To evaluate the effect of angiotensin-converting inhibition enzyme on spontaneous and insulin-stimulated endothelin-1 (ET-1) secretion in vitro and in vivo, human endothelial cells derived from umbilical cord veins were cultured onto acellular collagen-coated permeable membrane, thus mimicking in vivo conditions with a luminal and abluminal side. Insulin (10−6,−8,−9 mol/l) significantly stimulated ET-1 secretion by cultured cells (P < 0.05 starting from 2-h incubation). Captopril (10−7,−8,−9 mol/l) significantly reduced both spontaneous and insulin-stimulated ET-1 secretion, while increasing nitric oxide production. Considering each cell side, captopril significantly inhibited the apical secretion of ET-l, while its effect on the basolateral compartment was modest. In the presence of D-Arg,[Hyp3,Thi5,8,D-Phe7]-bradykinin (10−6 mol/l), a bradykinin B2 receptor antagonist, captopril had no effects on ET-1 and nitric oxide production and also when insulin was added to the culture media. With regard to in vivo experiments, oral captopril therapy (25 mg twice daily for 1 week) was given to normotensive (n = 5) and hypertensive (n = 6) subjects and significantly decreased plasma ET-1 concentration (normotensive subjects, before: 0.98 ± 0.09 pg/ml; after: 0.55 ± 0.08 pg/ml, P < 0.0001; hypertensive subjects, before: 1.05 ± 0.03 pg/ml; after: 0.56 ± 0.05 pg/ml, P < 0.0001). Transient hyperinsulinemia was accompanied by a significant rise in plasma ET-1 concentrations in both groups (P < 0.0001 at 180 and 210 min) before but not after captopril treatment. In conclusion, captopril inhibits both spontaneous and insulinstimulated ET-1 secretion by endothelial cells, acting on angiotensin-converting enzyme bound to the luminal cell side. In vivo, captopril significantly reduces plasma ET-1 levels in both basal and insulin-stimulated conditions.

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