Endogenous 11 beta-hydroxysteroid dehydrogenase inhibitors and their role in glucocorticoid Na+ retention and hypertension.
11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) metabolizes active glucocorticoids to their inactive 11-dehydro products and protects renal mineralocorticoid receptors from the high circulating levels of endogenous glucocorticoids. 11 beta-HSD has been suggested to be important not only in the control of renal sodium retention but also blood pressure. We had previously shown that 11 alpha- and 11 beta-hydroxyprogesterone (11 alpha- and 11 beta-OHP) were (I) potent inhibitors of 11 beta-HSD (Isoforms 1 and 2) activity in vitro, (ii) able to confer mineralocorticoid (MC) activity upon corticosterone (B) in vivo and (iii) hypertensinogenic when chronically infused into Sprague-Dawley (SD) rats. In addition we also showed that 3 alpha,5B-tetrahydroprogesterone (3 alpha,5B-THP) and chenodeoxycholic acid (CDCA) were potent inhibitors of 11 beta-HSD1 activity but not 11 beta-HSD2 activity, however, these substances were still able to confer MC activity upon B in the adrenalectomized rat. To assess the possible blood pressure modulating effects of 3 alpha,5B-THP and CDCA we have now infused these substances into intact SD rats continuously for 14 days. Both 3 alpha,5B-THP and CDCA caused a significant elevation in blood pressure within seven days, an effect that persisted throughout the 14-day infusion. These results show that both 3 alpha,5B-THP and CDCA are hypertensinogenic in the rat and that the inhibition of either 11 beta-HSD2 or 11 beta-HSD1 activity by endogenous progesterone metabolites and CDCA may be involved in the pathology of hypertension.
Morris
D J
DJ
Department of Pathology and Laboratory Medicine, Miriam Hospital, Lifespan and Brown University School of Medicine, Providence, RI 02906, USA.
Souness
G W
GW
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005938:Glucocorticoids / Q000378:metabolism*; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D006973:Hypertension / Q000209:etiology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D008297:Male; D011280:Pregnanolone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007527:Isoenzymes; D002635:Chenodeoxycholic Acid; D012964:Sodium; D011280:Pregnanolone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases