewes may be related in part to fetal exposure to the actions of cortisol derived from transplacental transfer during the first 10 days after the start of the restricted feeding regime.

Angiotensin-(1--7) in the ovine fetus.

In the adult animal, ANG-(1-7) may counterbalance some effects of ANG II. Its effects in the fetus are unknown. Basal ANG-(1-7), ANG I, ANG II, and renin concentrations were measured in plasma from ovine fetuses and their mothers (n = 10) at 111 days of gestation. In the fetus, concentrations of ANG I, ANG-(1-7), and ANG II were 86 +/- 21, 13 +/- 2, and 14 +/- 2 fmol/ml, respectively. In the ewe, concentrations of ANG I were significantly lower (20 +/- 4 fmol/ml, P < 0.05) as were concentrations of ANG-(1-7) (2.9 +/- 0.6 fmol/ml), whereas ANG II concentrations were not different (10 +/- 1 fmol/ml). Plasma renin concentrations were higher in the fetus (4.8 +/- 1.1 pmol ANG I x ml(-1) x h(-1)) than in the ewe (0.9 +/- 0.2 pmol x ml(-1) x h(-1), P < 0.05). Infusion of ANG-(1-7) (approximately 9 microg/h) for a 3-day period caused a significant increase in plasma concentrations of ANG-(1-7) reaching a maximum of 448 +/- 146 fmol/ml on day 3 of infusion. Plasma levels of ANG I and II as well as renin were unchanged by the infusion. Urine flow rate, glomerular filtration rate, and fetal arterial blood pressure did not change and were not different than values in fetuses receiving a saline infusion for 3 days (n = 5). However, the osmolality of amniotic and allantoic fluid was significantly higher in fetuses that received ANG-(1-7). Also, compared with the saline-infused animals, mRNA expression levels of renin, the AT(1) receptor, and AT(2) receptor were elevated in kidneys of fetuses that received infusions of ANG-(1-7). Infusion of an ANG-(1-7) antagonist ([D-Ala(7)]-ANG-(1-7), 20 microg/h) for 3 days had no effect on fetal blood pressure or renal function. In conclusion, although infusion of ANG-(1-7) did not affect fetal urine flow rate, glomerular filtration rate, or blood pressure, changes in fetal fluids and gene expression indicate that ANG-(1-7) may play a role in the fetal kidney.

Daily rhythms in renal blood flow and urine production rate in the near-term sheep fetus.

Daily rhythmicity of renal blood flow (RBF) and urine flow (UF) was studied in fetal sheep between 121-125 d of gestation. Fetal arterial blood pressure, heart rate, UF, and right RBF were measured continuously for 24-h periods in 10 sheep. Rhythmic variations during a 24-h period were found for all variables studied. The rhythms of arterial blood pressure and heart rate were highly correlated, whereas an inverse correlation was found between arterial blood pressure with RBF and between arterial blood pressure with UF. These findings indicate that fetal RBF is not blood pressure dependent. Furthermore, fetal UF appears not to be mediated by pressure-dependent diuresis.