Effect of boldine, secoboldine, and boldine methine on angiotensin II-induced neutrophil recruitment in vivo.
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.
Estellés
Rossana
R
Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibañez, 15, 46010 Valencia, Spain.
Milian
Lara
L
Nabah
Yafa Naim Abu
YN
Mateo
Teresa
T
Cerdá-Nicolás
Miguel
M
Losada
Mercedes
M
Ivorra
María Dolores
MD
Issekutz
Andrew C
AC
Cortijo
Julio
J
Morcillo
Esteban J
EJ
Blázquez
María Amparo
MA
Sanz
María-Jesús
MJ
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
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