In vitro and in vivo evidence for an indirect mechanism mediating enhanced aldosterone secretion by metoclopramide.
Metoclopramide (MCP), a dopaminergic antagonist, increases the levels of plasma aldosterone in man and sheep. The present studies were designed to determine how MCP exerts this effect. In in vitro studies using collagenase-dispersed rabbit adrenal zona glomerulosa cells, MCP (10(-4) M) failed to increase aldosterone biosynthesis and had no effect on the dose-related increases induced by angiotensin II (AII) or ACTH. Dopamine (10(-5) M) had no effect on the AII- or ACTH-induced aldosterone responses of these cells. Aldosterone production of cells pretreated with dopamine and stimulated by AII or ACTH was unaltered by the addition of MCP. Bolus intraarterial injections of MCP increased plasma aldosterone significantly; however, this response was completely abolished by concomitant administration of L-dopa. Chronic im administration of MCP produced significant elevations of plasma aldosterone that were associated with increases in adrenal weight and in the adrenal weight to body weight ratio. Glomerulosa cells isolated from these adrenal glands had normal basal aldosterone production and exhibited enhanced sensitivity to AII but normal responses to ACTH. These results suggest that MCP is devoid of intrinsic steroidogenic activity and that it increases aldosterone production by antagonizing a tonic inhibitory dopaminergic mechanism that leads to enhanced aldosterone production. This enhanced aldosterone production is mediated in part by increased adrenocortical sensitivity to AII.
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism*; D000311:Adrenal Glands / Q000033:anatomy & histology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D011817:Rabbits
D000804:Angiotensin II; D007980:Levodopa; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D008787:Metoclopramide