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(Hypertension. 1997;30:1525-1530.)
© 1997 American Heart Association, Inc.

Articles

Maintenance of Maternal Diet-Induced Hypertension in the Rat Is Dependent on Glucocorticoids

David S. Gardner; Alan A. Jackson; ; Simon C. Langley-Evans

From the Institute of Human Nutrition (D.S.G., A.A.J.), University of Southampton, Bassett Crescent East Southampton, and the Metabolic and Molecular Programming Group (S.C.L.-E.), University Medicine, Southampton General Hospital, Tremona Road, Southampton, UK.

Correspondence address to Dr S.C. Langley-Evans, Metabolic and Molecular Programming Group, Department of University Medicine, Southampton General Hospital, Level D South Block, Tremona Road, Southampton SO16 6YD. E-mail slang{at}soton.ac.uk

	Abstract

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Abstract Recent epidemiological evidence suggests that adult cardiovascular risk is determined by birth weight and factors that influence birth weight, such as maternal nutrition. Data from animal models suggest that an interaction between nutrition and glucocorticoid hormones "programs" increased risk of adult hypertension. Increased fetal exposure to maternal glucocorticoids that is proposed to occur from a reduction in the placental barrier to maternal glucocorticoid, 11ß-hydroxysteroid dehydrogenase, is suggested to program hypertension in the resultant offspring from both glucocorticoid-treated and maternally protein–restricted rats. The extent to which postnatal glucocorticoid stimulation may influence the progression of hypertension in the offspring from protein-restricted rat dams was assessed in 6-week-old male Wistar rats, prenatally exposed to either an 18% casein (control) or 9% casein (low protein) diet. Rats from each dietary group were sham operated, adrenalectomized or adrenalectomized, and treated with 20 mg corticosterone/kg body weight per day. Before surgery, systolic blood pressure was significantly higher in the low protein–exposed rats compared with controls (165±3.8 versus 142±3.3 mm Hg, P<.0001). Adrenalectomy of the low protein–exposed animals significantly reduced the blood pressure to control levels, while corticosterone replacement restored the hypertensive state. No effect of adrenalectomy on blood pressure was observed in 18% casein controls. In both dietary groups adrenalectomy decreased brain, but not hepatic, glucocorticoid-sensitive enzyme activities and corticosterone treatment elevated activities of all enzymes. The data suggest that maternal diet–induced hypertension is dependent on an intact adrenal gland postnatally and that glucocorticoids are key trophic agents in maintaining the high blood pressure.

Key Words: birth weight • glucocorticoids • protein • rats • blood pressure

	Introduction

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A weight of evidence from a number of human populations suggests an association between fetal undernutrition in mid-late gestation, leading to disproportionate patterns of fetal growth retardation, low birth weight, and elevated blood pressure in adult life.¹ The mechanisms through which fetal "programming" of the cardiovascular system are manifest are as yet unknown. Recent evidence from two animal models of hypertension suggest, however, that both hormonal and nutritional factors may initiate elevation of blood pressure in utero.^{2 3 4 5}

The placental enzyme 11-HSD2 regulates the transfer of maternal GC across the placenta and into the fetal compartment.⁶ The activity of 11-HSD2 correlates positively with birth weight in rats and in humans,^{2 7} suggesting an important role for this enzyme in regulating fetal growth and development. Furthermore, 11-HSD2 activity correlates negatively with placental weight in rats.² Thus, Edwards et al⁸ postulated that low birth weight fetuses with a correspondingly large placenta that, in humans, are associated with an increased cardiovascular risk⁹ are exposed to a greater level of maternal GC in late gestation, mediated by the relative inactivity of 11-HSD2. In support of this hypothesis, the administration of low-dose dexamethasone (a weak substrate for 11-HSD2) to rats throughout pregnancy "programmed" hypertension into the resultant adult offspring.² Moreover, treatment of pregnant rats with carbenoxolone, an 11-HSD2 inhibitor, induced hypertension in the adult offspring, an effect that was remediable by maternal adrenalectomy.⁵ Thus, programming of adult hypertension in this rat model appears to be a GC-inducible phenomenon.

