title: Effect of boldine, secoboldine, and boldine methine on angiotensin II-induced neutrophil recruitment in vivo.
abstract: Angiotensin-II (Ang-II) has inflammatory activity and is involved in different diseases associated with the cardiovascular system. This study has evaluated the effect of boldine (B), and two phenanthrene alkaloids semisynthesized by us, secoboldine (SB) and boldine methine (BM), on Ang-II-induced neutrophil recruitment. Intraperitoneal administration of 1 nM Ang-II induced significant neutrophil accumulation, which was maximal at 4-8 h. BM inhibited neutrophil infiltration into the peritoneal cavity at 4 h and 8 h by 73% and 77%, respectively, SB at 8 h by 55%, and B had no effect on this response. Although BM inhibited the release of cytokine-inducible neutrophil chemoattractant/keratinocyte-derived chemokine, macrophage inflammatory protein-2 (MIP-2), and platelet-activating factor (PAF) elicited by Ang-II, SB only reduced the release of MIP-2 after 4 h of its administration. Sixty-minute superfusion of the rat mesentery with 1 nM Ang-II induced a significant increase in the leukocyte-endothelial cell interactions and P-selectin up-regulation, which were inhibited by 1 microM BM and SB. The generation of reactive oxygen species (ROS) in endothelial cells stimulated with Ang-II was inhibited significantly by the three alkaloids tested. BM also diminished Ang-II-induced interleukin-8 release from endothelial cells and blocked the PAF receptor on human neutrophils (concentration of the compound needed to produce 50% inhibition value: 28.2 microM). Therefore, BM is a potent inhibitor of Ang-II-induced neutrophil accumulation in vivo. This effect appears to be mediated through inhibition of CXC chemokine and PAF release, ROS scavenging activity, and blockade of the PAF receptor. Thus, it may have potential therapeutic interest for the control of neutrophil recruitment that occurs in inflammation associated with elevated levels of Ang-II.
authors.affiliation: Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibañez, 15, 46010 Valencia, Spain.
authors.forename: Rossana
authors.initials: R
authors.lastname: Estellés
authors.forename: Lara
authors.initials: L
authors.lastname: Milian
authors.forename: Yafa Naim Abu
authors.initials: YN
authors.lastname: Nabah
authors.forename: Teresa
authors.initials: T
authors.lastname: Mateo
authors.forename: Miguel
authors.initials: M
authors.lastname: Cerdá-Nicolás
authors.forename: Mercedes
authors.initials: M
authors.lastname: Losada
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Ivorra
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Issekutz
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Morcillo
authors.forename: María Amparo
authors.initials: MA
authors.lastname: Blázquez
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Sanz
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D000818:Animals; D001060:Aporphines / Q000494:pharmacology*; D054426:Chemokine CXCL2; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007263:Infusions, Parenteral; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology; D008297:Male; D015394:Molecular Structure; D015846:Monokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D019007:P-Selectin / Q000187:drug effects / Q000276:immunology; D010616:Phenanthrenes / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D001060:Aporphines; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D015846:Monokines; D019007:P-Selectin; D010616:Phenanthrenes; D010972:Platelet Activating Factor; D017382:Reactive Oxygen Species; C506830:boldine methine; C109135:secoboldine; D000804:Angiotensin II; C011686:boldine