Metoclopramide (MCP), a dopaminergic antagonist, is effective in postural hypotension, but the mechanisms of action have not been well defined. We studied responses of mean arterial pressure (MAP), heart rate, cardiac output (CO), and total peripheral resistance (TPR) after 5 min of increasing degrees of head tilt (15 degrees to 90 degrees) before and after MCP (20 mg IV) in seven subjects with diabetic postural hypotension. Plasma renin activity (PRA) and plasma aldosterone levels (PA) were determined at each degree of tilt; responses to the cold pressor test were also assessed before and after MCP. Before MCP, the maximal degree of tilt tolerated was 75 degrees, while after MCP four subjects were able to support 90 degrees tilt. At 45 degrees tilt, the decreases in MAP were smaller after than before MCP (-7.6 +/- 3.3 and -28.1 +/- 8.5 mm Hg; means +/- SE). This was associated with responses of TPR to tilt after (from 18.6 +/- 2.6 to 24.0 +/- 3.9 arbitrary units [AU]) but not before (from 22.9 +/- 4.0 to 25.6 +/- 4.5 AU) MCP. Reductions in CO were of the same order before and after MCP. PRA responded to tilt better after than before MCP. Supine PA levels increased with MCP (delta PA = 5.4 +/- 0.7 ng/dl), but its response to tilt was unaltered. There were significant rises in MAP and HR during the cold pressor test after but not before MCP. Our data suggest that vasoconstriction is the main mechanism of MCP improvement in blood pressure response to an orthostatic stimulus in diabetic postural hypotension, possibly because of its antidopaminergic property.