Adrenocortical steroid hormones in production of hypertension in sheep

Abstract

In the conscious sheep the contribution of physiological and pharmacological levels of the two major classes of adrenal steroid hormones “glucocorticoids” and “mineralocorticoids” in the production of hypertension have been examined using the model of ACTH induced hypertension, an adrenally dependent steroid hypertension which can be reproduced by infusion over 5 days of a combination of cortisol (5 mg/h), corticosterone (0.5mg/h), 11-deoxycortisol (1 mg/h), DOC (25 mg/h), aldosterone (3μg/h), 17α-hydroxyprogesterone (1 mg/h) and 17α,20α-dihydroxyprogesterone (500 μg/h) at rates to produce blood levels seen with ACTH treatment. Hypertension cannot be reproduced by infusion of any of these steroids individually at these rates. Omission of 17α-hydroxyprogesterone and 17α,20α-dihyroxyprogesterone from the infusion results in similar metabolic effects to ACTH but only small increases in blood pressure. These studies together with in vitro and in vivo assessment of the lack of “mineralocorticoid” and “glucocorticoid” activity of 17α-hydroxyprogesterone and 17α,20α-dihydroxy-progesterone have led us to postulate a new class of steroid action—hypertensinogenic steroids. Infusion of 9α-fluorocortisol (9α-FF) at 0.2 mg/day increases blood pressure without the associated metabolic effects seen at higher dose (0.63 or 2 mg/day). Based on in vitro renal receptor affinity of 9α-FF for “mineralocorticoid” and “glucocorticoid” receptors, doses of aldosterone and cortisol approx. equivalent to either 0.63 or 2 mg/day of 9α-FF reproduce the metabolic effects of 9α-FF but have only a small effect on blood pressure. These data suggest that the hypertensive effects of adrenal steroid hormones are not simply related to their “mineralocorticoid” or “glucocorticoid” activity and support our proposal of a further class of steroid hormone action.