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1 Department of Biology, University of Saratov, Saratov, Astrakhanskaya str. 83, 410026, Saratov, Russia2 Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
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(Received 15 October 2003;
accepted after revision 19 March 2004;
first published online 19 March 2004)
Corresponding author N. Igosheva: Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Email: n.igosheva{at}imperial.ac.uk
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Introduction |
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In parallel to the low birthweight/cardiovascular risk literature there is also a considerable body of work which has focused on neuroendocrine and behavioural aspects of fetal programming. In these studies, a protocol frequently used to investigate long-term effects of early life environmental factors on the behavioural development of the offspring is that of prenatal stress (PS). In animal models, there is strong evidence that prenatal stress can reduce birthweight and also lead to developmental and behavioural disorders (Homer et al. 1990; Copper et al. 1996; Lordi et al. 1997; Schneider et al. 1999). However there are also some studies which describe higher birthweight in PS offspring (Szuran et al. 1991) and some which find no differences in birthweight between the groups (Weinstock et al. 1998a). Among the behavioural attributes of adult PS rats, increased emotionality, defensive behaviour and anxiety have been shown (Chapillon et al. 2002). These are associated with long-term changes in the adult offspring hypothalamic–pituitary–adrenal axis, in general programming a persistently hyperactive system and impaired negative feedback regulation (Barbazanges et al. 1996; Welberg & Seckl, 2001; Matthews, 2002). Offspring exposed to chronic stress during pregnancy have elevated basal and stress-induced plasma concentrations of adrenocorticotropin, corticosterone and a prolongation of stress-induced corticosterone and catecholamine responses (Weinstock et al. 1998a; Matthews, 2002).
Although it has been shown that intrauterine events can permanently affect the neuroendocrine and behavioural reactivity of the offspring, the extent to which prenatal stress may affect cardiovascular reactivity to stress in adulthood has not been studied. One small study showed that stressing the mother rat throughout pregnancy significantly increased systolic arterial pressure (SAP) in adult male offspring but not in females; there was no effect on diastolic pressure. Cardiovascular responses to stress were not analysed in this study (Holst et al. 2002).
There is growing evidence that the behavioural and neuroendocrine consequences of prenatal stress may differ significantly depending upon the sex of the offspring (McCormick et al. 1995; Szuran et al. 2000; Sternberg & Ridgway, 2003). However, sex-specific effects of prenatal stress on the cardiovascular system stress responsiveness have not been investigated.
Thus, the present experiments were designed to determine whether prenatal stress influences cardiovascular function in adult offspring and both female and male offspring from stressed dams were studied.
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Animals and housing conditions
Sprague-Dawley rats (250–300 g) were housed with free access to food and water, under a constant light–dark cycle (light on from 07.00 h to 20.00 h), with controlled temperature (22 ± 2°C). All female rats were handled for 2 weeks before starting the experimental protocol. For breeding, the virgin female rats were caged with mature males overnight during a whole oestrus cycle. A vaginal smear was examined the next morning. Day 0 of pregnancy was marked by the appearance of a copulation plug. Females who failed to become pregnant after developing a copulation plug were excluded from the study. Each pregnant female was separated and kept in an individual cage under standard conditions. Pregnant females were assigned randomly to prenatal stress (n= 8) or control (n= 8) groups. In the rat the duration of pregnancy is about 21 days and rat dams typically give birth to 12 pups per litter.
Prenatal stress protocol
Pregnant rats were stressed daily from day 15 to day 21 of pregnancy. They were exposed to a regimen of heat, light and restraint stress by placing the female into a Plexiglas restraint tube (20 cm x 6 cm x 8 cm) over which were poised two 100 W flood lights. This procedure produced no more than 60 lux direct exposure and an ambient temperature within the restraint tube of approximately 38°C. Animals were submitted to three 30 min stress sessions at 10.00, 13.00 and 18.00 h (Ward, 1984). Control mothers were left undisturbed for the duration of their pregnancies. This protocol was chosen because it has been used in many previous studies and shown to significantly affect neuroendocrine and behavioural stress reactivity in offspring (Insel et al. 1990; Henry et al. 1994; Barbazanges et al. 1996; Day et al. 1998; Williams et al. 1999; Szuran et al. 2000; Sternberg & Ridgway, 2003) It also produces permanent alterations in brain neurotransmitter systems which are involved in cardiovascular control (Insel et al. 1990; Cratty et al. 1995; Edwards et al. 1999).
