(Hypertension. 1999;33:1369-1373.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
From the Research Service, Harry S. Truman Memorial Veterans Hospital, and Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Missouri-Columbia, Columbia, Mo.
Correspondence to Elise P. Gómez-Sánchez, DVM, PhD, Harry S. Truman Memorial VA (151), 800 Hospital Dr, Columbia, MO 65201. E-mail intmdepg{at}showme.missouri.edu
| Abstract |
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-hydroxyprogesterone, or
carbenoxolone at doses known to produce hypertension with no renal
effects or with subcutaneous infusions of larger, equally
hypertensinogenic doses that produce systemic effects. Blood pressures
of all treated dams were significantly greater (P<0.01)
during gestation than those of the vehicle ICV control rats but not
significantly different from each other. The blood pressures of both
male and female progeny (n
6 per group, comprising
representatives from at least 4 litters) were measured
after 6 weeks of age. No significant difference was found in the blood
pressure of the pups regardless of the maternal gestational blood
pressure or treatment with an enzyme inhibitor, even after
high-salt diet challenge.
Key Words: hypertension, essential aldosterone mineralocorticoids glucocorticoids 11ß-hydroxysteroid dehydrogenase gestation carbenoxolone 11
-hydroxyprogesterone
| Introduction |
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The 11ß-hydroxysteroid dehydrogenase (11ß-HSD) enzyme family comprises at least 2 isoforms. The higher Km type 1 enzyme, 11ß-HSD1, interconverts corticosterone and cortisol to and from the inactive metabolites 11-dehydrocorticosterone and cortisone but acts primarily as a reductase. The lower Km type 2 enzyme, 11ß-HSD2, exhibits only oxidase activity and converts corticosterone and cortisol to their inactive metabolites at physiological concentrations of these steroids.6 7 Aldosterone that exists as a 11ß-18-hemiacetal or 11ß-18- to 11ß-20-bicyclical acetal is not catabolized by either 11ß-HSD1 or 11ß-HSD2. The mineralocorticoid receptor (MR) binds aldosterone, corticosterone, and cortisol with similar affinity. Because these glucocorticoids circulate at several orders of magnitude greater concentration than aldosterone, the unprotected MR generally is occupied by cortisol or corticosterone rather than aldosterone. Depending on the tissue, the 11ß-HSD enzymes regulate glucocorticoid access to either the MR and glucocorticoid receptor (GR) or both.8
Studies have proposed that placental 11ß-HSD2, which is tightly regulated throughout gestation,9 10 is crucial for maintenance of appropriate fetal levels of glucocorticoids in an environment in which maternal levels of these steroids are very high and that a deficiency of this enzyme leads to high fetal levels of glucocorticoids, which produces a low-birth-weight infant, an enlarged maternal placenta, and subsequent hypertension in the adult progeny.1 11 Although no relationship was found between 11ß-HSD mRNA levels and birth or placental weight in 111 human babies at birth12 or in placental 11ß-HSD2 activity in 50 normal babies delivered at term,13 placental 11ß-HSD2 activity for 12 deliveries complicated by intrauterine growth retardation was significantly lower than that in the 50 normal births.13 A comparison of placental 11ß-HSD activity and cord-blood cortisol levels between term normotensive and preeclamptic pregnancies demonstrated a significant decrease in placental 11ß-HSD activity and an increase in cord cortisol in the preeclamptic versus the normal pregnancies.14
The syndrome of apparent mineralocorticoid excess (AME) is caused by a mutation within the 11ß-HSD2 gene that, by decreasing or destroying enzymatic activity, allows cortisol to have access to the MR. AME is characterized by a pseudohypermineralocorticoid state, which includes hypertension, low plasma renin activity, low aldosterone levels, hypokalemia, and normal cortisol. The ratio of cortisol to cortisone metabolites in the plasma and urine and the half-life of cortisol are elevated.15 Mild intrauterine growth retardation has been reported in some AME patients, and although fetal viability does not appear to be jeopardized in most AME families, 1 AME family reportedly experienced an increased incidence of stillbirths.16 17
Message and activity of both 11ß-HSD1 and 11ß-HSD2 have been
described in the placenta of the rat and of the
human9 10 18 and are closely regulated throughout
pregnancy.10 Dexamethasone is a poor substrate
for 11ß-HSD. Progeny of rats that received large doses of
dexamethasone during the last gestational trimester had
significantly elevated blood pressures as adults,19 as did
progeny of dams that received large amounts of the 11ß-HSD
antagonist carbenoxolone (Cx) during
pregnancy.20 Although licorice and Cx inhibit both
11ß-HSD1 and 11ß-HSD2 isozymes similarly and are associated with
hypertension clinically and experimentally,21
11
-hydroxyprogesterone (11
-OHP), a steroid not produced in
animals, is a more effective inhibitor of 11ß-HSD2, the
"MR gate-keeper" enzyme that has almost exclusively oxidase
activity, than the bidirectional 11ß-HSD1.22 Like
the less-specific 11ß-HSD inhibitors, the administration
of 11
-OHP also causes hypertension.23 At the lowest
effective doses, 11
-OHP separates oxidase from reductase functions.
