title: Bradykinin B2 receptor antagonism attenuates inflammation, mast cell infiltration and fibrosis in remote myocardium after infarction in rats.
abstract: Bradykinin may interfere with myocardial remodelling by promoting inflammation and mast cell activation or, alternatively, by counteracting angiotensin II-dependent collagen accumulation. The aim of the present study was to investigate the role of bradykinin B2 receptor antagonism in inflammatory and mast cell infiltration, fibroplasia and fibrosis accumulation following myocardial infarction (MI). Myocardial infarction was produced by the ligature of the left coronary artery in male Wistar rats that were 10 weeks of age. Immediately after MI, rats received the B2 receptor antagonist Hoe140 (0.5 microg/kg per min, s.c.) or saline over a period of 3 days, 1 week or 4 weeks, constituting three separate groups and their respective controls. Coronal myocardial tissue sections underwent haematoxylin and eosin, Giemsa and picrosirius red staining, as well as immunohistochemistry for alpha-smooth muscle actin (SMA). Morphometric studies were undertaken in three different myocardial regions: MI, remote non-infarcted subendocardium (non-MI SE) and remote non-infarcted interventricular septum (non-MI IVS). The MI size was comparable between Hoe140-treated groups and their respective controls (day 3: 42 +/- 4%, n = 8, vs 43 +/- 3%, n = 6; week 1: 37 +/- 5%, n = 5, vs 39 +/- 2%, n = 5; week 4: 35 +/- 3%, n = 9, vs 36 +/- 3%, n = 7). At day 3, Hoe140 treatment reduced inflammatory cell reaction within the MI (585 +/- 59 vs 995 +/- 170 cells/mm2; P = 0.02), non-MI SE (77 +/- 12 vs 214 +/- 57 cells/mm2; P = 0.02) and non-MI IVS (93 +/- 16 vs 135 +/- 14 cells/mm2; P = 0.03) regions. Mast cells were reduced within the non-MI IVS region (0.8 +/- 0.1 vs 2.5 +/- 0.4 cells/mm2; P = 0.006), but not within the MI region. In non-MI SE, mast cells were rarely found. At week 1, Hoe140 treatment reduced alpha-SMA-positive myofibroblast infiltration within the MI (2535 +/- 383 vs 5636 +/- 968 cells/mm2; P = 0.01) and non-MI SE (222 +/- 33 vs 597 +/- 162 cells/mm2; P = 0.03) regions. In the non-MI IVS region, alpha-SMA-positive myofibroblasts were rarely found. At week 4, Hoe140 treatment reduced collagen volume fraction within the MI (37 +/- 4 vs 53 +/- 4%; P = 0.03), non-MI SE (1.3 +/- 0.2 vs 2.6 +/- 0.3%; P = 0.001) and non-MI IVS (1.1 +/- 0.2 vs 1.8 +/- 0.2%; P = 0.01) regions. Bradykinin promotes inflammation, fibroplasia and fibrosis after MI. Mast cells may have a role in fibrosis deposition through a bradykinin-related mechanism.
authors.affiliation: LIM-51, Emergências Clínicas, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.
authors.forename: Marcia Kiyomi
authors.initials: MK
authors.lastname: Koike
authors.forename: Clovis
authors.initials: C
authors.lastname: de Carvalho Frimm
authors.forename: Maria
authors.initials: M
authors.lastname: de Lourdes Higuchi
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D065094:Bradykinin B2 Receptor Antagonists; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis; D006352:Heart Ventricles / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D008297:Male; D008407:Mast Cells / Q000473:pathology*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000199:Actins; D065094:Bradykinin B2 Receptor Antagonists; C065679:icatibant; D003094:Collagen; D001920:Bradykinin