All dams delivered at term (on 21st–22nd day of gestation). The offspring were left undisturbed on the day of birth. On the postnatal day 2 the offspring born to stressed mothers were cross-fostered to recently parturient control dams to control for any possible mothering effects. During this procedure, stressed and control mothers were removed form their cages for less than 1 min and then the pups born to stressed mothers were exchanged for the same age litter born to control non-stressed mothers. Likewise, litters of control dams were cross-fostered to control dams who gave birth within the same 48-h period to control for any possible effects of a single separation and pup exchange. Litters were adjusted to 10 pups with equal numbers of males and females to standardize conditions and ensure an adequate milk supply. The offspring were weaned at 21 days. Upon weaning, litters were mixed so that the same-sex rats exposed to the same conditions (but from different litters) were housed together in groups of three to five subjects per cage. Animals were tested at 6 months of age. Two animals of each sex from any one litter were studied at a given age, and these were randomly chosen to remove any litter effects.
Cardiovascular parameters in the adult offspring
Surgical procedures. At 6 months animals of both groups (PS and control, n= 7 per group) were anaesthetized with an intraperitoneal injection of a mixture of ketamine hydrochloride (40 mg kg–1), xylazine (8 mg kg–1) and chlorpromazine hydrochloride (4 mg kg–1) and instrumented with femoral arterial and venous catheters (PE-50 heat-fused to PE-10) for the recording of arterial pressure and intravenous drug administration. Before surgery the rats were pretreated with the analgesic buprenorphine (0.1 mg kg–1S.C.) and received antibiotics gentamicine sulphate (0.2 ml kg–1S.C.). Supplemental anaesthesia was given when necessary as shown by marked changes in blood pressure, heart rate (HR), or respiration during surgery or in response to a pinch of the hind paw. The catheters were tunnelled subcutaneously and exteriorized at the back of the neck. They were flushed daily with heparinized saline, filled with heparin (1000 U ml–1), and plugged with a plastic obturator. The animals were given subcutaneous fluids and buprenorphine (0.1 mg kg–1S.C.) for postoperative analgesia before being placed in a recovery box. After immediate recovery from anaesthesia, animals were returned to their cages for 24 h.
Experimental protocols.
All experiments were conducted between 09.00 and 11.00 h. On day 1 the rat was transferred to the testing room and the arterial catheter was connected to a sterile disposable blood pressure transducer (ADInstruments, Australia). The output of the transducer passed through an analog-to-digital converter, whose signal was then fed into a computerized data acquisition system PowerLab/4SP (ADInstruments). The system was set to sample the blood pressure waveform at 200 Hz. A 30-min acclimatization period allowed arterial pressure (AP) and HR to reach a steady state and baseline haemodynamic parameters were recorded for 30 min. Baroreflex function was assessed in freely moving rats by recording the maximum HR changes at the time of maximum increase and decrease in arterial blood pressure produced by intravenous bolus injections of phenylephrine (PE; 1, 2, 4 µg kg–1) or sodium nitroprusside (SNP; 5, 10, 20 µg kg–1; each in 100 µl of 0.9% saline followed by 200 µl of 0.9% saline) at increasing rates. The doses of nitroprusside and phenylephrine were chosen according to the results of previous experiments so that the linear range of the relationship between mean arterial pressure (MAP) and HR was covered, i.e. changes of basal MAP up to ± 35 mmHg. Approximately 60 s was required to increase and decrease MAP. Subsequent injections of nitroprusside or phenylephrine were only performed when MAP and HR had returned to baseline. Baroreceptors were always uploaded first (PE administration) before unloading (SNP administration) to minimize any potential effects of reflexly released humoral agents, such as vassopressin or angiotensin II, on baroreflex function. The data from each animal were fitted to a sigmoid logistic function as described by Kent et al. (1972), using a non-linear regression program (GraphPad Prism v. 3.00 for Windows, GraphPad Software, San Diego, CA, USA). This analysis evaluates the relationship between HR and MAP, where
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| (2) |
Experimental protocol for effects of acute restraint stress. On day 2, the reactivity of PS and control rats was tested with restraint stress. Blood pressure was recorded continuously in the rat during 30 min of placement in a Plexiglas restraining tube (19 cm x 6 cm x 9 cm), and 30 min following return to the home cage. In order to assess the baroreflex control of heart rate during restraint stress, an intravenous bolus injection of PE (2 µg kg–1) and SNP (10 µg kg–1) was given 10 min after the onset of restraint stress. Only single doses of each drug were given to avoid overlapping stress-induced and drug-induced cardiovascular responses.
