Dihydropyridines and angiotensin converting enzyme inhibitor effects on superoxide and nitric oxide (NO) were compared in high glucose (20 mM, 24 h)-treated human Ea.hy 926 endothelial cells. High glucose stimulated superoxide both extracellularly (lucigenin chemiluminescence, cytochrome c reduction) and intracellularly (dihydrorhodamine 123 fluorescence). The dihydropyridines amlodipine, nisoldipine, BayK 8644 or the angiotensin converting enzyme inhibitors captopril and enalaprilat attenuated extra- and intracellular superoxide formation; nifedipine blocked extracellular increases only, ramiprilat was without antioxidant effect. Dihydropyridines and captopril also prevented NADPH-driven superoxide release. Antioxidant actions were blunted by a bradykinin B(2) receptor antagonist or an inhibitor of p38 mitogen activated protein kinase (MAPK), and were accompanied by improved NO release (amperometric sensor). p38MAPK inhibition prevented the NO-sparing actions of dihydropyridines but not angiotensin converting enzyme inhibitors. Thus, dihydropyridines and angiotensin converting enzyme inhibitors limit high glucose-induced superoxide formation and improve NO bioavailability in human endothelial cells, in part via bradykinin and p38MAPK.