1986 Volume 62 Issue 3 Pages 197-207
There is considerable information suggesting that dopamine is a physiological regulator of aldosterone secretion. Metoclopramide, a specific dopamine antagonist, elicits a rapid rise in plasma aldosterone independent of the known aldosterone-regulating factors. However, the mechanism and the site of action of metoclopramide, whether adrenal or extraadrenal, in stimulation of aldosterone production remain to be defined. The present studies were designed to investigate the mechanism of dopaminergic control of corticosteroid secretion and to determine at which step in the aldosterone biosynthetic pathway metoclopramide and dopamine exert their effect.
Plasma concentrations of progesterone, 11-deoxycorticosterone (DOC), and cortisol were not altered by a bolous intravenous administration of 10 mg metoclopramide in 8 healthy male volunteers. Metoclopramide increased plasma aldosterone from 6.9±2.8 (Mean±2SD) ng/100 ml to a maximum level of 18.2±4.7 ng/100 ml, 18-hydroxycorticosterone 0.09μg/100 ml to a maximum of 0.85±0.22 μg/100 ml. The aldosterone, 18-OHB and corticosterone responses displayed a parallel time course, with a significant response of each occurring within 5 minutes after metoclopramide administration. These data suggest that metoclopramide may modulate the activities of 18-hydroxylase and 1113-hydroxylase.
Studies in vitro revealed that metoclopramide (10-8-10-4M) had little effect on basal production of aldosterone, 18-OHB and corticosterone from human adrenal slices. Dopamine (10-4M) did not alter the basal secretion of aldosterone, 18-OHB and corticosterone, but suppressed the secretion of these 3 mineralocorticoids by ACTH, which were diminished by addition of 10-4 M metoclopramide.
There was a concentration-dependent inhibitory effect of dopamine on conversion of corticosterone to 18-OHB and DOC to corticosterone in vitro using bovine adrenal mitochondrial fractions. IC50 of dopamine inhibiting 18-hydroxylation and 11β-hydroxylation were 7.5×10-7M and 9.5×10-4M, respectively. It appears that physiological concentration of dopamine can modulate the activity of 18-hydroxylase enzyme.
In summary, it can be concluded that the in vivo and in vitro studies are compatible with a view that dopamine has a physiological role in the regulation of aldosterone by modulating the activity of 18-hydroxylase enzyme.
