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(Hypertension. 1999;33:1369-1373.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Maternal Hypertension and Progeny Blood Pressure

Role of Aldosterone and 11ß-HSD

Elise P. Gomez-Sanchez; Celso E. Gomez-Sanchez

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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Abstract—Epidemiological and experimental evidence suggests that gestational events modulate the level of blood pressure that will be "normal" for the individual as an adult. Glucocorticoid excess during gestation is associated with low birth weight, a large placenta, and adult hypertension in humans and animals. It has been proposed that the deficiency in placental 11ß-hydroxysteroid dehydrogenase activity in humans produces a gestational hormonal milieu, notwithstanding normal circulating levels of glucocorticoids, that predisposes the adult progeny to hypertension. Animal studies indicate that maternal hypertension, excess glucocorticoids, and hydroxysteroid dehydrogenase inhibition program adult blood pressure. Blood pressures of Sprague-Dawley rat dams were manipulated during gestation with continuous intracerebroventricular infusions of vehicle, aldosterone, 11-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 (n6 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 multiple interacting causes of essential hypertension may be classified as genetic or environmental (which includes the fetal milieu). The combination of low term birth weight and large placenta, an indicator of an adverse fetal environment, is associated with malnutrition, hypoxia, severe maternal anemia, decreased blood flow to the fetus, and glucocorticoid excess.¹ Low term birth weight has been reported to be a significant risk factor for cardiovascular disease, which includes hypertension, later in life.^{1 2 3} A review of published epidemiological studies found reports in which no association between term birth weight and adult blood pressure was indicated as well as studies in which a negative correlation existed, but high term birth weight was not found to be correlated with hypertension in the adult. Birth weight correlated positively with neonatal blood pressure but did not consistently predict adolescent blood pressure.⁴ A prospective study of black Americans found that term birth weight did not correlate with adult blood pressure, although blood pressure and weight at 4 months of age did predict subsequent blood pressures through age 28 years.⁵

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 human^{9 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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These studies were performed in accordance with a University of Missouri ACUC–approved protocol in an Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALAC)–accredited facility. Female Sprague-Dawley (Sasco, Wilmington, Mass) rats were trained to accept unheated indirect systolic blood pressure (IITC) measurements calmly before surgery for the implantation of ICV cannulas and miniosmotic pumps, as previously described.²⁵ Several experiments were run; each experiment had its own controls, and all the dams in a given experiment had the same dates of birth and arrival at our facility. To ensure a minimum of 4 litters from dams treated successfully (as verified by blood pressure measurements throughout gestation) 5 to 6 (given SC infusions) or 8 (given ICV infusions) females were started in each group. The treatment groups comprised the following: controls given vehicle ICV, rats given aldosterone 20 ng/h ICV, rats given vehicle ICV plus aldosterone 2 µg/h SC, rats given 11-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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Dams that did not whelp or with blood pressure that was significantly different from others in the group, in every case due to the disconnection of the pump from the cannula, were excluded from the experiment, which left at least 4 litters for each group. Body weights of the pregnant rats did not differ significantly between groups. Persistent seromas developed around the canula and pump assembly in several of the dams that received systemic Cx and 11-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.

View larger version (28K): [in this window] [in a new window]   Figure 1. Systolic blood pressures measured by indirect tail-cuff plethysmography are depicted by days of gestation for (A) dams receiving aldosterone ICV (icv) or SC (sc) and by age in weeks for (B) their progeny. aldo indicates aldosterone; con, control; and fem, female. n indicates number of individuals per group.

View larger version (26K): [in this window] [in a new window]   Figure 2. Systolic blood pressures measured by indirect tail-cuff plethysmography are depicted (A) by days of gestation for the dams receiving Cx (CBX) ICV or SC and (B) by age in weeks for their progeny. Other abbreviations are as in text and Figure 1.

View larger version (27K): [in this window] [in a new window]   Figure 3. Systolic blood pressures measured by indirect tail-cuff plethysmography are depicted (A) by days of gestation for the dams receiving 11-OHP and (B) by age in weeks for their male progeny. Abbreviations are as in text and Figure 1.

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 assumption on which these experiments were based is that the low ICV doses of aldosterone and inhibitors that do not alter urine volume and electrolyte excretion would also be subthreshold for direct effects on the placenta and fetus. If elevated blood pressure of the dam during gestation were the crucial environmental determinant of progeny hypertension (Hypothesis 1), the progeny of all hypertensive females should have had elevated blood pressure. If ligand binding to placental or fetal MR were crucial to programming the blood pressure, progeny of dams that received the larger SC aldosterone or SC 11ß-HSD inhibitors should have become hypertensive. If ligand binding to the GR were the determinant, only progeny of dams that received SC 11ß-HSD inhibitors should have become hypertensive.

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

 
This work was supported by funds from the National Programs of the American Heart Association and the Medical Research Service of the US Department of Veterans Affairs.

Received November 18, 1998; first decision December 14, 1998; accepted February 10, 1999.

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