11-BETA-HYDROXYSTEROID DEHYDROGENASE-ACTIVITY AND GENE-EXPRESSION IN THE HYPERTENSIVE BIANCHI-MILAN RAT

objective: 11beta-Hydroxysteroid dehydrogenase (11beta-HSD), by conver ting the active steroids cortisol and corticosterone to their inactive metabolites, regulates steroid exposure to the mineralocorticoid and glucocorticoid receptors. We explored the hypothesis that a defect in 11beta-HSD could result in overstimulation of either the mineralocorti coid or glucocorticoid receptors with subsequent hypertension in an es tablished animal model of hypertension, the Bianchi-Milan hypertensive (BMH) rat. Design and methods: Groups of BMH rats with established hy pertension (42-46 days old) and prehypertensive rats (22 days old) wer e compared with age-matched normotensive control rats. Kidney and live r 11beta-HSD and glucocorticoid receptor messenger RNA (mRNA) levels w ere assessed by Northern and dot-blot analyses, and 11beta-HSD activit y as percentage conversion of [H-3]-corticosterone to [H-3]-ll-dehydro corticosterone by tissue homogenate. Results: Hepatic 11beta-HSD activ ity and gene expression were significantly reduced in the hypertensive BMH rat compared with its normotensive genetic control. 11beta-HSD ac tivity was also reduced in the prehypertensive BMH rat (aged 25 days) from hypertensive parents, excluding hypertension per se as the cause of the abnormality. Plasma corticosterone was higher in the hypertensi ve rats. There was no difference in renal 11beta-HSD activity or gene expression between hypertensive and normotensive BMH rats, or in gluco corticoid receptor gene expression in the liver or kidney. Conclusions : Normal levels of renal 11beta-HSD mRNA and activity are found in the BMH rat. However, the hypertensive BMH rat does demonstrate impaired hepatic 11beta-HSD activity which occurs at a pretranslational level, although it is not clear how this relates to the pathogenesis of hyper tension in this model.