The values of diastolic (DAP) and systolic arterial pressure (SAP) and HR were measured and analysed with PowerLab, ChartTM. software (PowerLab, ADInstruments). In addition, the standard deviation of mean arterial pressure (S.D.MAP) was calculated for every minute of the recording period. The mean S.D.MAP was used as a measure of the short-term variability of blood pressure, i.e. the extent of the variation in blood pressure within every minute (Parati et al. 1987; Van Vliet et al. 1996).
Animals were killed by sodium pentobarbitone overdose (I.P.).
Statistical analysis
Results are expressed as means ± standard error of the mean (S.E.M.) with P < 0.05 taken as the minimum level of significance. Baseline resting haemodynamic parameters were analysed using Student's unpaired t test. Haemodynamic data were analysed using mixed design repeated measures ANOVA with prenatal condition (prenatal stress and control) and sex (males, females) as between-subject factors and time as a within-subject factor with time being the repeated measure. Separate two-way repeated measures ANOVAs were performed on cardiovascular responses during the restraint stress and during recovery from restraint in the home cage. ANOVAs were performed on both absolute values and percentage changes in cardiovascular variables. A two-way analysis of variance was also used to evaluate differences in baroreflex function parameters (P1, P3 and P4), maximum HR, maximum gain of arterial baroreflex regulation of HR (Gmax), and the average rate of change in blood pressure during generation of baroreflex curves. Finally, where appropriate, post hoc comparisons were undertaken, using Duncan's multiple range method. All statistical analyses were performed using the Statistica 5.0 software package (StatSoft Inc., Tulsa, OK, USA).
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Sex differences in baroreflex parameters were not apparent in either group. Sexes were therefore combined in subsequent analysis of baroreflex gain. Mean sigmoid curves describing the baroreflex control of HR in control and PS rats are shown in Fig. 1A.Figure 1B illustrates the gain of the baroreflex curves as a function of arterial pressure. There were no differences in any baroreflex parameter or the maximum baroreflex gain between control and PS rats (Table 2).
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Upon exposure to restraint stress all rats exhibited a marked rise in SAP (F= 4.3, P < 0.01) (Fig. 2). Prenatal stress had a significant main effect (F= 10.2, P < 0.01) on the SAP response evoked by restraint stress whereas sex did not affect acute SAP stress responses. Separate ANOVAs for each sex showed that PS females had a higher SAP increase than control females (F= 5.2, P < 0.05). Significant prenatal stress–time interactions (F= 2.2, P < 0.05) were also found for SAP, indicating that PS and control females changed in different ways over time in response to restraint stress. Thus, post hoc analysis revealed that PS females showed higher SAP values almost across the whole stress period than females of the control group (P < 0.01, minutes 1–20). There was also a significant effect of prenatal stress (F= 11.2, P < 0.01) on SAP responses to restraint stress in males: the magnitude of stress-induced SAP responses was significantly higher in PS males in comparison with control males (P < 0.01, minutes 1–22).
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Diastolic arterial pressure responses to restraint stress and recovery in control and PS rats
Figure 3 presents changes in DAP in PS and control rats during restraint stress and the recovery period. Restraint stress caused a significant but transient DAP increase in all animals (F= 4.1, P < 0.01, minutes 1–3). ANOVAs yielded no significant effect of either prenatal stress or sex on acute DAP responses to restraint stress.
