title: Contributions of ACE and mast cell chymase to endogenous angiotensin II generation and leucocyte recruitment in vivo.
abstract: OBJECTIVE
  In vitro studies suggest that mast cell chymase (MCP) is more important than angiotensin-converting enzyme (ACE) for generating angiotensin II (Ang II) within the cardiovascular system. We investigated in vivo the relative contributions of ACE and MCP to leucocyte recruitment induced by endogenously generated Ang II.
  
  
  RESULTS
  Exposure of the murine cremasteric microcirculation of C57BL/6 mice to Ang I (100 nM for 4 h) induced leucocyte-endothelium interactions. Either losartan (an Ang II receptor-1 antagonist, AT(1)) or enalapril (an ACE inhibitor), but not chymostatin (a chymase inhibitor), inhibited Ang I-induced responses. Mast cell degranulation with compound 48/80 (CMP48/80, 1 μg/mL) also induced leucocyte adhesion but this was only weakly affected by the inhibitors. When Ang I and CMP48/80 were co-administered, AT(1B) receptor expression was increased, MCP-4 was found surrounding the vessel wall, and ACE was detected in the endothelium. Ang I + CMP48/80 induced enhanced leucocyte adhesion that was attenuated by losartan, enalapril, enalapril + chymostatin, and cromolyn (a mast cell stabilizer). The use of male mast cell-deficient WBB6F1/J-Kit(w)/Kit(w-v) mice (C57BL/6 background) confirmed these findings.
  
  
  CONCLUSIONS
  In vivo, Ang II is primarily generated by ACE under basal conditions, but in inflammatory conditions, the release of MCP amplifies local Ang II concentrations and the associated inflammatory process. Thus, AT(1) receptor antagonists may be more effective than ACE inhibitors for treating ongoing Ang II-mediated vascular inflammation.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Chantal
authors.initials: C
authors.lastname: Company
authors.forename: Laura
authors.initials: L
authors.lastname: Piqueras
authors.forename: Yafa
authors.initials: Y
authors.lastname: Naim Abu Nabah
authors.forename: Paula
authors.initials: P
authors.lastname: Escudero
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: Blanes
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Jose
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Morcillo
authors.forename: Maria-Jesus
authors.initials: MJ
authors.lastname: Sanz
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000096:biosynthesis*; D000818:Animals; D002465:Cell Movement; D053818:Chymases / Q000502:physiology*; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D008407:Mast Cells / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D003189:p-Methoxy-N-methylphenethylamine; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D053818:Chymases