title: Endogenous bradykinin suppresses myocardial fibrosis through the cardiac-generated endothelin system under chronic angiotensin-converting enzyme inhibition in heart failure.
abstract: In congestive heart failure, angiotensin-converting enzyme inhibitors (ACEIs) may prevent cardiac fibrosis via interaction with both angiotensin II and endothelin-1, which enhance myocardial collagen synthesis. However, whether endogenous bradykinin with an ACEI modifies the cardiac collagen architecture, affecting the endothelin system, has not yet been fully elucidated. We evaluated the changes in circulating hormonal factors, myocardial fibrosis and cardiac gene expression closely linked with heart failure, using an orally active specific bradykinin type 2 receptor antagonist, FR173657 (0.3 mg/kg/day, n = 6), with an ACEI, enalapril (1 mg/kg/day), in dogs with tachycardia-induced congestive heart failure (270 p.p.m., 22 days) and compared the effects with enalapril alone (n = 6). Although there were no differences observed in blood pressure, plasma renin activity, aldosterone and endothelin-1 levels, combined FR173657 significantly increased the cardiac expression of preproendothelin- 1 mRNA (P < 0.05) and collagen type I and type III mRNA (P < 0.05), and cardiac collagen deposits (P < 0.05), and decreased eNOS gene expression (P < 0.05) in the left ventricle compared with the ACEI-treated group. Furthermore, there was a significant negative correlation between the expression of preproendothelin- 1 and eNOS mRNA levels (r = -0.708, P < 0.001). In conclusion, bradykinin may prevent cardiac fibrosis in part via suppression of the local endothelin system in the failing heart through the enhancement of nitric oxide production under chronic angiotensin-converting enzyme inhibition.
authors.affiliation: Intensive Care Unit, Shiga University of Medical Science, Tsukinowa, Seta, Otsu, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujii
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Wada
authors.forename: Masato
authors.initials: M
authors.lastname: Ohnishi
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Tsutamoto
authors.forename: Takehiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Takayama
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Dohke
authors.forename: Takahiro
authors.initials: T
authors.lastname: Isono
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Eguchi
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000450:Aldosterone / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000378:metabolism*; D065094:Bradykinin B2 Receptor Antagonists; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D004656:Enalapril / Q000494:pharmacology*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D012083:Renin / Q000097:blood
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D065094:Bradykinin B2 Receptor Antagonists; D019332:Endothelin-1; C105311:FR 173657; D011804:Quinolines; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D009569:Nitric Oxide; D000450:Aldosterone; D004656:Enalapril; D003094:Collagen; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D012083:Renin; D001920:Bradykinin