Endogenous bradykinin suppresses myocardial fibrosis through the cardiac-generated endothelin system under chronic angiotensin-converting enzyme inhibition in heart failure.
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.
Fujii
Masanori
M
Intensive Care Unit, Shiga University of Medical Science, Tsukinowa, Seta, Otsu, Japan.
Wada
Atsuyuki
A
Ohnishi
Masato
M
Tsutamoto
Takayoshi
T
Matsumoto
Takehiro
T
Yamamoto
Takashi
T
Takayama
Tomoyuki
T
Dohke
Tomohiro
T
Isono
Takahiro
T
Eguchi
Yutaka
Y
Horie
Minoru
M
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
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