Effect of 3β-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat

Abstract

The brains of rats and humans express the enzymes required for the synthesis of aldosterone from cholesterol, including the 3␤-steroid dehydrogenase that catalyzes the conversion of pregnenolone to progesterone in the pathway of adrenal steroid synthesis. Salt-induced hypertension in the Dahl inbred salt-sensitive (SS/jr) rat is associated with normal to low levels of circulating aldosterone, yet it is abrogated by the central infusion of mineralocorticoid receptor antagonists. To test the hypothesis that de novo synthesis of aldosterone in the brain has a pathophysiological role in the salt-induced hypertension of the SS rat, the 3␤-steroid dehydrogenase antagonist trilostane was infused continuously intracerebroventricularly or subcutaneously in two different cohorts of Dahl SS/jr rats, one female, the other male, during and after the development of salt-induced hypertension. The doses of trilostane used had no effect on blood pressure when infused subcutaneously. Animals receiving vehicle intracerebroventricularly experienced a 30-to 45-mmHg increase in systolic blood pressure measured by tail cuff. The intracerebroventricular, but not subcutaneous, infusion of 0.3 g/h trilostane effectively blocked the increase in systolic blood pressure and reversed the hypertension produced by drinking 0.9% saline. Trilostane was equally effective in female and male rats. Weight gain, serum aldosterone and corticosterone concentrations, and behavior assessed subjectively and by elevated plus maze were unchanged by the trilostane treatment. These studies suggest that the synthesis in the brain of a mineralocorticoid receptor agonist, probably aldosterone, is responsible in part for the salt-induced hypertension of the inbred Dahl SS/jr rat. hypertension; aldosterone synthesis; 11␤-hydroxylase; corticosterone; brain ALL OF THE ENZYMES REQUIRED for the synthesis of adrenal corticosteroids from cholesterol are expressed in specific anatomic areas of the rat brain, albeit in very small amounts (7,12,31,32). The mRNAs for these enzymes have also been demonstrated in human brain (46).

Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

“…Thus, in contrast to the effects of a high-salt diet and plasma [Na ϩ ] on adrenal regulation of aldosterone production and release, it appears that an increase in CSF [Na ϩ ] results in an opposite response, i.e., increases hypothalamic aldosterone. Blockade of biosynthesis of mineralocorticoids (likely aldosterone) in the CNS by intracerebroventricular infusion of the 3␤-hydroxysteroid dehydrogenase blocker trilostane prevented hypertension in Dahl S rats on high salt intake (15). Together with the present results, these studies suggest that aldosterone biosynthesis in the brain can be enhanced by high salt intake if leading to an increase in CSF [Na ϩ ].…”

“…In adrenalectomized Wistar rats, aldosterone remains present in the brain (13). Blockade of aldosterone biosynthesis in the CNS by intracerebroventricular infusion of the 3␤-hydroxysteroid dehydrogenase blocker trilostane prevents hypertension in Dahl S rats on high salt intake (15). These studies suggest that aldosterone in the CNS mediates the hypertension in Dahl S rats on high salt.…”

Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats

“…Saltinduced sympathetic hyperactivity and hypertension can be prevented by central blockade of steroid biosynthesis by the steroid synthase 3␤-hydroxysteroid dehydrogenase (HSD) inhibitor trilostane (14) or central blockade of mineralocorticoid receptors (MR) (13).…”

“…Inasmuch as central infusion of trilostane has antihypertensive effects (14), it appears that local production of a steroid in the CNS plays a major role. However, trilostane blocks the synthesis not only of the mineralocorticoid hormone aldosterone but also of the glucocorticoid hormone corticosterone (14,24). Aldosterone and corticosterone can be synthesized in the brain (11,12,24).…”

Expression of mineralocorticoid and glucocorticoid receptors in preautonomic neurons of the rat paraventricular nucleus

“…Inappropriate activation of MR in the brain increases blood pressure and SNS activation in both sexes, though cycling females generally have lower blood pressures (46,49,107). While the relationship between sodium intake and activation of the RAAS is the same in males and females (17, 40 -42, 45, 49, 51, 52), sexual dimorphism must be considered when comparing absolute mineralocorticoid levels between males and females because progesterone is a competitive antagonist of the MR that reaches relevant concentrations for MR occupation during the luteal phase (3).…”