(Hypertension. 1996;27:421-425.)
© 1996 American Heart Association, Inc.
Articles |
11
- and 11ß-Hydroxyprogesterone, Potent Inhibitors of 11ß-Hydroxysteroid Dehydrogenase, Possess Hypertensinogenic Activity in the Rat
From the Department of Pathology and Laboratory Medicine, The Miriam Hospital, and the Division of Biology and Medicine, Brown University, Providence, RI.
Correspondence to Graham W. Souness, PhD, The Miriam Hospital, Department of Pathology and Laboratory Medicine, 164 Summit Ave, Providence, RI 02906.
Abstract The progesterone derivatives 11
- and
11ß-hydroxyprogesterone are potent inhibitors of
11ß-hydroxysteroid dehydrogenase (isoforms 1 and 2) in vitro and
can confer mineralocorticoid activity on corticosterone in the rat in
vivo. 11ß-Hydroxysteroid dehydrogenase metabolizes active
glucocorticoids to their inactive 11-dehydro products and protects
renal mineralocorticoid receptors from the high circulating levels of
endogenous glucocorticoids. 11ß-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 11- and
11ß-hydroxyprogesterone, we infused these substances into both
intact and adrenalectomized Sprague-Dawley rats continuously
for 14 days. Both 11- and 11ß-hydroxyprogesterone caused a
significant elevation in blood pressure within 3 days, an effect that
persisted throughout the 14-day infusion. The hypertensive effects of
11-hydroxyprogesterone were abolished by adrenalectomy and
significantly attenuated when 11-hydroxyprogesterone was infused
together with the specific mineralocorticoid receptor
antagonist RU28318. In an additional series of experiments,
11-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 11- and
11ß-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.
11ß-Hydroxyprogesterone, and similar endogenous
progesterone metabolites that inhibit 11ß-hydroxysteroid
dehydrogenase, may be involved in the pathology of certain hypertensive
states.
Key Words: progesterone • corticosterone • 11ß-hydroxysteroid dehydrogenase • hypertension, experimental
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