11α- and 11β-Hydroxyprogesterone, Potent Inhibitors of 11β-Hydroxysteroid Dehydrogenase, Possess Hypertensinogenic Activity in the Rat

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Abstract
Abstract The progesterone derivatives 11α- and 11β-hydroxyprogesterone are potent inhibitors of 11β-hydroxysteroid dehydrogenase (isoforms 1 and 2) in vitro and can confer mineralocorticoid activity on corticosterone in the rat in vivo. 11β-Hydroxysteroid dehydrogenase metabolizes active glucocorticoids to their inactive 11-dehydro products and protects renal mineralocorticoid receptors from the high circulating levels of endogenous glucocorticoids. 11β-Hydroxysteroid dehydrogenase has been suggested to be important not only in the control of renal sodium retention but also of blood pressure. To assess the possible blood pressure–modulating effects of 11α- and 11β-hydroxyprogesterone, we infused these substances into both intact and adrenalectomized Sprague-Dawley rats continuously for 14 days. Both 11α- and 11β-hydroxyprogesterone caused a significant elevation in blood pressure within 3 days, an effect that persisted throughout the 14-day infusion. The hypertensive effects of 11α-hydroxyprogesterone were abolished by adrenalectomy and significantly attenuated when 11α-hydroxyprogesterone was infused together with the specific mineralocorticoid receptor antagonist RU28318. In an additional series of experiments, 11α-hydroxyprogesterone significantly amplified the hypertensive effects of corticosterone in adrenalectomized spontaneously hypertensive rats but had no effects by itself in this experimental animal. These results demonstrate that both 11α- and 11β-hydroxyprogesterone are potently hypertensinogenic in the rat and that this activity depends on an intact adrenal and at least in part on the activation of mineralocorticoid receptors. 11β-Hydroxyprogesterone, and similar endogenous progesterone metabolites that inhibit 11β-hydroxysteroid dehydrogenase, may be involved in the pathology of certain hypertensive states.