Epidemiological studies of early life programming of cardiovascular disease indicate that maternal nutrition has a role in programming increased risk.¹⁰ Thus, high intake of carbohydrate in early pregnancy together with a low intake of dairy protein in early or late pregnancy is associated with lower birth weight babies¹¹ and increased SBP at 40 years of age.¹² The GC model of Edwards et al⁸ does not take into account a nutritional origin in the programming of adult hypertension in the rat. However, nutritional programming of adult blood pressure in the rat has been clearly demonstrated.^{3 13 14} Feeding a maternal low protein diet to rat dams lowers the birth weight of the resultant rat pups,³ reduces the activity of placental 11-HSD2 by 33%,¹⁴ and programs hypertension in the adult offspring.³ Furthermore, the low protein-induced hypertension is prevented by pharmacological blockade of maternal corticosterone synthesis,¹⁵ an effect that is reversed by maternal corticosterone replacement. Thus, low protein diet–induced hypertension is also a GC-dependent phenomenon. A major consequence of maternal protein restriction appears to be a resetting of hypothalamic-pituitary-adrenal axis function in the offspring. Low protein–exposed rats exhibit increased sensitivity to low-normal concentrations of corticosterone and have increased numbers of GC receptors,⁴ which may elevate SBP through direct actions in the vasculature.^{16 17 18}

While the hypertension associated with maternal undernutrition is dependent on prenatal GC action, it is uncertain whether the higher blood pressure exhibited by low protein–exposed animals is dependent on continued GC influence in adult life, as in the spontaneously hypertensive rat.¹⁹ The aim of the study was to assess the importance of an intact adrenal gland, with respect to blood pressure regulation, in the offspring of rat dams exposed to either a maternal low protein or control diet throughout pregnancy.

	Methods

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Chemicals
All chemicals and reagents cited in text were purchased from Sigma.

Animals
All animal procedures were conducted in accordance with the Home Office Animals Act (1986). Wistar rats bred in the Southampton University animal facility were used in all experiments. The animals were housed in standard wire-mesh cages at a temperature of 22°C on a 12-hour light-dark cycle. A total of 14 female rats (n=7 per group) weighing between 200 to 250 g were habituated (14 days) to either a semi-synthetic control diet containing 18% casein or an equivalent isoenergetic low protein diet containing 9% casein (Table 1), as previously described.³ After 14 days the animals were mated (1 to 6 days) and maintained on the semi-synthetic diet throughout gestation. At birth (day 22) the animals were transferred to a standard laboratory chow diet (18.3% protein, CRMX, Special Diet Services) and litters culled to 8 pups (4 male, 4 female). At 4 weeks of age the litters were weaned onto the nonpurified chow diet.

View this table: [in this window] [in a new window]   Table 1. Composition of Synthetic Diets

At approximately 47±1 days of age the male offspring from each dietary group (18% casein n=24, 9% casein n=20) were either bilaterally adrenalectomized (A) under sodium pentobarbital anesthesia or sham operated (S).²⁰ Postoperatively, adrenalectomized animals had free access to 0.9% NaCl solution to maintain physiological electrolyte concentrations. The four groups generated (18% casein-A, 18% casein-S, 9% casein-A and 9% casein-S) were then each subdivided into two further groups that received either corticosterone (C) replacement (10 mg/kg in 0.1 mL arachis oil) or vehicle (V) (0.1 mL arachis oil, an inert vehicle for the steroid suspension) twice daily (9 AM and 5 PM) for 14 days post surgery. A total of 8 groups were thus studied: 18AC, 18AV, 18SC, 18SV, 9AC, 9AV, 9SC, and 9SV (18% casein n=6/group, 9% casein n=5/group). The body weights of all animals were determined daily throughout the treatment period. The SBPs of all animals were determined before surgery (day 0), and then at 7 and 14 days after commencement of treatment. After the final blood pressure measurement on day 14, all animals were placed under nonrecoverable anesthesia and blood and organs collected. Animals receiving corticosterone replacement were killed approximately 1 hour after their last injection.

Blood Pressure Measurement
SBP was measured using an indirect tail-cuff method as described in detail by Langley-Evans et al.²¹ An IITC model 229 blood pressure recorder linked to a computer software package was used to measure blood pressure using a preset alogorithm (Linton Instrumentation). All blood pressures were measured between 11 AM and 4 PM. Blood pressure readings for each animal were taken in triplicate with the average value recorded. The indirect tail-cuff method has been validated against direct arterial cannulation measurements taken in conscious, unrestrained animals, and a correlation coefficient of r=.974 established between the two methods.²² In our hands, intra- and interassay variations of 4.7% and 7.9%, respectively, were recorded.

Collection of Tissues
Blood was collected in heparinized tubes via cardiac puncture, and whole brain and liver were rapidly excised and either maintained on ice (brain) or snap-frozen in liquid nitrogen (liver). The cerebellum, hippocampus, and hypothalamus were dissected from whole brain as previously described.²³ All tissues were then frozen in liquid nitrogen and stored at -80°C for up to 3 months before biochemical analyses.