The systemic administration of aldosterone or the 11ß-HSD
antagonists glycyrrhizic acid, Cx, or 11
-OHP produces
classic hypermineralocorticoid signs of hypertension and saline
polydipsia in normotensive outbred rats. Aldosterone and
11ß-HSD antagonists can be infused
intracerebroventricularly (ICV) at
rates that are too low to alter the blood pressure when infused
systemically yet produce hypertension without altering urinary volume
and electrolytes, saline appetite, or heart weight and
fibrosis.21 24
On the basis of this information, we formulated and tested the following hypotheses. Hypothesis 1: Maternal blood pressure programs the normal level of adult blood pressure during gestation regardless of fetal or placental MR or GR occupation by either aldosterone or corticosterone. Alternatively Hypothesis 2: Excessive occupation of the MR or GR by high levels of either aldosterone or endogenous corticosterone rather than by maternal hypertension per se programs the normal level of adult blood pressure during gestation.
| Methods |
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-OH-P 30 ng/h ICV, rats given vehicle ICV plus 11
-OH-P 3 µg/h
SC, rats given Cx 3 µg/h ICV, rats given vehicle ICV plus Cx 30,
and rats given vehicle ICV plus Cx 52 µg/h SC. Miniosmotic
pumps (Alzet 2002 and 2004, Alza Corp) that delivered 0.5±0.02 µL/h
for 14 days or 0.25±0.02 µL/h for 28 days were filled under sterile
conditions with solutions filtered through 0.22-µm syringe
filters. All rats ate standard chow ad libitum (0.3% NaCl, Purina,
Inc) and were given 0.45% saline to accelerate their increase in blood
pressure.25 Rats were harem-bred for 2 weeks. Blood
pressure and weight measurements continued twice a week with a few
days' postpartum moratorium. A maximum of 2 male and 2 female pups was
randomly selected from each litter to be trained at 5 to 6 weeks of age
and their blood pressures measured without and with salt challenge
(0.9% saline to drink instead of water). Experiments were repeated
with different cohorts of females with essentially the same results.
Data were compared by ANOVA and the Dunnett t and Fisher
paired least significant difference tests (StatView 512+,
BrainPower, Inc). | Results |
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-OHP, especially
in those that received the highest dose, 52 µg/h, of Cx (6 of 6).
Figures 1A, 2A, and 3A
depict the indirect systolic blood pressures of pregnant dams
that received the ICV or SC infusions of aldosterone, Cx,
or 11-
hydroxyprogesterone, respectively. As expected from previous
experiments, the ICV and SC doses produced similar and significant
elevations of blood pressure compared with blood pressures in the
control dams (P<0.01). The blood pressure of the dams
returned to normal within a week of the pumps running out.
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Pups were not weighed at birth, but no difference was visible in size and appearance between neonates of the different treatment groups, nor did a statistical difference exist in the litter sizes between groups. After 4 weeks of age, when the pups were first weighed, no difference in weights existed among progeny of the different groups. Figures 1B, 2B, and 3B are the blood pressures of the progeny of the dams in Figures 1A, 2A, and 3A, respectively. There was no significant difference in blood pressures. Hypertension due to excess mineralocorticoids or local concentrations of endogenous glucocorticoids in the otherwise healthy dam did not increase the blood pressure of her progeny at adulthood.
| Discussion |
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The blood pressure elevation in the hypertensive dams was of short duration, which minimized the effects of maternal end-organ pathology associated with chronic hypertension. Intrauterine growth retardation due to uterine vascular pathology and fetal malnourishment is associated with hypertension in the progeny.26 The extent of end-organ damage varies depending on the cause as well as the duration of the hypertension, and, in the case of mineralocorticoid excess, is independent of the blood pressure.24 27 28 When rats are made equally hypertensive for the same amount of time by either a low ICV dose that does not increase circulating aldosterone levels or a 100-fold-higher SC dose of aldosterone, as in this experiment, only those rats that received the high SC dose developed cardiac hypertrophy.24 Because mineralocorticoid-induced cardiac fibrosis requires 4 to 8 weeks of treatment to become significant,27 28 the variable of different degrees of cardiovascular pathology in the treatment groups was avoided by elevating the dams' blood pressure only during gestation.
