(Hypertension. 1996;27:1200-1204.)
© 1996 American Heart Association, Inc.
Articles |
Inhibition of 11ß-Hydroxysteroid Dehydrogenase in Pregnant Rats and the Programming of Blood Pressure in the Offspring
From the Department of Medicine, University of Edinburgh (UK), Western General Hospital.
Correspondence to Dr R.S. Lindsay, Department of Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
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Abstract Recent epidemiological studies have linked low birth weight with the later occurrence of cardiovascular and metabolic disorders, particularly hypertension. We have proposed that fetal exposure to excess maternal glucocorticoids may underpin this association. Normally, the fetus is protected from maternal glucocorticoids by placental 11ß-hydroxysteroid dehydrogenase (11ß-HSD). We have previously shown that treatment of pregnant rats with dexamethasone, a synthetic glucocorticoid that is poorly metabolized by the enzyme, reduces birth weight and produces elevated blood pressure in the adult offspring. Moreover, low activity of placental 11ß-HSD correlates with low birth weight in rats. Here, we show that maternal administration of carbenoxolone, a potent inhibitor of 11ß-HSD, throughout pregnancy leads to reduced birth weight (mean 20% decrease) and elevated blood pressures (increase in mean arterial pressure, 9 mm Hg in males, 7 mm Hg in females) in the adult offspring of carbenoxolone-treated rats. This effect requires the presence of maternal adrenal products, as carbenoxolone given to adrenalectomized pregnant rats had no effect on birth weight or blood pressure. These data support the hypothesis that excess exposure of the fetoplacental unit to maternal glucocorticoids reduces birth weight and programs subsequent hypertension and indicate a key role for placental 11ß-HSD in controlling such exposure.
Key Words: blood pressure • corticosterone • birth weight • glucocorticoid • carbenoxolone
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Introduction |
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Recent epidemiological data have shown that babies with lower birth weight (small-for-dates, not premature) have a greater chance of developing high blood pressure1 2 3 4 5 and non–insulin-dependent diabetes mellitus4 6 7 as adults and have increased mortality from ischemic heart disease.8 9 10 These associations hold in populations and individuals and are apparently independent of other risk factors, such as adult weight, smoking, alcohol intake, and social class. Indeed, such lifestyle risk factors are additive to the influence of early life.11 12 The association of lower birth weight with higher blood pressure, along with the documented "tracking" of blood pressure from infancy to adulthood in humans,13 implicates early events in the determination of blood pressure throughout life. For hypertension, lower birth weight, in some studies in association with a large placenta, has been demonstrated in several distinct populations to predict higher blood pressures in children3 14 15 16 and adult men and women up to late middle age.1 2 4 5 17 18 Importantly, the relationship between birth weight and adult blood pressure is continuous and represents birth weights within the normal range rather than severely growth-retarded babies.1 Those studies not displaying an association of birth weight and later blood pressure either have involved groups with only very low birth weights14 or have studied subjects aged 15 to 19 years19 at a time when blood pressure tracking is known to diminish during the adolescent growth spurt.20
Several mechanisms have been proposed to explain this association.12 Maternal malnutrition, either generalized or of specific dietary components (eg, protein or iron deficiency), has been suggested to provide a causal link,12 21 and indeed in rats, protein restriction during pregnancy leads to elevated blood pressures in the offspring.22 However, the importance of maternal nutrition has yet to be clearly established within the range of dietary variation occurring in the reported populations.11 23 We have been testing an alternative hypothesis that fetal exposure to excessive maternal glucocorticoids may be key.24 25 Fetal cortisol levels are elevated in human intrauterine growth retardation26 and alter tissue growth and maturation when given exogenously both in humans27 and in animal models.28 29 30 Furthermore, glucocorticoids exert well-known effects on blood pressure in adulthood in humans31 and animals32 and increase fetal blood pressure when directly infused in utero, at least in sheep.33 Treatment of pregnant rats with dexamethasone, in a modest pharmacological dose that reduces average birth weight by 14% and does not alter gestation length, produces elevated systolic pressures in the adult offspring many months after exposure to exogenous glucocorticoid.34
Dexamethasone is a synthetic corticosteroid that readily passes the placenta, but normally the fetus is protected from high maternal levels of physiological glucocorticoids by the type 2 isoform of 11ß-hydroxysteroid dehydrogenase (11ß-HSD 2) present in the placenta35 and catalyzing the rapid metabolism of cortisol (corticosterone in rats) to inert 11-keto derivatives (cortisone, 11-dehydrocorticosterone).36 11ß-HSD 2 is highly expressed in the placental syncytiotrophoblast35 and maintains a gradient of cortisol from the maternal to the fetal circulation.37 11ß-HSD activity in the placenta is directly related to birth weight both in the rat34 and in humans,38 39 and patients bearing mutations of the gene encoding 11ß-HSD 2 have low birth weight,40 supporting a role of 11ß-HSD 2 in the determination of birth weight. Nevertheless, before 11ß-HSD deficiency can convincingly explain, at least in part, the human epidemiological observations, it is important to determine whether inhibition of placental 11ß-HSD leads to elevated blood pressure in the rat offspring. In this study we have used the licorice-related drug carbenoxolone, a potent inhibitor of 11ß-HSD 2,35 to explore the role of 11ß-HSD in the determination of fetal growth and offspring blood pressure.
