Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0105048 on June 8, 2005

Published online before print June 8, 2005
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(Journal of Leukocyte Biology. 2005;78:696-704.)
© 2005 by Society for Leukocyte Biology

Effect of boldine, secoboldine, and boldine methine on angiotensin II-induced neurtrophil recruitment in vivo

Rossana Estellés*, Lara Milian*, Yafa Naim Abu Nabah*, Teresa Mateo*, Miguel Cerdá-Nicolás{dagger}, Mercedes Losada*, María Dolores Ivorra*, Andrew C. Issekutz{ddagger}, Julio Cortijo*,§, Esteban J. Morcillo*, María Amparo Blázquez* and María-Jesús Sanz*,1

* Departments of Pharmacology and
{dagger} Pathology, Faculty of Medicine, Universidad de Valencia, Spain;
{ddagger} Department of Pediatrics, Division of Immunology, Dalhousie University, Halifax, Nova Scotia, Canada; and
§ Valencia General Hospital Foundation, Spain

1Correspondence: Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibañez, 15, 46010 Valencia, Spain. E-mail: Maria.J.Sanz{at}uv.es

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 µM 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 µM). 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.

Key Words: aporphine alkaloids • phenanthrene alkaloids • leukocyte • endothelium • intravital microscopy • chemokines






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