Adrenocortical steroid requirements for initiation of ACTH-dependent hypertension in sheep.
1. Previous studies demonstrated that the combined infusion of cortisol (F), aldosterone (ALDO), deoxycorticosterone (DOC), corticosterone (B), 11-deoxycortisol (S), 17 alpha-hydroxyprogesterone (17 alpha OHP) and 17 alpha, 20 alpha- dihydroxy-4-pregnane-3-one (17 alpha 20 alpha OHP), at rates equivalent to their production during adrenocorticotrophic hormone (ACTH) treatment, reproduced the pressor and metabolic responses to ACTH administration in sheep. 2. This study examined which of these adrenocortical steroids were necessary for the initiation of the hypertension produced by these steroids in sheep. 3. Infusion of F, ALDO, 17 alpha OHP and 17 alpha 20 alpha OHP together, increased MAP by 19 mmHg, similar to both complete steroid cocktail (+25 mmHg) or ACTH administration (+21 mmHg). Infusion of F, 17 alpha OHP and 17 alpha 20 alpha OHP increased MAP by +7 mmHg. Infusion of ALDO, 17 alpha OHP and 17 alpha 20 alpha OHP had no effect on MAP. Thus F and ALDO were essential for the pressor effects of the steroid infusion. 4. To determine the role of glucocorticoid activity in the MAP rise, prednisolone, a non-pressor glucocorticoid, was substituted for cortisol. Combined prednisolone, ALDO, 17 alpha OHP and 17 alpha 20 alpha OHP infusion did not raise blood pressure. This suggested that the mineralocorticoid component rather than glucocorticoid component of cortisol's activity was involved in the pressor response. 5. Aldosterone (7 micrograms/h) was substituted for cortisol, giving a total of 10 micrograms/h aldosterone. High dose ALDO (10 micrograms/h), 17 alpha OHP and 17 alpha 20 alpha OHP infusion raised blood pressure by 18 mmHg. Thus, the essential role of cortisol appeared to be due to its occupancy of mineralocorticoid receptors, rather than glucocorticoid receptors. 6. Given that ACTH produces a transient initial increase in aldosterone secretion of up to 10 micrograms/h, it appears that aldosterone and not cortisol is essential for the pressor effects of ACTH. 7. Hypertension resulting from the combined steroid infusion in the sheep appears to be produced by a mechanism which involves a complex interaction between ALDO, F, 17 alpha OHP and 17 alpha 20 alpha OHP. Therefore, the putative 'hypertensinogenic' receptor may be multivalent with binding sites for F, ALDO and 17 alpha 20 alpha OHP, or is a site of single interactive receptors for these steroids and that F exerts its permissive action by occupying the same site as ALDO on the hypertensinogenic receptors.
Spence
C D
CD
Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria, Australia.
Coghlan
J P
JP
Denton
D A
DA
Mills
E H
EH
Whitworth
J A
JA
Scoggins
B A
BA
D019326:17-alpha-Hydroxyprogesterone; D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D003345:Corticosterone / Q000494:pharmacology; D003350:Cortodoxone / Q000494:pharmacology; D003900:Desoxycorticosterone / Q000494:pharmacology; D005260:Female; D006854:Hydrocortisone / Q000494:pharmacology; D006908:Hydroxyprogesterones / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced*; D011239:Prednisolone / Q000494:pharmacology; D012756:Sheep
D000305:Adrenal Cortex Hormones; D006908:Hydroxyprogesterones; C007433:17,20-dihydroxy-4-pregnen-3-one; D003900:Desoxycorticosterone; D000450:Aldosterone; D019326:17-alpha-Hydroxyprogesterone; D000324:Adrenocorticotropic Hormone; D011239:Prednisolone; D003345:Corticosterone; D003350:Cortodoxone; D006854:Hydrocortisone