The brains of rats and humans express the
enzymes required for the synthesis of
aldosterone from
cholesterol, including the 3beta-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 3beta-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 microg/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.