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Methods |
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Carbenoxolone Treatment in Adrenal Intact Rats
Female Wistar rats (Harlan, UK, 200 to 250 g) were maintained under conditions of controlled lighting (lights on 7 AM to 7 PM) and temperature (22°C) and allowed free access to food (standard rat chow; 56.3% carbohydrate, 18.3% protein, 0.7% NaCl; BS & S Scotland Ltd) and tap water. The rats were time-mated and then given either carbenoxolone (CBX, 12.5 mg/d in 0.1 mL saline SC) or vehicle alone (CON) throughout pregnancy. At birth, the offspring were weighed and then no further treatment was given (to mothers and pups). A separate cohort of pregnant rats underwent identical treatment but was subjected to carotid cannulation under brief halothane anesthesia on day 15 of pregnancy to permit subsequent measurement of maternal blood pressure and blood sampling.
Carbenoxolone Treatment in Adrenalectomized Rats
Nonpregnant female rats underwent adrenalectomy by the dorsal
approach under halothane anesthesia. Controls were
sham-operated (SHAM). Blood for plasma corticosterone estimation
was subsequently taken at 9 AM by tail tipping for
assessment of the completeness of adrenalectomy. Adrenalectomized rats
were additionally given saline to drink. Adrenalectomized rats were
mated 8 to 15 days after surgery and treated throughout pregnancy
with carbenoxolone (ADX+CBX, 12.5 mg/d in saline SC) or saline alone
(ADX). Sham-adrenalectomized controls received saline.
Blood Pressure Measurement
When the offspring were 6 (males) or 8 (females) months old, a
cannula was inserted into the right carotid artery under halothane
anesthesia, and the rats were allowed to recover for at
least 72 hours. Blood pressure was measured directly in conscious,
unrestrained rats, taken from all litters, with a pressure transducer
(Lectromed Multitrace 2) for 10 minutes on 3 consecutive days and
assessed as the mean of the readings. A total of 60 rats (CON, n=13;
CBX, n=10; SHAM, n=14; ADX, n=10; ADX+CBX, n=13) were initially
studied, but only those surviving surgery and with patent cannulas were
included (CON, n=11; CBX, n=9; SHAM, n=8; ADX, n=10; ADX+CBX, n=11).
The coefficient of variation for the repeated measures of blood
pressure was 6.9% for mean arterial pressure.
Corticosterone and Glucose Assays
Plasma samples were diluted in buffer (135 mmol/L sodium borate,
0.5% bovine serum albumin, 1% methanol, 0.1% ethylene
glycol, pH 7.4) and heated to 80°C to inactivate
corticosterone binding globulin. Antibody specific to corticosterone
(final titer, 1:10 000) was added along with
[3H]corticosterone (Amersham), and samples were incubated
at 4°C overnight. Unbound activity was precipitated by the addition
of activated charcoal, and bound activity was estimated in a
beta counter (Minaxi Tricarb 4000, Canberra Packard) after the addition
of scintillant (Picofluoro 40, Canberra Packard). Corticosterone was
estimated by comparison with unlabeled corticosterone standards (Sigma
Chemical Co). The intra-assay coefficient of variation was
3.8%.
