Steroid antagonism of the hypertensinogenic activity of adrenocortical steroids.
Previous studies in sheep have provided evidence for a separate "hypertensinogenic" class of adrenocortical steroid activity which is not simply related to their classical mineralocorticoid (MC) and/or glucocorticoid (GC) actions. This study investigated the structure-activity relationships of the effects of structural analogues of prednisolone on mean arterial pressure (MAP), and MC and GC actions in sheep. Infusions of these synthetic GC at 0.6 and 24 mg/day produced variable pressor effects which were dissociated from their MC and GC actions. In other experiments, the minimum adrenocortical steroid requirement to reproduce the onset of ACTH-dependent hypertension was determined. Infusion of cortisol, aldosterone, 17 alpha-hydroxy progesterone and 17 alpha,20 alpha-dihydroxy-4-pregnene-3-one was found to be sufficient to reproduce the hypertensive response to ACTH administration in sheep. A subsequent experiment showed that substitution of cortisol by the more potent synthetic GC, prednisolone had no effect on MAP. Therefore, cortisol appears to exert an essential action in ACTH hypertension which is not dependent on its GC activity. Other studies have found that prednisolone (100 mg/day) antagonized 9 alpha-fluoro-prednisolone (0.6 mg/day) induced hypertension but not its MC effects. The effect of progesterone (500 mg/day) and the progesterone analogues, norethisterone, medroxy-progesterone and 16 alpha-methyl progesterone on ACTH (5 micrograms/kg per day) hypertension was investigated. Progesterone completely blocked the hypertension and MC effects of ACTH infusion, while medroxy-progesterone partially blocked the increase in MAP. These data support our concept of a "hypertensinogenic" class of steroid activity.
Reid
A F
AF
Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Australia.
Spence
C D
CD
Coghlan
J P
JP
Denton
D A
DA
Whitworth
J A
JA
Scoggins
B A
BA
D000305:Adrenal Cortex Hormones / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D005477:Fluprednisolone / Q000494:pharmacology / Q000031:analogs & derivatives; D005938:Glucocorticoids / Q000494:pharmacology*; D008901:Mineralocorticoids / Q000494:pharmacology*; D011239:Prednisolone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011374:Progesterone / Q000031:analogs & derivatives / Q000494:pharmacology; D012756:Sheep; D013329:Structure-Activity Relationship
D000305:Adrenal Cortex Hormones; D005938:Glucocorticoids; D008901:Mineralocorticoids; C010958:9-fluoroprednisolone; D011374:Progesterone; D000324:Adrenocorticotropic Hormone; D005477:Fluprednisolone; D011239:Prednisolone