Kinin B1 receptors stimulate nitric oxide production in endothelial cells: signaling pathways activated by angiotensin I-converting enzyme inhibitors and peptide ligands.
We reported previously a novel mode of action of angiotensin I-converting enzyme (kininase II; ACE) inhibitors mediated through the direct activation of bradykinin B(1) receptor, independent of endogenous kinins or ACE (J Biol Chem 277:16847-16852, 2002). We aimed to further clarify the mechanism of activation of B(1) receptor, which leads to prolonged nitric oxide (NO) release. The ACE inhibitor enalaprilat and the peptide ligand desArg(10)-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. DesArg(10)-kallidin enhances inositol-phosphate generation and elevates [Ca(2+)](i) by first augmenting intracellular release and then the influx of extracellular Ca(2+). In contrast, enalaprilat stimulates only the influx of extracellular Ca(2+) through rare earth-sensitive channels, and its effect is blocked by cholera toxin or protein kinase C inhibitors. In addition, unlike desArg(10)-kallidin, enalaprilat can also release NO independent of Ca(2+) in bovine endothelial cells. The inflammatory cytokines interleukin-1beta and interferon-gamma induce both B(1) receptor and iNOS in human endothelial cells. In contrast to eNOS, B(1) ligands activate iNOS similarly. Both desArg(10)-kallidin and ACE inhibitors enhance arginine uptake and release NO independent of [Ca(2+)](i) elevation. This is the first report on the direct activation of B(1) 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.
Ignjatovic
Tatjana
T
Department of Pharmacology, College of Medicine University of Illinois, (MC 868), 835 South Wolcott Avenue, Room E403, Chicago, IL 60612-7344, USA.
Stanisavljevic
Sinisa
S
Brovkovych
Viktor
V
Skidgel
Randal A
RA
Erdös
Ervin G
EG
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002772:Cholera Toxin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007705:Kinins; D008024:Ligands; D009569:Nitric Oxide / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; D007705:Kinins; D008024:Ligands; D010455:Peptides; D043783:Receptor, Bradykinin B1; D009569:Nitric Oxide; D002772:Cholera Toxin; D001120:Arginine; D011493:Protein Kinase C; D002118:Calcium