Both domperidone (DOMP) and metoclopramide (MCP) are D2 receptor antagonists, MCP being a central and peripheral dopamine antagonist, whereas DOMP is exclusively a peripheral antagonist. MCP, but not DOMP, has been shown to stimulate aldosterone production. To elucidate whether aldosterone stimulation by dopamine antagonism is centrally mediated, we injected DOMP (28 μg/kg body wt) via a cannula into the third ventricle in Sprague-Dawley rats. Plasma aldosterone and renin concentration were measured before and 15 min after the injection. Centrally administered DOMP resulted in an increment in plasma aldosterone (23.8 ± 7.4 ng/dl) that was not significantly greater than that induced by vehicle alone (15.8 ± 4.5 ng/dl). This increase was inhibited by pretreatment dexamethasone (100 μg three times daily) and attenuated by captopril (1 mg/kg ip) but not by L-β-3,4-dihydroxyphenylalanine (30 mg/kg), thus reflecting a stress effect. Similarly, central administration of MCP (2l μg/kg) resulted in a significant rise in plasma aldosterone. This increase. however, was eliminated by pretreatment with dexamethasone and attenuated by captopril. Peripherally administered DOMP (280 μg/kg) had no effect on plasma aldosterone. The effect of DOMP and MCP on aldosterone secretion by freshly obtained adrenal capsules was also tested. Angiotensin II and MCP, but not DOMP, induced a dose-dependent increase in aldosterone secretion, with a maximal increment (15.7 ± 5.8 ng·mg capsular protein-1·10 min-1; 50% increase) with MCP at 10-7 M (P < 0.01 compared with controls). Dopamine completely inhibited this MCP-induced rise in aldosterone release. Thus the dichotomous aldosterone response to MCP and DOMP cannot be explained by the inability of DOMP to cross the blood-brain barrier. These data support the concept of direct adrenal stimulation by MCP and suggest that centrally administered DOMP or MCP does not enhance aldosterone release by a specific antidopaminergic mechanism but by a nonspecific stress effect.
|Journal||American Journal of Physiology - Endocrinology and Metabolism|
|State||Published - 1989|