Plasma glucose was determined by an enzymatic (glucose oxidase) method with a Synchron CX3 multichannel analyzer (Beckman Instruments Ltd). The intra-assay coefficient of variation was less than 1%.
Statistics
All data are expressed as mean±SE. Data were assessed for
multiple comparisons by one- or two-way ANOVA, as detailed, with
post hoc testing using the Student-Newman-Keuls test. Student's
t test was used for two-group comparisons. Data were
reported as significant at a value of P<.05.
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Results |
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Effect of Carbenoxolone on Adrenal-Intact Pregnant Rats and Their Litters
Carbenoxolone treatment of pregnant rats significantly reduced birth weight (CBX, 4.54±0.08 g, n=35; CON, 5.68±0.07 g, n=39; P<.0001; mean 20% decrease; Fig 1
).
However, carbenoxolone administration did not alter litter size (CON,
9.7±1.1, n=4; CBX, 8.7±1.7, n=4) or gestation length (CON, 22.2±0.2
days, n=4; CBX, 22±0.1 days, n=4). Maternal weight gain through
pregnancy was significantly reduced by carbenoxolone administration
(CON, 72±5 g, n=4; CBX, 50±5 g, n=4; P<.05). In the
separate cohort of pregnant rats with chronic carotid cannulas,
carbenoxolone treatment had no significant effect on maternal blood
pressure on days 18 to 20 of pregnancy (CON systolic, 117±2 mm
Hg; CON diastolic, 86±5 mm Hg, n=4; CBX systolic,
119±3 mm Hg; CBX diastolic, 77±4 mm Hg, n=3), maternal
plasma glucose (CON, 5.3±0.3 mmol/L, n=4; CBX, 6.4±0.3 mmol/L, n=4),
or 9 AM plasma corticosterone levels (CON, 692±172 nmol/L;
CBX, 647±101 nmol/L).
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Effect of Carbenoxolone in Adrenalectomized Pregnant
Rats
Plasma corticosterone levels were less than 60 nmol/L in
adrenalectomized rats and 898±103 nmol/L in sham-operated rats.
Maternal adrenalectomy was associated with a reduction in offspring
birth weight (SHAM, 5.34±0.15 g, n=36; ADX, 4.86±0.06 g, n=24;
P<.05), but there was no additional effect of
carbenoxolone in adrenalectomized rats (ADX+CBX, 5.02±0.11 g, n=22).
Adrenalectomy with or without carbenoxolone did not affect litter size
(SHAM, 7.2±1.3, n=5; ADX, 8±0, n=4; ADX+CBX, 7.3±2.7, n=3) or
gestation length (SHAM, 22.2±0.4 days; ADX, 22±0 days; ADX+CBX,
21.7±0.9 days). Adrenalectomized and sham-operated rats showed
similar weight gains through pregnancy (SHAM, 84±7 g; ADX,
83±15 g; ADX+CBX, 66±18 g).
Effect of Treatment on Offspring in Adulthood
Carbenoxolone treatment during pregnancy led to rises in offspring
mean arterial pressure in both males, studied at 6 months
(CON, 127±1.4 mm Hg, n=11; CBX, 136±2.1 mm Hg, n=9; Fig 2,
Table), and females, studied at 8 months
(CON, 113±2.0 mm Hg, n=11; CBX, 120±1.8 mm Hg, n=8). Prenatal
carbenoxolone treatment did not result in any persisting changes in
body or organ weights. In particular, male offspring of
saline-treated controls and carbenoxolone-treated pregnant rats
were of similar weight (CON, 491±6 g, n=11; CBX, 461±13 g, n=9),
whereas female offspring showed slightly higher body weight (CON,
270±5 g, n=11; CBX, 298±7 g, n=7; P<.01). Organ weights
(spleen, heart, kidney; data not shown) in males and females did not
differ.
