RT Journal Article SR Electronic T1 Kinin B1 Receptors Stimulate Nitric Oxide Production in Endothelial Cells: Signaling Pathways Activated by Angiotensin I-Converting Enzyme Inhibitors and Peptide Ligands JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1310 OP 1316 DO 10.1124/mol.104.001990 VO 66 IS 5 A1 Tatjana Ignjatovic A1 Sinisa Stanisavljevic A1 Viktor Brovkovych A1 Randal A. Skidgel A1 Ervin G. Erdos YR 2004 UL http://molpharm.aspetjournals.org/content/66/5/1310.abstract AB We reported previously a novel mode of action of angiotensin I-converting enzyme (kininase II; ACE) inhibitors mediated through the direct activation of bradykinin B1 receptor, independent of endogenous kinins or ACE (J Biol Chem277:16847-16852, 2002OpenUrlAbstract/FREE Full Text). We aimed to further clarify the mechanism of activation of B1 receptor, which leads to prolonged nitric oxide (NO) release. The ACE inhibitor enalaprilat and the peptide ligand desArg10-kallidin (in nanomolar concentrations) release NO by activating endothelial NO synthase (eNOS) in bovine and inducible NO synthase (iNOS) in stimulated human endothelial cells. The peptide and the ACE inhibitor ligands activate eNOS by facilitating different signaling pathways. DesArg10-kallidin enhances inositol-phosphate generation and elevates [Ca2+]i by first augmenting intracellular release and then the influx of extracellular Ca2+. In contrast, enalaprilat stimulates only the influx of extracellular Ca2+ through rare earth-sensitive channels, and its effect is blocked by cholera toxin or protein kinase C inhibitors. In addition, unlike desArg10-kallidin, enalaprilat can also release NO independent of Ca2+ in bovine endothelial cells. The inflammatory cytokines interleukin-1β and interferon-γ induce both B1 receptor and iNOS in human endothelial cells. In contrast to eNOS, B1 ligands activate iNOS similarly. Both desArg10-kallidin and ACE inhibitors enhance arginine uptake and release NO independent of [Ca2+]i elevation. This is the first report on the direct activation of B1 receptor by ACE inhibitors in human endothelial cells. This interaction leads to prolonged NO release and possibly contributes to the documented benefits of the use of ACE inhibitors.