Enzyme Assays
For markers of GC activity the GC-inducible oligodendritic enzyme GPDH (EC 1.1.1.8),²⁴ hepatic TAT(EC 2.6.1.5),²⁵ and astrocyte GS (EC 6.3.1.2)²⁶ were assayed together with the GC-insensitive control enzyme MD (EC 1.1.1.37) using the methods of Langley and York.²³ All enzyme activities are expressed as nmoles substrate converted per minute per mg protein. The methods of Smith et al²⁷ or Lowry et al²⁸ were used as appropriate to estimate protein concentrations.

Hormone Analyses
Corticosterone concentrations were determined in ethanolic plasma extracts by a radioimmunoassay procedure, as previously described.²³

Statistical Analysis
Data are expressed as mean±SEM. Results were compared by three-way ANOVA followed by Tukey's test for individual comparisons where differences were indicated. Student's t test was used for other analyses. Differences were accepted as statistically significant at P<.05.

	Results

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Before surgery there was no difference in body weight between the two maternal dietary groups (18% casein: 190±7.8 g, n=24, versus 9% casein: 180±2.8 g, n=20) (Table 2). Throughout the experimental period vehicle-injected ADX animals maintained a steady weight gain that was slightly below (nonsignificant) the weight gain achieved by vehicle-injected sham-operated controls. Corticosterone replacement significantly reduced the weight gain experienced by all CORT-treated animals. Body weight gain was not influenced by maternal diet in any of the groups except 9AC, which gained significantly more weight than group 18AC (Table 2).

View this table: [in this window] [in a new window]   Table 2. Effect of Adrenalectomy and Corticosterone Replacement on Body Weight

In ADX and sham-operated animals twice-daily corticosterone injections for 14 days elevated plasma corticosterone concentrations to 2- to 3-fold above concentrations observed in sham-operated vehicle-treated control animals (Table 3). Adrenalectomy reduced the corticosterone concentration to nondetectable levels when measured at day 14. Maternal diet had no effect on the plasma corticosterone concentration (Table 3).

View this table: [in this window] [in a new window]   Table 3. Effect of Adrenalectomy and Corticosterone Replacement on Plasma Corticosterone Levels

Before the surgical procedure, the low protein–exposed rats had significantly higher SBP than the 18% casein exposed controls (9% casein: 165±3.8 mm Hg, n=20; 18% casein: 145±3.3 mm Hg, n=24; P<.0001). Table 4 illustrates the blood pressure response of each dietary group to the experimental protocol. Significant differences of 14 to 19 mm Hg were maintained between groups 18SV and 9SV throughout the 14-day experiment. The higher blood pressure exhibited by the low protein–exposed animals was reduced (19 mm Hg) by day 7 after ADX (group 9AV). No effect of ADX on blood pressure was observed in the parallel 18% casein group (18AV) (Table 4). Corticosterone replacement to ADX animals increased blood pressure, measured at day 7, in both dietary groups (18AC and 9AC), although group 9AC appeared to exhibit a greater response (mean blood pressure increase after 7 days of CORT injections; group 18AC=31±16 mm Hg, group 9AC=37±18 mm Hg; P>.05). Corticosterone replacement transiently raised blood pressure in group 18SC, but had no effect on the blood pressure of group 9SC.

View this table: [in this window] [in a new window]   Table 4. Effect of Postnatal Adrenalectomy on Blood Pressure of Animals Exposed to Either an 18% or 9% Casein Diet In Utero

Activities of GC-inducible GPDH, TAT, and GS were determined in liver and brain regions. The activity of GPDH was higher in group 9SV compared with group 18SV in both the hippocampus (P=.09) and the cerebellum (P=.05). Hippocampal GPDH appeared more sensitive to the corticosterone replacement protocol in both ADX and sham-operated rats of the low protein–exposed group. In both brain regions of low protein–exposed rats and the cerebellum of control rats, ADX significantly reduced the activity of GPDH (Table 5). ADX decreased hippocampal GPDH by 24% in control rats (18AV), but this did not achieve statistical significance (Table 5). Corticosterone replacement significantly elevated GPDH activity, relative to vehicle control animals, in both brain regions of all sham and ADX animals. The specific activity of hippocampal MD was similar in both dietary groups after corticosterone replacement. Previous studies, using the same methodology, have observed no effect of maternal diet on MD in either the hippocampus, cerebellum, or liver,⁴ suggesting that alterations to GC-inducible enzyme activities represent a GC-specific effect.