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The male offspring of females subjected to adrenalectomy before
pregnancy were studied at 6 months. By contrast to the offspring of
adrenal-intact females, blood pressure did not change significantly
in the adult offspring of adrenalectomized females treated with either
vehicle (SHAM, 127±2.3 mm Hg; ADX, 125±3.1 mm Hg) or carbenoxolone
(ADX+CBX, 129±3.2 mm Hg, n=10; Fig 2
, Table). The offspring of the
sham and adrenalectomized mothers were lighter than the original
controls, but there were no differences between the groups (SHAM,
409±7 g, n=8; ADX, 415±6 g, n=11; ADX+CBX, 419±10 g, n=10).
We combined the results for all 6-month male offspring to consider the effects of adrenalectomy and carbenoxolone. Two-way ANOVA revealed a significantly higher blood pressure in the offspring of carbenoxolone-treated (F=7.6) but not adrenalectomized females. Post hoc testing revealed an effect of carbenoxolone in the offspring of adrenal-intact females (CBX) versus both controls and the ADX+CBX group (Student-Newman-Keuls, P<.05), suggesting that carbenoxolone treatment resulted in higher blood pressure only in the offspring of adrenal-intact females.
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Discussion |
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The key finding in this study is that treatment of pregnant rats with the 11ß-HSD inhibitor carbenoxolone reduces birth weight and elevates blood pressure in the adult offspring. These data therefore support the hypothesis24 25 that excess fetal exposure to maternal glucocorticoids may explain the epidemiological link between low birth weight and subsequent hypertension in humans.11 In previous studies, we demonstrated that dexamethasone administration to pregnant rats reduces birth weight and elevates blood pressure in offspring.34 The present data suggest that endogenous glucocorticoids may exert similar effects in this rat model, once the placental enzymic barrier is inhibited.
The mechanism by which carbenoxolone reduces birth weight and leads to elevated blood pressure in adult offspring is unclear but merits discussion. Licorice, its active component glycyrrhetinic acid, and the hemisuccinate derivative carbenoxolone are inhibitors of 11ß-HSD. The enzyme exists in at least two isoforms41 ; both, including the NAD-associated placental isoform,35 are potently inhibited by these compounds.42 Moreover, although carbenoxolone may bind to corticosteroid receptors directly,43 this action requires doses at least 104-fold higher than needed to inhibit 11ß-HSD,44 and these levels are unlikely to be achieved in vivo. Similarly, although carbenoxolone and glycyrrhetinic acid also may inhibit other enzymes,45 46 47 most notably prostaglandin dehydrogenases, these effects require substantially higher concentrations than are likely to be relevant to in vivo experimentation.48 The role of maternal glucocorticoid is supported by the lack of effect of carbenoxolone on birth weight and blood pressure in the offspring of adrenalectomized females.
In principle, the effects of carbenoxolone on birth weight might be mediated by actions on the mother, placenta, and/or fetus. However, some clues as to the site of action are provided by these experiments. Licorice derivatives inhibit renal 11ß-HSD, allowing illicit occupation of mineralocorticoid receptors in the distal nephron by glucocorticoids (cortisol, corticosterone),49 50 which causes sodium retention and hypertension in humans and rats.51 52 Elevation of maternal blood pressure might be anticipated to alter fetoplacental function and perhaps growth.53 However, no change in maternal blood pressure at the end of pregnancy was observed. This was perhaps unexpected but might reflect the reduced efficacy of carbenoxolone in pregnant rats or a lack of hypertensive actions by a sodium- and water-retaining mechanism in the already volume-expanded state of pregnancy. In any event, maternal hypertensive effects per se appear unlikely to explain fetal growth retardation and subsequent blood pressure elevation in the offspring. The design of these studies did not allow exclusion of persisting effects of carbenoxolone treatment on maternal behavior after birth but before weaning. However, since maternal treatment stopped at birth, this possibility is less likely.
