Whether the dopaminergic system may be involved in essential hypertension is of pathogenetic as well as therapeutic interest. Therefore, we investigated in eight hypertensive and 12 normal subjects cardiovascular, endocrine, and renal responses to fenoldopam, which has been characterized experimentally as an agonist of peripheral postsynaptic dopamine, receptors. A single oral dose of fenoldopam, 100 mg, changed blood pressure (BP) in hypertensive subjects (from 163/103 to 147/76 mm Hg;p< 0.01 for systolic andp< 0.001 for diastolic BP) and normal subjects (from 121/81 to 123/65 mm Hg;p< 0.001 for diastolic BP); percentage decreases in diastolic BP averaged −20 ± 6 and −1 6 ± 7%, respectively. Fenoldopam-induced effects on other variables were similar in the two groups. Heart rate rose (p< 0.001) on average from 69 to 92 beats/min in hypertensive and from 64 to 84 beats/min in normal subjects. Effective renal plasma flow increased (from 552 to 765 and 634 to 937 ml/min/1.73 m2;p< 0.01), while glomerular nitration rate tended to decrease (from 121 to 99 ml/min/1.73 m2in the hypertensive and from 119 to 97 ml/min/1.73 m2;p< 0.001 in the normal group). Fractional sodium clearance was elevated (from 2.8 to 5.2 and 1.7 to 3.8%;p< 0.01), as was free water clearance (from −1.7 to 0.6 and −1.7 to 0.1 ml/min/1.73 m2;p< 0.01). Potassium clearance was largely unchanged. Plasma renin activity increased about twofold (p< 0.01 in normal subjects), and plasma aldosterone by 40% (NS). Plasma norepinephrine levels increased twofold to 2.5-fold (p< 0.001), and urinary norepinephrine excretion fivefold to 10-fold (p< 0.01). Fenoldopam-induced changes were not significantly modified by intravenous and/or oral pretreatment with the dopamine-receptor antagonist metoclopramide or the cyclooxygenase inhibitor indomethacin. These findings suggest that in humans, fenoldopam may acutely override the dopaminergic antagonism of metoclopramide given in clinical dosage and that its cardiovascular and renal effects are not prostaglandin-mediated. Although acute sympathetic stimulation may be partially antagonistic, the concomitant BP-lowering, renal vasodilating, and natriuretic actions of fenoldopam represent a desirable profile of a potential antihypertensive agent.