View this table: [in this window] [in a new window]   Table 5. Effect of Adrenalectomy and Corticosterone Replacement on GC-Inducible Enzyme Activities

Hepatic TAT is a peripheral GC-inducible enzyme.²⁵ In low protein–exposed, sham-operated controls (group 9SV), the activity of hepatic TAT was significantly higher (55%) than in the 18% casein–exposed, sham-operated control animals (group 18SV) (P=.01). The specific activity of TAT increased in response to corticosterone replacement in groups 18AC, 18SC, 9AC, and 9SC (Table 5) but was unaltered after ADX. Hepatic GS activity increased after corticosterone replacement and was unaltered after ADX, thereby exhibiting a response pattern similar to that observed for TAT (Table 5). The specific activity of hepatic MD was similar between control groups (Table 5). Prenatal dietary experience had no effect on the activity of hepatic GS.

	Discussion

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The key finding of the present study is that the elevated SBP of adult rats rendered hypertensive by prenatal protein restriction is reduced, after ADX, to give pressures similar to rats exposed to an adequate protein diet in utero. No such effect of ADX on SBP was observed in animals exposed to a protein replete diet in utero. The reduction of SBP in the low protein–exposed animals after ADX is reversed by GC replacement. The results suggest that maintenance of the hypertensive state in this nutrition-induced model of hypertension is dependent on a functional adrenal gland and, in particular, corticosterone activity in adult life.

Successful ADX was confirmed by analysis of plasma CORT concentrations, which were nondetectable at 14 days post surgery. The level of CORT replacement dose was chosen on the basis of previous data in which a dose of 10 mg/kg per day CORT was ineffective at inducing increased activity of GC-inducible enzymes.²⁰ It is apparent from the observed reduction in body weight after CORT treatment, consistent with the catabolic nature of high dose GCs,²⁹ that the replacement dose of corticosteroid can be considered pharmacological rather than physiological and thus that it may obscure a specific GR-mediated effect from a mineralocorticoid receptor–mediated effect. Responses attributed to classic GC action must therefore be treated with some caution. Nevertheless, maintenance of ADX animals on 0.9% saline has no significant effect on their blood pressure,³⁰ as reproduced here (group 18AV). Therefore the observed response (significantly decreased SBP over 14 days) in group 9AV may be largely attributable to the absence of GC stimulation rather than secondary mineralocorticoid action. This clearly implicates a functional role for the adrenal gland in maintaining the hypertensive state induced by prenatal protein restriction. A slight, delayed decrease in SBP, observed at postoperative day 14 relative to day 7, occurred in CORT-treated animals (except group 9SC), indicating an apparent vascular accommodation to the high GC replacement dose. A downregulation of GR receptors may facilitate such a response since GCs autoregulate their receptor population.³¹

GPDH activity provides an indirect central marker of GC action.²⁴ The cerebellum, hippocampus, and hypothalamus are central GC target regions reflected by high densities of type II (GR) receptors through which almost exclusively all GC effects are mediated.³² The higher specific activities of central GPDH and hepatic TAT found in group 9SV relative to 18SV are consistent with our previous reports.⁴ This may reflect a tonic overstimulation of GR by a higher circulating CORT concentration, or rather increased GR densities. The latter appears more robust since the offspring of protein-restricted rat dams have moderately increased GR numbers in hippocampus and hypothalamus⁴ and exhibit an increased central sensitivity to corticosterone replacement as reflected by the elevated specific activities of GPDH in groups 9AC and 9SC relative to protein-replete control animals (group 18AC and 18SC). Furthermore, the present study and others^{4 33} have demonstrated low to normal plasma CORT concentrations in prenatally protein-restricted rats, which is inconsistent with overstimulation of normal GR densities. However, the possibility that prenatal protein restriction influences postnatal circulating GC concentrations cannot be excluded by the present study. Clearly the specific activity of GPDH in particular and, to a limited extent, the activities of hepatic GS and TAT parallel the changes in GC status in the present study, emphasizing the utility of these enzymes as markers of GC action.