Placental 11ß-HSD is an efficient but probably incomplete barrier to maternal glucocorticoids, and a minor proportion of fetal corticosteroids derive from the maternal compartment.54 Although reduced fetal adrenal secretion of glucocorticoids may adjust for increased transplacental glucocorticoid passage within a certain tolerance, elevated maternal glucocorticoids eventually may overcome fetal adjustments or even flood the metabolic capacity of the enzyme, although the latter is unlikely.36 It might be predicted that inhibition of 11ß-HSD, which is an important pathway of glucocorticoid metabolism, would increase maternal plasma glucocorticoid levels, perhaps exceeding the limits of placental 11ß-HSD. However, this does not appear to be the case, as maternal corticosterone levels were similar in carbenoxolone-treated and control rats. Indeed, whatever the status of glucocorticoid metabolism, corticosterone negative feedback control of hypothalamic-pituitary-adrenal axis activity will presumably ensure that plasma glucocorticoid levels are tightly controlled. However, two additional caveats concerning glucocorticoid levels and carbenoxolone bear mention. First, total glucocorticoid levels do not necessarily reflect "free" hormone concentrations, and it is conceivable that the treatments alter corticosterone-binding globulin levels, although this is perhaps unlikely to be of significance given the very similar total corticosterone values. Second, we have examined glucocorticoids only during the diurnal nadir. Although this pertains for the majority of the day, the diurnal peak (evening) values might be higher in carbenoxolone-treated rats. Nevertheless, there is no reason to assume this occurs, and the data presented here do not support maternal glucocorticoid excess per se as causal of the fetal growth retardation. It is well known that maternal hyperglycemia can alter fetal growth and offspring glycemic control in animals55 56 and humans,53 57 but this did not seem to be responsible for the effects of carbenoxolone in adrenally intact rats.
If the effects of carbenoxolone on intrauterine growth are mediated by inhibition of placental 11ß-HSD, then these ought to be dependent on maternal glucocorticoids. This appears to be the case, as carbenoxolone was without significant effect on birth weight or adult blood pressure in the offspring of adrenalectomized rats. Interestingly, adrenalectomy per se reduced birth weight (although not as potently as carbenoxolone) but had little if any effect on adult blood pressure. Clearly, many factors other than glucocorticoid excess play a role in determining fetal growth, but not all may have later effects on blood pressure.
Carbenoxolone may also have effects on the fetus itself. Fetal animals58 59 and humans60 express 11ß-HSD at some developmental stages. The function of the enzyme is unclear, but it is potentially involved in the protection of both mineralocorticoid and glucocorticoid receptors as in the adult. Given the similar effects of maternally administered dexamethasone (which is a poor substrate for the enzyme) and carbenoxolone on both fetal growth and subsequent offspring blood pressure, it seems probable that carbenoxolone acts by increasing fetoplacental glucocorticoid exposure. We have demonstrated clear effects of carbenoxolone in the presence of maternal adrenals on later offspring blood pressure. There is a nonsignificant trend upward of blood pressure with carbenoxolone treatment in the absence of a maternal adrenal, suggesting a possibility of direct effects of carbenoxolone on the fetus; however, this cannot be validated without greater numbers.
The detailed mechanisms whereby blood pressure is programmed by maternal glucocorticoid administration or 11ß-HSD inhibition are unknown.24 25 Corticosteroids have well-documented effects on the maturation of tissues and organ systems relevant to blood pressure control. These include actions on the development of autonomic innervations and catecholamine receptor expression,30 61 62 second messenger systems in vascular and renal tissues,63 organizational effects on neural pathways64 and gene expression,65 and structural effects in a spectrum of tissues.61 Such effects may also be indirectly mediated via growth factor induction.66 67 Whatever the tissue processes involved, the data presented here show that inhibition of 11ß-HSD in pregnant rats reduces fetal growth and produces higher blood pressures in the adult offspring, supporting a role for intrauterine glucocorticoid exposure in altering later blood pressure in this animal model.
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Acknowledgments |
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This work was supported by a Wellcome Trust Senior Clinical Research Fellowship (J.R.S.), a program grant from the Wellcome Trust (C.R.W.E. and J.R.S.), and project grants from the Scottish Hospital Endowments Research Trust (J.R.S.) and the Sir Stanley and Lady Davidson Research Fund (J.R.S.).
Received October 10, 1995; first decision November 20, 1995; accepted February 12, 1996.
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