The potential role of endothelin-1 (ET-1) in essential hypertension in humans is still subject to debate. We recently reported strong sodium retention and renal vasoconstriction during pathophysiological increments in plasma ET-1. Apart from this vasoconstrictor action, ET-1 also has mitogenic properties that play a role in the pathophysiology of hypertension. On the other hand, some data refute an important role of ET-1 in hypertension. We therefore investigated in nine subjects with essential hypertension the constrictor actions of ET-1 by challenging these subjects with a systemic infusion of ET-1 (0.5 ng/kg per minute for 60 minutes, then 1.0 ng/kg per minute for 60 minutes, and finally 2.0 ng/kg per minute for 60 minutes). Furthermore, we studied whether these effects of ET-1 could be modulated by oral use of the angiotensin-converting enzyme inhibitor enalapril (20 mg BID) or the calcium channel blocker nifedipine (60 mg OD). ET-1 infusion increased plasma ET-1 levels from 2.5 +/- 0.4 to 11.6 +/- 1.0 pmol/L (P < .05). Blood pressure rose by approximately 10 mm Hg (P < .05). Cardiac index decreased by 21 +/- 2%, whereas calculated systemic vascular resistance increased by 27 +/- 6% (P < .05). Renal blood flow decreased from 1051 +/- 94 to 707 +/- 60 mL/min at the end of the ET-1 infusion (P < .05), and calculated renal vascular resistance increased from 118 +/- 19 to 189 +/- 19 mm Hg [center dot] min/L (P < .05). Sodium excretion decreased from 227 +/- 39 to 111 +/- 15 micro mol/min (P < .05). Both enalapril and nifedipine treatment prevented the systemic effects of ET-1 infusion in these subjects. However, during enalapril treatment, despite renal predilatation, ET-1 reduced renal blood flow (from 1119 +/- 132 to 701 +/- 75 mL/min, P < .05) and increased renal vascular resistance (from 111 +/- to 187 +/- 28 mm Hg [center dot] min/L, P < .05) to the same levels as during ET-1 infusion alone. Nifedipine pretreatment attenuated the ET-1-induced fall in renal blood flow (from 1088 +/- 93 to 907 +/- 68 mL/min) and increase in renal vascular resistance (from 105 +/- 9 to 133 +/- 10 mm Hg [center dot] min/L). Although neither drug modulated the antinatriuretic effect of ET-1, nifedipine increased basal sodium excretion (P < .05), which compensated for the decrease during ET-1 infusion. In conclusion, essential hypertensive subjects are sensitive to the vasoconstrictor effects of ET-1. Both enalapril and nifedipine can prevent the systemic effects of ET-1, but nifedipine seems more effective in attenuating the renal constrictor effects of ET-1. (Hypertension. 1997;30[part 1]:15-21.)