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Arterial pressure variability during stress and recovery in control and PS rats
Figure 4 shows changes in standard deviation of blood pressure signal (S.D.MAP) during restraint stress and recovery periods in control and PS rats of both sexes. Following exposure to restraint stress blood pressure variability increased markedly in all animals (F= 3.2, P < 0.01). ANOVAs revealed a significant effect of prenatal stress on blood pressure variability changes during acute restraint stress (F= 5.6, P < 0.02). Post hoc analysis indicated that this effect was due to the higher S.D.MAP values of PS animals compared to that of the control group (P < 0.05, 1–20 min). There were no sex-related differences in S.D.MAP changes during the acute restraint stress period.
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Heart rate responses to restraint stress and recovery in control and PS rats
The time course of changes in HR during restraint stress and recovery is shown in Fig. 5. Upon exposure to restraint all animals exhibited a marked increase in HR (F= 4.5, P < 0.01). This response was similar in magnitude in PS and control rats. ANOVAs for HR stress values also revealed no differences between sexes. There were, however, differences in the time course of HR stress responses: in control rats stress resulted in a short-term transient increase in HR whereas in PS rats stress-induced tachycardia was sustained for 12 min of the stress period.
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Arterial baroreflex regulation of HR during restraint stress in control and PS rats
As shown in Table 3 phenylephrine increased mean arterial pressure by approximately 25% in both PS and control animals. A subsequent HR response to baroreceptor uploading did not differ between the groups. The magnitudes of nitroprusside-induced changes in MAP and HR were also similar in PS and control animals. There were no sex-related differences in baroreflex regulation of HR during stress exposure.
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Discussion |
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Alterations in cardiovascular function of PS rats were evident when the animals were challenged by acute restraint stress. Prenatal stress also determined the duration of the cardiovascular responses during recovery and their return to baseline levels. The results demonstrated that PS rats had an increased peak of SAP responses following the restraint stress and an extended duration of SAP responses during both acute stress and recovery. Diastolic arterial pressure responses to the acute restraint did not differ between the groups but the return to rest was again delayed in PS rats. In addition, PS animals showed more prolonged HR responses to acute stress and delayed recovery in comparison with control rats. Interestingly, although PS animals demonstrated enhanced SAP stress responsiveness, arterial baroreflex control of HR during the restraint stress did not differ between PS and control rats. Finally, our results showed that PS rats had a greater increase in blood pressure variability compared with control animals during exposure to restraint stress. In the recovery period PS females showed higher blood pressure variability than control females and PS males.
At rest, we did not detect any differences in the baroreflex gain between the groups. The baroreflex function curve was shifted to the right in the rats of stressed dams, suggesting resetting of baroreflex regulation to a higher level in PS animals. However, this difference in our experiments was not large enough to be statistically significant. Although we attempted to standardize the baroreflex testing protocol, it is possible that a high degree of variability was introduced using this method and therefore prevented us from detecting any differences in baroreflex function between PS and control animals. We also cannot exclude the possibility that the sample size was not large enough to detect significant differences in baroreflex curve parameters and the baroreflex sensitivity between the groups. The methodology did not provide detailed information regarding the relative contribution of the sympathetic and parasympathetic systems to baroreflex heart rate responses. Further research will be necessary to address these points and gain a more detailed understanding of the underlying mechanisms.
The only previous study, to our knowledge, that has examined prenatal stress in relation to cardiovascular function is that of Holst et al. (2002). However, in that study the authors stressed the pregnant females throughout their pregnancy and only basal cardiovascular parameters were measured in the adult offspring. In contrast to our data they reported increased basal SAP in prenatally stressed males while no effects on females. These different findings may be due to the different prenatal stress protocol; also the timing of prenatal manipulations may affect cardiovascular function differently.
Two recent studies on fetal programming have also found an effect on cardiovascular responses but not basal haemodynamics. Maternal malnutrition (Tonkiss et al. 1998) and prenatal hypoxia (Peyronnet et al. 2002) were used as adverse prenatal factors. Resting cardiovascular parameters were unaltered in the adult offspring but blood pressure responses to acute stress were higher in the groups of animals prenatally exposed to the adverse environment. These data and our own results show that physiological differences between PS and control animals may only become apparent under testing conditions of adult stress (Weinstock, 1997). The similarities between the physiological consequences of malnutrition, prenatal hypoxia and maternal stress suggest that there may be common mechanisms that mediate the effects of the prenatal environment on the cardiovascular responses to stress in adulthood, possibly alterations of the hypothalamic–pituitary–adrenal axis.
