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Kinin B₁ Receptors Stimulate Nitric Oxide Production in Endothelial Cells: Signaling Pathways Activated by Angiotensin I-Converting Enzyme Inhibitors and Peptide Ligands

Departments of Pharmacology and Anesthiology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

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 Chem 277:16847-16852, 2002). 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-1 and interferon- 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.

Address correspondence to: Dr. Ervin G. Erdös, University of Illinois College of Medicine, Department of Pharmacology (MC 868), 835 South Wolcott Avenue, Room E403, Chicago, IL 60612-7344. E-mail: egerdos{at}uic.edu

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