Permanent alterations to GR expression may be a manifestation of the poor nutritional environment encountered in utero by the protein-restricted fetuses. Relatively mild neonatal stress elicited by daily handling permanently alters the subsequent expression and responsiveness of central receptor populations.³⁴ The nutritional regimen used in this study, which is known to program central and peripheral GR densities,⁴ may incur a comparable physiological stress given that the normal doubling of body weight observed in control animals over the last 2 days' gestation is severely curtailed in the low protein–exposed group.³⁵

The mechanisms that relate the prenatal nutritional environment to later cardiovascular dysregulation are unknown. Our hypothesis is that under conditions of protein restriction, the fetus responds, in the short-term, by making suitable adaptations to accommodate the disturbance in substrate supply. The long-term outcome of these adaptations is represented as an increased blood pressure and a relative propensity toward a diseased state. The maternal and/or fetal endocrine systems facilitate such adaptations, and evidence suggests that GC hormones, in particular, are essential agents in the development of high blood pressure in our rat model.^{4 14 15 36 37}

11-HSD2 serves as a biochemical barrier for maternal GC access to the fetal compartment, converting bioactive steroid (corticosterone) into its inactive stable metabolite 11-dehydrocorticosterone.³⁸ The activity of this enzyme correlates positively with placental weight in rats and negatively with fetal weight in both rats and humans,^{2 7} suggesting a role for the enzyme in modulating fetal growth. In late gestation the activity of 11-HSD in protein-restricted rats is significantly reduced relative to control animals,¹⁴ implying an increased transfer of GC from maternal to fetal compartments. Whether the efficacy of 11-HSD is such that it is still able to metabolize maternal GC despite reduced activity is unclear. The GC environment certainly influences the progression of hypertension in protein-restricted animals, since both pharmacological¹⁵ and surgical³⁷ ADX of rat dams reverses the hypertensive effect of protein restriction. Moreover, inhibition of 11-HSD by carbenoxolone during pregnancy in the rat produces hypertensive offspring (Reference 5⁵ and Langley-Evans, unpublished data, 1997). The effect is abolished if the dams are ADX, suggesting that prenatal exposure to excess maternal GC programs hypertension in these offspring.⁵

GCs have marked effects on the development and growth of many organs, particularly the lung, brain, and liver.³⁹ At the central level, GCs decrease and mineralocorticoids increase blood pressure via their respective receptors.⁴⁰ Disturbances in the activity of placental 11-HSD and central GR populations, both of which have been observed within our model of hypertension,^{4 14} may have the potential to alter future blood pressure control. Indeed, elevated activities of central GC-inducible enzymes observed in the present study and altered secretion of adrenocorticotrophic hormone observed previously⁴ may suggest just such a centrally orientated programming effect. Since significantly higher binding to GR has been observed in the aorta of prenatally protein-restricted animals,⁴ a peripheral mechanism for maintaining elevated SBP is possible. GCs increase transluminal Na⁺ and Ca²⁺ transport⁴² and expression of angiotensin II type 1 receptors,¹⁸ both acting in concert to increase vascular tone and raise blood pressure. A permissive effect of GC is to enhance reactivity to not only angiotensin II but also noradrenaline.⁴³ Essential hypertensive patients have an increased vascular responsiveness to GC stimulation⁴⁴ despite "normal" secretion rates and plasma concentrations of cortisol.

In conclusion we have demonstrated that in the model of maternal diet–induced hypertension, ADX reduces the high SBP exhibited by low protein–exposed animals to levels observed in control rats. Corticosterone replacement restores the higher blood pressure of these animals. Such a response is indicative of a GC-dependent phenomenon. We propose that an increased peripheral vascular, or central, sensitivity to GC action maintains the hypertensive state mediated either directly through GC receptors or indirectly through a permissive effect of GC on vasomodulatory compounds. The present findings support the Barker hypothesis¹ in its most fundamental sense, that poor maternal nutrition may predispose the resultant offspring to adult-onset disease, and provide a parallel between this and the hypothesis proposed by Edwards et al,⁸ that a role for GCs exists in the etiology of adult hypertension.

	Selected Abbreviations and Acronyms

 

A = study group adrenalectomized under anesthesia ADX = adrenalectomy/adrenalectomized C = substudy group receiving corticosterone replacement V = substudy group receiving vehicle CORT = corticosterone 11-HSD = 11ß-hydroxysteroid dehydrogenase 11-HSD2 = 11-HSD type II GC = glucocorticoid GPDH = glycerol 3-phosphate dehydrogenase GR = glucocorticoid receptor GS = glutamine synthetase MD = malate dehydrogenase S = sham-operated study group SBP = systolic blood pressure TAT = tyrosine aminotransferase

	Acknowledgments

 
This work was supported by the British Heart Foundation (Grant No. FS/95038) and the Wellcome Trust (Grant No. 043034/Z/94/Z/MS/PK).

Received May 22, 1997; first decision June 12, 1997; accepted June 12, 1997.

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