Animal studies suggest that glucocorticoids can be important ‘fetal programming’ factors in prenatal stress protocols. In rodent models prenatal stress has been shown to result in up-regulation of glucocorticoid concentrations in both mother and fetus (Dauprat et al. 1984; Cadet et al. 1986) and excessive exposure of the fetus to maternal steroids may constitute at least part of the programming stimulus. (Dodic et al. 1999; Seckl, 2001). Indeed, several studies have demonstrated that prenatal glucocorticoids or stress can affect the development and maturation of specific organs related to blood pressure control and maintenance, such as heart, vasculature, kidney and brain (Seckl, 2001; Welberg & Seckl, 2001; Dodic et al. 2002). Administration of prenatal glucocorticoids have been shown to induce long-term alterations in brainstem, forebrain and hippocampal monoaminergic systems which are key mediators of integrated cardiovascular and autonomic responses to stress (Slotkin et al. 1992; Muneoka et al. 1997). In addition, glucocorticoids can directly regulate blood pressure, increasing sodium and calcium uptake by vascular smooth muscle (Kornel, 1993) and increasing vascular responsiveness to angiotensin II (Provencher et al. 1995) and noradrenaline (Walker & Williams, 1992). These glucocorticoid-induced changes in both central and effector sites of the cardiovascular control may be reflected in enhanced cardiovascular responses to acute stress seen here in PS rats.
A second major mechanism by which prenatal stress may have programmed subsequent enhanced blood pressure responsiveness to stress is by causing direct alteration in the sympathoadrenal system. There is growing evidence that central catecholaminergic areas in the brain can be permanently altered by fetal or neonatal exposures (Peters, 1982; Takahashi et al. 1992; Muneoka et al. 1997; Hayashi et al. 1998; Young, 2002). Catecholaminergic neurones constitute essential components of the central pathways mediating the principal homeostatic cardiovascular reflexes, and any alteration in their metabolism/function may have significant consequences for cardiovascular regulation in adulthood (Dampney, 1994). Other effects of prenatal manipulations on the catecholaminergic system also include alterations in sympathetic efferent pathways (Huff et al. 1991; Bian et al. 1992; Buchholz & Duckles, 2001; Peyronnet et al. 2002) and attenuation of adrenal medullarly function (McMillen et al. 2001).
We found here that PS rats demonstrated a greater increase in systolic arterial pressure and blood pressure variability during restraint stress than control animals. Given that restraint stress has been reported to increase blood pressure largely due to sympathoadrenal system activation (Chen & Herbert, 1995) and the stress-induced increase in blood pressure variability is mediated by sympathetic excitation (Blanc et al. 1991; Gaudet et al. 1996), it is possible that the increased SAP and BP variability seen in PS rats under stressful conditions is due to higher activation of the sympathetic nervous system. Indeed, Weinstock et al. have reported that prenatal stress induces long-term changes in the sensitivity of the sympathoadrenal system to stress. They showed higher plasma noradrenaline and dihydroxyphenylglycol levels in PS than control offspring following footshock stress (Weinstock et al. 1998a). It seems likely that the sensitivity and/or density of vascular adrenergic receptors rather than cardiac adrenergic receptors is altered in PS rats, since the magnitude of HR stress responses did not differ between PS and control animals. This hypothesis is supported by a recent study (O'Regan et al. 2003). These authors reported enhanced blood pressure responsiveness to stress and increased vascular sensitivity, both in vivo and in vitro, to sympathomimetic and vasoactive agents in adult offspring who had been prenatally exposed to dexamethasone.
The present experiments also demonstrate the sex-specific effects of prenatal stress on the cardiovascular responsiveness to stress in adult offspring. PS females showed delayed HR recovery compared with PS males and a greater increase in SAP and blood pressure variability following return to the home cage. Recent studies on nutritional programming (Ozaki et al. 2001; Khan et al. 2003) and placental insufficiency (Jansson & Lambert, 1999) have also shown that alterations in intrauterine environment can affect cardiovascular function in female and male offspring differently. Sex differences in cardiovascular responses to stress have been demonstrated in both human and animal studies, with greater cardiovascular and plasma catecholamine responses to environmental challenges generally observed in males (Zukowska-Grojec et al. 1991). However, some studies have found greater stress-induced increases in catecholamines in female than in male rats (Livezey et al. 1985; Weinstock et al. 1998b) and higher cardiac stress reactivity in women compared with men (Girdler et al. 1990).
