11 alpha- and 11 beta-hydroxyprogesterone, potent inhibitors of 11 beta-hydroxysteroid dehydrogenase, possess hypertensinogenic activity in the rat.
The progesterone derivatives 11 alpha- and 11 beta-hydroxyprogesterone are potent inhibitors of 11 beta-hydroxysteroid dehydrogenase (isoforms 1 and 2) in vitro and can confer mineralocorticoid activity on corticosterone in the rat in vivo. 11 beta-Hydroxysteroid dehydrogenase metabolizes active glucocorticoids to their inactive 11-dehydro products and protects renal mineralocorticoid receptors from the high circulating levels of endogenous glucocorticoids. 11 beta-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 alpha- and 11 beta-hydroxyprogesterone, we infused these substances into both intact and adrenalectomized Sprague-Dawley rats continuously for 14 days. Both 11 alpha- and 11 beta-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 alpha-hydroxyprogesterone were abolished by adrenalectomy and significantly attenuated when 11 alpha-hydroxyprogesterone was infused together with the specific mineralocorticoid receptor antagonist RU28318. In an additional series of experiments, 11 alpha-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 alpha- and 11 beta-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. 11 beta-Hydroxyprogesterone, and similar endogenous progesterone metabolites that inhibit 11 beta-hydroxysteroid dehydrogenase, may be involved in the pathology of certain hypertensive states.
Souness
G W
GW
Department of Pathology, Brown University, Providence, Rhode Island 02906, USA.
Morris
D J
DJ
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000315:Adrenalectomy; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006908:Hydroxyprogesterones / Q000008:administration & dosage*; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D011918:Rats, Inbred SHR
D006908:Hydroxyprogesterones; C030228:11-hydroxyprogesterone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases