INHIBITION OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE IN PREGNANT RATS AND THE PROGRAMMING OF BLOOD-PRESSURE IN THE OFFSPRING

Recent epidemiological studies have linked low birth weight with the l ater occurrence of cardiovascular and metabolic disorders, particularl y hypertension. We have proposed that fetal exposure to excess materna l glucocorticoids may underpin this association. Normally, the fetus i s protected from maternal glucocorticoids by placental 11 beta-hydroxy steroid dehydrogenase (11 beta-HSD). We have previously shown that tre atment of pregnant rats with dexamethasone, a synthetic glucocorticoid that is poorly metabolized by the enzyme, reduces birth weight and pr oduces elevated blood pressure in the adult offspring. Moreover, low a ctivity of placental 11 beta-HSD correlates with low birth weight in r ats. Here, we show that maternal administration of carbenoxolone, a po tent inhibitor of 11 beta-HSD, throughout pregnancy leads to reduced b irth weight (mean 20% decrease) and elevated blood pressures (increase in mean arterial pressure, 9 mm Hg in males, 7 mm Hg in females) in t he adult offspring of carbenoxolone-treated rats. This effect requires the of presence of maternal adrenal products, as carbenoxolone given to adrenalectomized pregnant rats had no effect on birth weight or blo od pressure. These data support the hypothesis that excess exposure of the fetoplacental unit to maternal glucocorticoids reduces birth weig ht and programs subsequent hypertension and indicate a key role for pl acental 11 beta-HSD in controlling such exposure.