The enhanced cardiovascular sensitivity of PS females resembles other sex-specific effects of prenatal stress. Indeed, sex differences in the neuroendocrine effects of PS are well known in the literature, with the female offspring generally showing larger neuroendocrine and behavioural alterations than males (Kinsley et al. 1989; Rohde et al. 1989; Weinstock et al. 1992; McCormick et al. 1995). There is, however, considerable variability in outcome following PS in male offspring. Thus, in some studies PS males had either attenuated (Reznikov & Nosenko, 1995) or unaffected neuroendocrine responses (Szuran et al. 2000) whereas other studies reported a more marked effect on emotional locomotor activity (Nishio et al. 2001) and spatial learning (Szuran et al. 2000) in male than in female offspring.
The mechanisms underlying the sex-specific effects of prenatal stress on cardiovascular function are unknown but some possible explanations are plausible. The higher and prolonged cardiovascular responses during recovery seen here in PS females may indicate alterations in the mechanisms responsible for returning the system to its basal state, such as prejunctional 
2-adrenoreceptors, opioid receptors and endothelium-dependent relaxation. These have now been shown to be involved in fetal programming of vascular disorders (Buchholz & Duckles, 2001; Ghosh et al. 2001).
In the present study we did not weigh the neonates because we have experienced some cases of infanticide in this strain of rats even in control litters. However, our results demonstrated that adult PS males had higher body weight than control males. In contrast, Keshet & Weinstock (1995) showed that the body weight of PS offspring at the age of 60 days was somewhat lower than that of age-matched control animals. This discrepancy may be due to the different prenatal stress protocols used and the fact that the PS male rats in our study were older than those in the previous one.
A possible explanation for a greater increase in the body weight of PS males is that prenatal stress may results in alterations in sex steroid levels, thereby influencing fat metabolism and body composition of adult PS males. Indeed, permanent behavioural feminization and demasculinization have been reported in prenatally stressed male rats. These behavioural abnormalities are associated with reduced prenatal and postnatal testosterone levels in prenatally stressed males (Ward & Weisz, 1980; Anderson et al. 1986). Androgens are important hormonal regulators of protein and lipid homeostasis and their deficiency has been shown to promote visceral fat accumulation and obesity (Tchernof et al. 1996; Jensen, 2000). Since the effect of PS on body weight was evident only in PS male offspring our findings might point to decreased levels of testosterone in PS males and higher sensitivity of PS male offspring to the metabolic effects of prenatal stress.
In summary, the present data clearly show that prenatal stress has long-term effects on the cardiovascular function of the offspring. Prenatally stressed rats coped less effectively with acute restraint stress, as demonstrated by enhanced blood pressure and blood pressure variability responses to stress and slow adaptation of stress-induced tachycardia and hypertension in the post-stress period. In general, the female offspring demonstrated greater and more prolonged cardiovascular responses during recovery than males. These findings suggest that PS rats are at high risk for ultimate development of hypertension or other stress-related cardiovascular disorders if exposed to a stressful environment. Further clarification of changes in the central or local control of the cardiovascular system is required to understand the mediating mechanisms.
Such a pattern of haemodymanic responses to stress would have significant consequences for adult cardiovascular health, if also apparent in humans. Thus, in clinical studies, delayed blood pressure (Floras & Senn, 1991) and heart rate (Cole et al. 1999; Watanabe et al. 2001) recovery to basal levels after the stress of exercise has been shown to correlate highly with increased cardiovascular morbidity and mortality. Furthermore, augmented blood pressure variability is found in patients with hypertension and it may play a pathophysiololgical role in the development of end-organ damage (Mancia & Parati, 2003).
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, n= 7; PS, prenatally stressed offspring, 
, n= 7. Values are given as means ±S.E.M.*P < 0.01versus basal values; •P < 0.05, 
P < 0.01versus prenatally stressed group. Single doses of phenylephrine and sodium nitroprusside were administered at the time interval depicted by the arrow.