Our results do not support either of our original hypotheses. No significant difference existed in the blood pressure of the progeny of these genetically normotensive Sprague-Dawley rats regardless of the maternal gestational BP. This is in contrast to the conclusion that maternal blood pressure during gestation was instrumental in programming blood pressure in the progeny that was reached in studies of the blood pressure of the progeny of spontaneously hypertensive rat dams treated with converting enzyme.29
No significant increase existed in the blood pressure of the progeny of
the dams treated with a dose of aldosterone that
significantly increased circulating aldosterone levels or
with higher systemic concentrations of the 11ß-HSD
inhibitors, which presumably are "seen" by the
placenta. The inability to adequately heal and encapsulate the pumps of
dams that received the higher doses of Cx and 11
-OHP may be
attributed to the antiinflammatory and anticicatrization effect of
local concentrations of endogenous
corticosteroids30 and serves as an
indication that these higher doses were effective in inhibiting the
11ß-HSDs. This suggests that neither excess MR or GR occupation in
the otherwise healthy maternal-fetal complex influences the blood
pressure later in life.
Our studies did not corroborate those in which large doses of dexamethasone (100 µg/kg) or Cx (12.5 mg) given as daily SC injections were found to program the blood pressure of the progeny at a higher-than-normal basal level.19 20 Dams that received larger doses of dexamethasone and Cx during gestation gained less weight than controls during the last trimester of pregnancy,19 20 and loss of condition in some animals near term was profound (J. Seckl, personal communication, 1998). Although the blood pressures of our dams were clearly elevated, the rats continued to gain weight, and, with the exception of seromas in rats given higher SC doses of 11ß-HSD inhibitors, were healthy. Significant morbidity may be the reason pregnant rats that received the high-dose Cx had no elevation in blood pressure at day 20 of gestation20 even though they received significantly more Cx than necessary to produce hypertension.21 This may have been a model of maternal cachexia producing intrauterine growth retardation and subsequent hypertension of the progeny.1 Rats become hypertensive when they receive chronic infusions of dexamethasone at doses below those that cause a loss of body weight.31 These studies should be repeated with a lower dose of dexamethasone.
The mechanism by which Cx increases the blood pressure is
probably more complex than the simple inhibition of a gatekeeper
enzyme. Cx binds the MR at high concentrations.32 However,
the development of the Cx-induced hypertension at the doses used for
these studies, Cx 3 µg/h ICV and Cx 30 µg/h SC, is more rapid than
that of mineralocorticoid-induced hypertension,21 which
suggests that occupation of the MR by either endogenous
glucocorticoids or Cx is not the only mechanism by which Cx increases
the blood pressure. The doses of 11
-OHP (30 ng/h ICV) and 11
-OH-P
(3 µg/h SC) were more similar to the doses of aldosterone
(20 ng/h ICV and 2 µg/h SC). 11
-OHP is an 11ß-HSD
inhibitor with no intrinsic mineralocorticoid activity in
the adrenalectomized rat.33
Because of the abundance of 11ß-HSD in the placenta, it has been assumed that the effects of Cx on this organ were mediated solely by enzyme inhibition. Cx also potentiates catecholamine-mediated vasoconstriction,34 perhaps through direct effects on the endothelium.35 High levels in the pregnant individual might decrease uterine blood flow and thus cause intrauterine growth retardation in the progeny. Cx has been found to have effects on ion transport in leukocytes that are independent of those of either mineralocorticoids or glucocorticoids.36 Placental regulation of the ionic content of amniotic fluid, particularly of sodium and potassium, has been implicated in blood pressure programming in SHR37 and might be important in genetically normotensive animals.
The studies presented in this article involved the elevation of blood pressure by various means in otherwise healthy rats. Maternal blood pressure per se is not the determinant of progeny blood pressure in outbred Sprague-Dawley rats. It is also unlikely that a maternal deficiency of 11ß-HSD activity during gestation is alone an important determinant, but it may be a risk factor in combination with other factors. Such gestational factors in otherwise healthy rats must be in operation, as evidenced by reciprocal embryo transfer studies between genetically normotensive and hypertensive strains.38
| Acknowledgments |
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Received November 18, 1998; first decision December 14, 1998; accepted February 10, 1999.
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